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Yeh DW, Liu C, Hernandez JC, Tahara SM, Tsukamoto H, Machida K. Polycomb repressive complex 2 binds and stabilizes NANOG to suppress differentiation-related genes to promote self-renewal. iScience 2023; 26:107035. [PMID: 37448562 PMCID: PMC10336160 DOI: 10.1016/j.isci.2023.107035] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 03/20/2023] [Accepted: 05/31/2023] [Indexed: 07/15/2023] Open
Abstract
The synergistic effect of alcohol and HCV mediated through TLR4 signaling transactivates NANOG, a pluripotency transcription factor important for the stemness of tumor-initiating stem-like cells (TICs). NANOG together with the PRC2 complex suppresses expression of oxidative phosphorylation (OXPHOS) genes to generate TICs. The phosphodegron sequence PEST domain of NANOG binds EED to stabilize NANOG protein by blocking E3 ligase recruitment and proteasome-dependent degradation, while the tryptophan-rich domain of NANOG binds EZH2 and SUZ12. Human ARID1A gene loss results in the resistance to combined FAO and PRC2 inhibition therapies due to reduction of mitochondrial ROS levels. CRISPR-Cas9-mediated ARID1A knockout and/or constitutively active CTNNB1 driver mutations promoted tumor development in humanized FRG HCC mouse models, in which use of an interface inhibitor antagonizing PRC2-NANOG binding and/or FAO inhibitor blocked tumor growth. Together, the PRC2-NANOG interaction becomes a new drug target for HCC via inducing differentiation-related genes, destabilizing NANOG protein, and suppressing NANOG activity.
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Affiliation(s)
- Da-Wei Yeh
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
| | - Cheng Liu
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
| | - Juan Carlos Hernandez
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
| | - Stanley M. Tahara
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
| | - Hidekazu Tsukamoto
- Department of Pathology; University of Southern California, Los Angeles, CA 90033, USA
- Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA 90033, USA
| | - Keigo Machida
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
- Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA 90033, USA
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Machida K. HCV and tumor-initiating stem-like cells. Front Physiol 2022; 13:903302. [PMID: 36187761 PMCID: PMC9520593 DOI: 10.3389/fphys.2022.903302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 07/11/2022] [Indexed: 12/24/2022] Open
Abstract
Neoplasms contain tumor-initiating stem-like cells (TICs) that are characterized by increased drug resistance. The incidence of many cancer types have trended downward except for few cancer types, including hepatocellular carcinoma (HCC). Therefore mechanism of HCC development and therapy resistance needs to be understood. These multiple hits by hepatitis C virus (HCV) eventually promotes transformation and TIC genesis, leading to HCC development. This review article describes links between HCV-associated HCC and TICs. This review discusses 1) how HCV promotes genesis of TICs and HCC development; 2) how this process avails itself as a novel therapeutic target for HCC treatment; and 3) ten hall marks of TIC oncogenesis and HCC development as targets for novel therapeutic modalities.
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Hepatitis C: Does Successful Treatment Alter the Natural History and Quality of Life? Gastroenterol Clin North Am 2020; 49:301-314. [PMID: 32389364 DOI: 10.1016/j.gtc.2020.01.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The cure of chronic hepatitis C infection has a major impact on the morbidity and mortality of infected patients. It is now clear that sustained virologic response improves overall survival and significantly reduces the risk of liver failure, fibrosis progression, need of liver transplantation, and incidence of hepatocellular carcinoma. Moreover, hepatitis C eradication improves a broad range of extrahepatic manifestations, such as dermatologic, neoplastic, cardiovascular, and endocrine, and improves quality of life.
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Jain A, Miller D, Schreibman I, Riley TR, Krok KL, Dohi T, Sharma R, Kadry Z. Is there increased risk of hepatocellular carcinoma recurrence in liver transplant patients with direct-acting antiviral therapy? Hepatol Int 2019; 13:190-198. [PMID: 30680672 DOI: 10.1007/s12072-019-09930-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 01/10/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Recently, a controversy has emerged: is the rate of recurrence of hepatocellular carcinoma (HCC) higher following treatment of hepatitis C virus (HCV) with direct-acting antiviral (DAA) therapy? However, the risk of HCC recurrence has not been studied in liver transplant (LTx) recipients who received DAA therapy. The aim of the present study is to compare the rate of HCC recurrence in LTx recipients who did or did not receive DAA therapy. PATIENTS AND METHODS Sixty-three patients received LTx with HCC. Twenty-seven (42.9%) with HCV received DAA therapy (Group A), 20 (31.7%) with HCV did not receive DAA therapy (Group B), and 16 (25.4%) did not have HCV (Group C). RESULTS In group A, three (11%), in group B, one (5%), and in group C, none had recurrence of HCC. Actuarial 4-year recurrence-free survival was 88.9, 95, and 100% in group A, B, and C, respectively (p = 0.37). Group A was subdivided into two groups for comparison with Group B: A1 included five patients who had end of treatment response (ETR) without sustained virological response (SVR), and A2 included 20 patients who achieved SVR. Three patients from A1 had HCC recurrence and no patients from A2 had HCC recurrence. (p = 0.0038; group A1, A2, and B). CONCLUSIONS The rate of HCC recurrence in LTx patients with DAA therapy was significantly higher with ETR, without SVR, after DAA therapy compared to patients with SVR or patients who did not receive DAA therapy. LTx recipients with HCC receiving DAA therapy requires further studies.
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Affiliation(s)
- Ashokkumar Jain
- Division of Transplantation, Department of Surgery, College of Medicine, Pennsylvania State University, Mail Code H062, 500 University Drive, PO Box 850, Hershey, PA, 17033-0850, USA.
| | - Danielle Miller
- Division of Transplantation, Department of Surgery, College of Medicine, Pennsylvania State University, Mail Code H062, 500 University Drive, PO Box 850, Hershey, PA, 17033-0850, USA
| | - Ian Schreibman
- Division of Gastroenterology, Department of Medicine, College of Medicine, Pennsylvania State University, Hershey, PA, USA
| | - Thomas R Riley
- Division of Gastroenterology, Department of Medicine, College of Medicine, Pennsylvania State University, Hershey, PA, USA
| | - Karen L Krok
- Division of Gastroenterology, Department of Medicine, College of Medicine, Pennsylvania State University, Hershey, PA, USA
| | - Takehiko Dohi
- Division of Transplantation, Department of Surgery, College of Medicine, Pennsylvania State University, Mail Code H062, 500 University Drive, PO Box 850, Hershey, PA, 17033-0850, USA
| | - Rajeev Sharma
- CSL Behring, 1020 First Ave, King of Prussia, PA, USA
| | - Zakiyah Kadry
- Division of Transplantation, Department of Surgery, College of Medicine, Pennsylvania State University, Mail Code H062, 500 University Drive, PO Box 850, Hershey, PA, 17033-0850, USA
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Jain A, Riley TR, Krok KL, Schreibman I, Karamchandani DM, Liao X, Tian Y, Dohi T, Kadry Z. Incidence of Post-Liver Transplant Hepatic Dysfunction After Sustained Virologic Response Following Direct-Acting Anti-Hepatitis C Therapy. EXP CLIN TRANSPLANT 2018; 18:345-352. [PMID: 30295586 DOI: 10.6002/ect.2018.0127] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Newly developed, direct-acting antiviral therapy is effective in over 90% of cases to eradicate hepatitis C virus infection. Direct-acting antiviral therapy is also effective in liver transplant recipients with recurrent hepatitis C virus infection. However, hepatic function after sustained virologic response in transplant recipients is unknown. Here, we aimed to uncover the incidence of hepatic dysfunction in this patient group at our center. MATERIALS AND METHODS Our study included 40 consecutive (January 2014 to February 2016) and compliant posttransplant recipients who achieved sustained viral response from direct-acting antiviral therapy. Patients were investigated for incidence and causes of hepatic dysfunction. RESULTS In our patient group, 4 (10%) experienced hepatic dysfunction with stable baseline immunosuppression, with 2 having drastic increases in alanine aminotransferase at 15 and 32 weeks after direct-acting antiviral therapy. Biopsies showed hepatitis, and both patients were treated with hydrocortisone, which increased their baseline immunosuppression. The 3rd patient had an increase in bilirubin at 21 weeks posttherapy, with biopsy showing macrovascular steatosis. The 4th patient had a rapid increase in bilirubin at 7 weeks after direct-acting antiviral therapy, with biopsy showing significant duct loss. CONCLUSIONS During the study period, 10% of patients experienced hepatic dysfunction after sustained viral response. Presumed causative factors included partial immune reconstitution and nonalcoholic fatty liver disease.
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Affiliation(s)
- Ashokkumar Jain
- From the Department of Surgery, The Pennsylvania State University, College of Medicine, Hershey, Pennsylvania, USA
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González TM, Ligorría MR, Tercero E. Prevalencia de Hepatitis B y C en Pacientes con Cirrosis. REVISTA DE LA FACULTAD DE MEDICINA 2018. [DOI: 10.37345/23045329.v1i25.23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Abstract
Introducción: A nivel mundial la cirrosis representa una causa importante de morbi-mortalidad. En Guatemala no se cuenta con datos sobre las etiologías de la misma ni su frecuencia. Además, se ha demostrado que los pacientes infectados por virus hepatotropos, progresan más rápido hacia la muerte que los pacientes con enfermedad hepática crónica de otras etiologías. Estos pacientes son el principal interés del estudio, ya que la progresión podría desacelerarse con el tratamiento antiviral adecuado. Objetivos: Evaluar la prevalencia de infección crónica por hepatitis B y C en pacientes cirróticos, las principales causas de la misma, motivos de consulta en la EMA (Emergencia de Medicina de Adultos) y coinfección con VIH. Metodología: Se llevó a cabo un estudio prospectivo de 143 records médicos en la EMA (Emergencia de Adultos) de Gastroenterología del Hospital General San Juan de Dios, en los meses de octubre del 2017 a enero del 2018. Resultados: La ingesta excesiva de alcohol fue la principal causa de cirrosis, mientras que, los VHB y VHC son las principales causas de hepatopatía crónicas en países de primer mundo
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Koretz RL, Jakobsen JC, Djurisic S, Poropat G, Hauser G, Bjelakovic M, Bjelakovic G, Gluud C. Who is wrong? Responses to Kwo et al. Am J Gastroenterol 2018; 113:779-780. [PMID: 29487409 DOI: 10.1038/s41395-018-0029-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2017] [Accepted: 01/05/2018] [Indexed: 12/11/2022]
Affiliation(s)
- Ronald L Koretz
- Granada Hills, Los Angeles, CA, USA. The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Cardiology, Holbaek Hospital, Holbaek, Denmark. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Gastroenterology, Clinical Hospital Centre Rijeka, Rijeka, Croatia. Medical Faculty, University of Nis, Nis, Serbia. Department of Internal Medicine, Medical Faculty, University of Nis, Nis, Serbia
| | - Janus Christian Jakobsen
- Granada Hills, Los Angeles, CA, USA. The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Cardiology, Holbaek Hospital, Holbaek, Denmark. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Gastroenterology, Clinical Hospital Centre Rijeka, Rijeka, Croatia. Medical Faculty, University of Nis, Nis, Serbia. Department of Internal Medicine, Medical Faculty, University of Nis, Nis, Serbia.,Granada Hills, Los Angeles, CA, USA. The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Cardiology, Holbaek Hospital, Holbaek, Denmark. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Gastroenterology, Clinical Hospital Centre Rijeka, Rijeka, Croatia. Medical Faculty, University of Nis, Nis, Serbia. Department of Internal Medicine, Medical Faculty, University of Nis, Nis, Serbia
| | - Snezana Djurisic
- Granada Hills, Los Angeles, CA, USA. The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Cardiology, Holbaek Hospital, Holbaek, Denmark. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Gastroenterology, Clinical Hospital Centre Rijeka, Rijeka, Croatia. Medical Faculty, University of Nis, Nis, Serbia. Department of Internal Medicine, Medical Faculty, University of Nis, Nis, Serbia
| | - Goran Poropat
- Granada Hills, Los Angeles, CA, USA. The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Cardiology, Holbaek Hospital, Holbaek, Denmark. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Gastroenterology, Clinical Hospital Centre Rijeka, Rijeka, Croatia. Medical Faculty, University of Nis, Nis, Serbia. Department of Internal Medicine, Medical Faculty, University of Nis, Nis, Serbia
| | - Goran Hauser
- Granada Hills, Los Angeles, CA, USA. The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Cardiology, Holbaek Hospital, Holbaek, Denmark. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Gastroenterology, Clinical Hospital Centre Rijeka, Rijeka, Croatia. Medical Faculty, University of Nis, Nis, Serbia. Department of Internal Medicine, Medical Faculty, University of Nis, Nis, Serbia
| | - Milica Bjelakovic
- Granada Hills, Los Angeles, CA, USA. The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Cardiology, Holbaek Hospital, Holbaek, Denmark. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Gastroenterology, Clinical Hospital Centre Rijeka, Rijeka, Croatia. Medical Faculty, University of Nis, Nis, Serbia. Department of Internal Medicine, Medical Faculty, University of Nis, Nis, Serbia
| | - Goran Bjelakovic
- Granada Hills, Los Angeles, CA, USA. The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Cardiology, Holbaek Hospital, Holbaek, Denmark. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Gastroenterology, Clinical Hospital Centre Rijeka, Rijeka, Croatia. Medical Faculty, University of Nis, Nis, Serbia. Department of Internal Medicine, Medical Faculty, University of Nis, Nis, Serbia
| | - Christian Gluud
- Granada Hills, Los Angeles, CA, USA. The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Cardiology, Holbaek Hospital, Holbaek, Denmark. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Gastroenterology, Clinical Hospital Centre Rijeka, Rijeka, Croatia. Medical Faculty, University of Nis, Nis, Serbia. Department of Internal Medicine, Medical Faculty, University of Nis, Nis, Serbia
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Predictors of hepatitis C virus recurrence after living donor liver transplantation: Mansoura experience. Arab J Gastroenterol 2017; 18:151-155. [PMID: 28958486 DOI: 10.1016/j.ajg.2017.09.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Revised: 06/22/2017] [Accepted: 09/05/2017] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND STUDY AIMS Hepatitis C virus (HCV)-related cirrhosis is the leading cause of liver transplantation (LT). All patients who undergo LT with detectable serum HCV-RNA experience graft reinfection, which is the most frequent cause of graft loss and death in these patients. We estimated the rate of HCV recurrence and evaluated the current therapeutic regimens. PATIENTS AND METHODS The records of consecutive 325 living donor LT (LDLT) surgeries performed between May 2004 and August 2014 were retrospectively analysed; 207 of them were followed-up throughout the study. Clinical, laboratory, radiological and histopathological examinations were performed thoroughly. Patients received treatment in the form of either pegylated interferon (PEG-IFN) or sofosbuvir, both in combination with ribavirin. RESULTS In total, 90.3% of recipients who were transplanted because of HCV-related end-stage liver disease experienced recurrence due to the virus. The donor age was older in the HCV recurrent group versus the non-recurrence group (28.7±7.1 versus 22.6±2.6years: p≤0.001), warm ischaemia time was prolonged (46.1±18.1 versus 28.6±4.1min: p≤0.001), median cold ischaemia time was 40.0 (10-175) versus 22.5 (15-38) min (p≤0.001) and basal PCR was 414000 (546-116000000) versus 10766 (1230-40000) (p≤0.001). Sustained virological response was achieved in 95.4% of patients treated with a combination of a fixed daily dose of 400mg sofosbuvir with ribavirin and in 65.1% of those who were treated with PEG-IFN with ribavirin. CONCLUSIONS Older donor age and prolonged warm ischaemia time are independent predictors of HCV recurrence after LDLT, and early treatment with the direct-acting sofosbuvir is helpful in resolving the problem of post-LT HCV recurrence.
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Zanetto A, Shalaby S, Vitale A, Mescoli C, Ferrarese A, Gambato M, Franceschet E, Germani G, Senzolo M, Romano A, Angeli P, Rugge M, Farinati F, Forton DM, Cillo U, Burra P, Russo FP. Dropout rate from the liver transplant waiting list because of hepatocellular carcinoma progression in hepatitis C virus-infected patients treated with direct-acting antivirals. Liver Transpl 2017; 23:1103-1112. [PMID: 28544587 DOI: 10.1002/lt.24790] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Revised: 05/08/2017] [Accepted: 05/13/2017] [Indexed: 12/13/2022]
Abstract
Concerns about an increased hepatocellular carcinoma (HCC) recurrence rate following direct-acting antiviral (DAA) therapy in patients with cirrhosis with a prior complete oncological response have been raised. Data regarding the impact of HCV treatment with DAAs on wait-list dropout rates in patients with active HCC and HCV-related cirrhosis awaiting liver transplantation (LT) are lacking. HCV-HCC patients listed for LT between January 2015 and May 2016 at Padua Liver Transplant Center were considered eligible for the study. After enrollment, patients were divided into 2 groups, depending on whether they underwent DAA treatment while awaiting LT or not. For each patient clinical, serological, and virological data were collected. HCC characteristics were radiologically evaluated at baseline and during follow-up (FU). For transplanted patients, pathological assessment of the explants was performed and recurrence rates were calculated. A total of 23 patients treated with DAAs and 23 controls were enrolled. HCC characteristics at time of LT listing were comparable between the 2 groups. Median FU was 10 and 7 months, respectively, during which 2/23 (8.7%) and 1/23 (4.3%) dropout events due to HCC progression were registered (P = 0.90). No significant differences in terms of radiological progression were highlighted (P = 0.16). A total of 9 out of 23 (39%) patients and 14 out of 23 (61%) controls underwent LT, and histopathological analysis showed no differences in terms of median number and total tumor volume of HCC nodules, tumor differentiation, or microvascular invasion. During post-LT FU, 1/8 (12.5%) DAA-treated patient and 1/12 (8.3%) control patient experienced HCC recurrence (P = 0.60). In conclusion, viral eradication does not seem to be associated with an increased risk of dropout due to neoplastic progression in HCV-HCC patients awaiting LT. Liver Transplantation 23 1103-1112 2017 AASLD.
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Affiliation(s)
- Alberto Zanetto
- Gastroenterology/Multivisceral Transplant Unit, Padua, Italy
| | - Sarah Shalaby
- Gastroenterology/Multivisceral Transplant Unit, Padua, Italy
| | - Alessandro Vitale
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, Padua, Italy
| | | | | | - Martina Gambato
- Gastroenterology/Multivisceral Transplant Unit, Padua, Italy
| | | | - Giacomo Germani
- Gastroenterology/Multivisceral Transplant Unit, Padua, Italy
| | - Marco Senzolo
- Gastroenterology/Multivisceral Transplant Unit, Padua, Italy
| | - Antonietta Romano
- Unit of Internal Medicine and Hepatology, Department of Medicine, Padua University Hospital, Padua, Italy
| | - Paolo Angeli
- Unit of Internal Medicine and Hepatology, Department of Medicine, Padua University Hospital, Padua, Italy
| | - Massimo Rugge
- Surgical Pathology and Cytopathology Unit, Padua, Italy
| | | | - Daniel M Forton
- Department of Gastroenterology and Hepatology, St. George's University Hospitals National Health Service Foundation Trust, London, United Kingdom
| | - Umberto Cillo
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, Padua, Italy
| | - Patrizia Burra
- Gastroenterology/Multivisceral Transplant Unit, Padua, Italy
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Favorable Outcomes of Chinese HCV-Related Cirrhotic Patients with Sustained Virological Response after Pegylated Interferon Plus Ribavirin Treatment. BIOMED RESEARCH INTERNATIONAL 2017; 2017:8061091. [PMID: 28232944 PMCID: PMC5292367 DOI: 10.1155/2017/8061091] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Revised: 12/08/2016] [Accepted: 01/04/2017] [Indexed: 02/07/2023]
Abstract
Few studies have conducted follow-up investigations of the clinical course in HCV-related cirrhotic patients who achieved a sustained virological response (SVR) with pegylated interferon plus ribavirin treatment (PegIFN + RBV). We investigated the clinical course and laboratory data in a prospective cohort study enrolling HCV-related cirrhotic patients who received PegIFN + RBV between August 2008 and July 2013 in China. Complete blood counts, liver function tests, and HCV-RNA were serially examined. Liver-related complications were recorded. To detect hepatocellular carcinoma (HCC), alpha-fetoprotein assays, and ultrasound scans were repeated at 6-month intervals. Twenty-five patients were enrolled, including 8 patients with decompensation events before treatment. Eighteen patients achieved SVR with a mean follow-up period of 25.78 months. During the follow-up period, only one patient exhibited HCV-RNA positivity and no decompensation events were detected, but 4 patients developed HCC after SVR. APRI decreased more in patients with SVR than in patients with non-SVR (median, -1.33 versus 0.86, P < 0.001). The albumin levels and platelet counts significantly increased during the follow-up period after SVR (44.27 ± 4.09 versus 42.63 ± 4.37, P = 0.037 and 173.89 ± 87.36 versus 160.11 ± 77.97, P = 0.047). These data indicated that HCV-related cirrhotic patients with SVR after PegIFN + RBV may have a favorable clinical course and improvements in laboratory data. Moreover, HCC should be monitored.
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Existence of cancer stem cells in hepatocellular carcinoma: myth or reality? Hepatol Int 2016; 11:143-147. [PMID: 27990610 DOI: 10.1007/s12072-016-9777-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 12/01/2016] [Indexed: 12/11/2022]
Abstract
The cancer stem cell (CSC) hypothesis has been disproved in many cancers. CSCs may exist in blood cancer, while many epithelial cancers may not have CSCs but tumor-initiating cells (TICs). Several independent studies have provided strong evidence for existence of CSCs in brain, skin, and colon cancers (Mani et al. in Cell 133:704-715, 2008, Joseph et al. in Cancer Cell 13:129-140, 2008, Reya et al. in Nature 414:105-111, 2001), while the CSC hypothesis remains controversial (Magee et al. in Cancer Cell 21:283-296, 2012). Liver TICs have bipotential to give rise to two different lineage types: hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). In the liver cancer field, the origin of HCC and CC is extensively debated. Several groups have validated that TICs gave rise to HCC and CC. Hepatocytes gave rise to HCC. Several groups have demonstrated that oval cells (or liver progenitor cells) give rise to TICs. However, CSCs may be a myth in gastrointestinal cancer, while many groups have validated liver TICs. The definition of CSCs includes pluripotency, while TICs do not have to have pluripotency and only need to have bi- or multipotential to give rise to diverse tumor types and tumor initiation potential in mouse models. The CSC hypothesis therefore controversial (Magee et al. in Cancer Cell 21:283-296, 2012). Cancer tissues contain subpopulations of cells known as tumor-initiating stem-like cells (TICs, so-called CSCs) that have been identified as key drivers of tumor growth and malignant progression with drug resistance. Stem cells proliferate via self-renewing division in which the two daughter cells differ in proliferative potential, with one displaying differentiated phenotype and the other retaining self-renewing activity.
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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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Majumdar A, Kitson MT, Roberts SK. Systematic review: current concepts and challenges for the direct-acting antiviral era in hepatitis C cirrhosis. Aliment Pharmacol Ther 2016; 43:1276-92. [PMID: 27087015 DOI: 10.1111/apt.13633] [Citation(s) in RCA: 122] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Revised: 10/06/2015] [Accepted: 03/29/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND The burden of HCV cirrhosis is high and projected to increase significantly over the next decade. While interferon therapy is problematic in HCV cirrhosis, the era of direct-acting anti-viral (DAA) therapy provides effective treatment for patients with cirrhosis. AIM To systematically review the results of DAA therapy to date in patients with HCV cirrhosis, and highlight the ongoing challenges for DAA therapy in this population. METHODS A structured Medline search was conducted to obtain phase II and III HCV trials in patients with cirrhosis. Citations from review articles were cross-referenced and conference abstracts from EASL and AASLD liver meetings for the preceding 3 years were reviewed manually. Keywords used included hepatitis C, cirrhosis and the DAA's: sofosbuvir, ledipasvir, velpatasvir, grazoprevir, elbasvir, daclatasvir, beclabuvir, asunaprevir, simeprevir, paritaprevir, ombitasvir and dasabuvir. RESULTS Successful direct-acting anti-viral treatment is now possible in patients with HCV-related cirrhosis including those with liver decompensation with several regimens now offering sustained virological response (SVR) of 90-95%. Overall success rates in GT1 cirrhosis are excellent while GT3-infected patients with cirrhosis remain hard to cure. The pangenotypic combination of sofosbuvir and velpatasvir holds promise for GT3 cirrhosis achieving SVR of ~90%. CONCLUSIONS Potent DAA therapies provide much needed, safe and highly effective treatment options for persons with HCV cirrhosis including those previously deemed unsuitable for treatment. Combination therapy with two or more classes of drug is essential to achieve high efficacy and minimise viral resistance, with the role of ribavirin still under evaluation. However, several challenges remain including the hard-to-cure groups of GT3 cirrhosis and direct-acting anti-viral failures, and managing drug-drug interactions.
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Affiliation(s)
- A Majumdar
- Department of Gastroenterology, Alfred Hospital, Melbourne, Vic., Australia.,UCL Institute for Liver and Digestive Health and Sheila Sherlock Liver Centre Royal Free Hospital, London, UK
| | - M T Kitson
- Department of Gastroenterology, Alfred Hospital, Melbourne, Vic., Australia
| | - S K Roberts
- Department of Gastroenterology, Alfred Hospital, Melbourne, Vic., Australia
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15
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Al-hamoudi WK. Management of hepatitis c genotype 4 in the liver transplant setting. Saudi J Gastroenterol 2016; 22:173-82. [PMID: 27184634 PMCID: PMC4898085 DOI: 10.4103/1319-3767.182453] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2015] [Accepted: 08/17/2015] [Indexed: 12/20/2022] Open
Abstract
End-stage liver disease secondary to hepatitis C virus (HCV) infection is the major indication for orthotopic liver transplantation (OLT) worldwide. The percentage of HCV patients infected with genotype 4 (G4) among recipients of OLT varies depending on geographic location. In the Middle East, including Saudi Arabia, G4 infection is the most common genotype among transplant recipients. Due to the low prevalence of HCV-G4 in Europe and the United States, this genotype has not been adequately studied in prospective trials evaluating treatment outcomes and remains the least studied variant. The aim of this review is to summarize the natural history and treatment outcome of HCV-G4 following liver transplantation, with particular attention to new HCV therapies. This review incorporates all published studies and abstracts including HCV-G4 patients.
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Affiliation(s)
- Waleed K. Al-hamoudi
- Department of Medicine, Gastroenterology Unit, College of Medicine, Liver Disease Research Center, King Saud University, Riyadh, Saudi Arabia
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16
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Treatment of hepatitis C in patients with cirrhosis: remaining challenges for direct-acting antiviral therapy. Drugs 2016; 75:823-34. [PMID: 25943281 DOI: 10.1007/s40265-015-0401-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Chronic hepatitis C virus (HCV) infection is a major global health concern, resulting in significant morbidity and mortality. Treatment using interferon-based therapy in patients with HCV-related cirrhosis has been problematic due to toxicity and poor tolerability. Furthermore, interferon therapy is contraindicated in those with advanced cirrhosis or clinical decompensation, who are arguably the group most in need of viral eradication. The arrival of the direct-acting antiviral (DAA) era has resulted in the development of well-tolerated and highly effective interferon-free drug regimens that promise to dramatically change the therapeutic landscape for those with advanced HCV-related liver disease, including patients with clinical decompensation or pre-liver transplantation. Many successful DAA combinations have emerged; however, a number of challenges remain including the establishment of the optimal treatment duration, the ideal combination of drug classes and determining the role of ribavirin. Moreover, the identification of treatment-experienced patients with genotype 3 HCV cirrhosis as a difficult-to-treat subgroup is a significant impediment to overcome, as are those who have failed prior DAA therapy. Despite these barriers, the ongoing prolific development of safe and effective DAA combinations indicates the future is optimistic for the ultimate goal of HCV eradication.
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17
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Wilder JM, Muir AJ. Strategies for treating chronic HCV infection in patients with cirrhosis: latest evidence and clinical outcomes. Ther Adv Chronic Dis 2015; 6:314-27. [PMID: 26568808 PMCID: PMC4622314 DOI: 10.1177/2040622315603642] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
The burden of chronic hepatitis C virus (HCV) infection is significant and growing. HCV is considered one of the leading causes of liver disease worldwide and the leading cause of liver transplantation globally. While those infected is estimated in the hundreds of millions, this is likely an underestimation because of the indolent nature of this disease when first contracted. Approximately 20% of patients with HCV infection will progress to advanced fibrosis and cirrhosis. Those that do are at risk of decompensated liver disease including GI bleeding, encephalopathy, severe lab abnormalities, and hepatocellular carcinoma. Those individuals with advanced fibrosis and cirrhosis have historically been difficult to treat. The backbone of previous HCV regimens was interferon (IFN). The outcomes for IFN based regimens were poor and resulted in increased adverse events among those with advanced fibrosis and cirrhosis. Now, in the era of new direct acting antiviral (DAA's) medications, there is hope for curing chronic HCV in everyone, including those with advanced fibrosis and cirrhosis. This article provides a review on the most up to date data on the use of DAA's in patients with advanced fibrosis and cirrhosis. We are at a point where HCV could be truly eradicated, but to do so will require ensuring there are effective and safe treatments for those with advanced fibrosis and cirrhosis.
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Affiliation(s)
- Julius M. Wilder
- Division of Gastroenterology, Duke University School of Medicine, and Duke Clinical Research Institute, Durham, NC, USA
| | - Andrew J. Muir
- Division of Gastroenterology, Duke University Medical Center, Duke Clinical Research Institute, DUMC 3913, Durham, NC 27710, USA
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18
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Fung J. Era of direct acting antivirals in chronic hepatitis C: Who will benefit? World J Hepatol 2015; 7:2543-2550. [PMID: 26523206 PMCID: PMC4621468 DOI: 10.4254/wjh.v7.i24.2543] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Revised: 09/07/2015] [Accepted: 10/13/2015] [Indexed: 02/06/2023] Open
Abstract
In the era of highly effective direct acting antiviral (DAA) drugs for the treatment of chronic hepatitis C (CHC) infection, where eradication is almost ensured with minimal side effects, all hepatitis C carriers should benefit theoretically. In the real world setting however, only a small proportion will benefit at this time point due to the multiple barriers to accessing therapy. Given that universal treatment is unlikely, treatment with DAAs will likely be restricted to those with the highest health benefits, and for those who can afford the high expense of a treatment course. Those with the highest unmet needs include those who have failed previous interferon-based therapy or who are interferon-ineligible with evidence of active disease, those with advance liver disease, and those with recurrence of hepatitis C after liver transplantation. In the future, the focus should be on increasing access to treatment for those infected with CHC.
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19
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Righi E, Londero A, Carnelutti A, Baccarani U, Bassetti M. Impact of new treatment options for hepatitis C virus infection in liver transplantation. World J Gastroenterol 2015; 21:10760-75. [PMID: 26478668 PMCID: PMC4600578 DOI: 10.3748/wjg.v21.i38.10760] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Revised: 07/12/2015] [Accepted: 09/15/2015] [Indexed: 02/06/2023] Open
Abstract
Liver transplant candidates and recipients with hepatitis C virus (HCV)-related liver disease greatly benefit from an effective antiviral therapy. The achievement of a sustained virological response before transplantation can prevent the recurrence of post-transplant HCV disease that occurs universally and correlates with enhanced progression to graft cirrhosis. Previous standard-of-care regimens (e.g., pegylated-interferon plus ribavirin with or without first generation protease inhibitors, boceprevir and telaprevir) displayed suboptimal results and poor tolerance in liver transplant recipients. A new class of potent direct-acting antiviral agents (DAA) characterized by all-oral regimens with minimal side effects has been approved and included in the recent guidelines for the treatment of liver transplant recipients with recurrent HCV disease. Association of sofosbuvir with ribavirin and/or ledipasvir is recommended in liver transplant recipients and patients with decompensated cirrhosis. Other regimens include simeprevir, daclatasvir, and combination of other DAA. Possible interactions should be monitored, especially in coinfected human immunodeficiency virus/HCV patients receiving antiretrovirals.
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Abstract
PURPOSE OF REVIEW Hepatitis C virus (HCV) infection remains the leading indication for liver transplant, and viral eradication prior to liver transplant to prevent disease recurrence has traditionally been challenging because of the poor tolerability and efficacy of available therapies. However, with the recent introduction of potent interferon (IFN)-free direct acting antiviral regimens, viral eradication prior to liver transplant is now possible. RECENT FINDINGS Although data are limited, several proof of concept studies have now shown high rates of safety and efficacy in patients with compensated as well as mild-to-moderately decompensated cirrhosis. Although, treatment on the liver transplant waiting list can safely prevent postliver transplant recurrence in selected patients, the ideal regimen and treatment duration have yet to be determined. SUMMARY Although IFN-free therapies represent a tremendous advance in our ability to cure this previously difficult to treat population, additional data on the safety of these regimens, particularly in patients with severely decompensated cirrhosis, the consequences of virologic failure and the impact of viral eradication on short- and long-term liver function are urgently needed.
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21
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Interferon Treatment of Hepatitis C Reinfection after Liver Transplantation: A Meta-Analysis. Gastroenterol Res Pract 2015; 2015:206302. [PMID: 26167174 PMCID: PMC4488578 DOI: 10.1155/2015/206302] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Revised: 05/31/2015] [Accepted: 06/04/2015] [Indexed: 01/15/2023] Open
Abstract
Background. Graft reinfection with hepatitis C (HCV) after liver transplantation is a significant problem in transplant hepatology. This meta-analysis was performed to compare the effectiveness and risk of adverse events of interferon-based therapy with no treatment after liver transplantation. Methods. We searched electronic databases up to July 31, 2013, to obtain relevant research reports that satisfied the inclusion criteria. Meta-analyses were done on randomized controlled trials (RCTs) and nonrandomized trials. Results. A meta-analysis was performed on 2 RCTs and 2 cohort studies comprising a total of 326 patients (171 of whom accepted interferon-based antiviral therapy). The treatment group was found to have higher virological response (VR) rates than controls at 12, 24, 48, and 72 weeks. Patients in the antiviral group had higher sustained virological response (SVR) rates and lower mean alanine aminotransferase levels relative to controls at 48 weeks, but more total serious adverse events (AEs) than controls. Conclusions. Interferon-based treatment has some efficacy in the treatment of HCV graft reinfection following liver transplantation.
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Filipec Kanizaj T, Kunac N. Hepatitis C: New challenges in liver transplantation. World J Gastroenterol 2015; 21:5768-77. [PMID: 26019441 PMCID: PMC4438011 DOI: 10.3748/wjg.v21.i19.5768] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Revised: 02/28/2015] [Accepted: 04/17/2015] [Indexed: 02/06/2023] Open
Abstract
In an era of great achievements in liver transplantation, hepatitis C viral infection (HCV) remains an unsolved problem. As a leading indication for liver transplantation in Western countries, HCV poses a significant burden both before and after transplantation. Post-transplant disease recurrence occurs in nearly all patients with detectable pretransplant viremia, compromising the lifesaving significance of transplantation. Many factors involving the donor, recipient and virus have been evaluated throughout the literature, although few have been fully elucidated and implemented in actual clinical practice. Antiviral therapy has been recognized as a cornerstone of HCV infection control; however, experience and success are diminished following transplantation in a challenging cohort of patients with liver cirrhosis. Current therapeutic protocols surpass those used previously, both in sustained viral response and side-effect profile. In this article we review the most relevant and contemporary scientific evidence regarding hepatitis C infection and liver transplantation, with special attention dedicated to novel, more efficient and safer antiviral regimens.
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23
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Fortune BE, Martinez-Camacho A, Kreidler S, Gralla J, Everson GT. Post-transplant survival is improved for hepatitis C recipients who are RNA negative at time of liver transplantation. Transpl Int 2015; 28:980-9. [PMID: 25818896 DOI: 10.1111/tri.12568] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Revised: 10/13/2014] [Accepted: 03/13/2015] [Indexed: 12/16/2022]
Abstract
UNLABELLED Hepatitis C virus (HCV) infection recurs universally in patients who are viremic at liver transplantation and likely accounts for the diminished post-transplant graft and patient survival. We evaluated whether undetectable HCV RNA pretransplant improves graft and patient survival after transplantation. Cases, defined by HCV listing diagnosis and positive HCV antibody, were selected from the Scientific Registry of Transplant Recipients database and further grouped as HCV RNA-positive (n = 4978) or negative (n = 445) based upon pretransplant testing. Controls were non-HCV recipients (n = 2995). RNA-negative cases had significantly better 5-year graft (72% vs. 64%) and patient (79% vs. 69%) survival than RNA-positive cases (P < 0.01 for both), and similar survival as controls (Graft: 72% vs. 74%, PATIENT 79% vs. 80%; P > 0.05 for both). Nonproportional hazards modeling of RNA-positive cases identified a subgroup with rapid progression leading to early graft loss and death. Multivariable analyses confirmed that a positive HCV RNA prior to transplantation was a significant independent predictor of graft loss and death. In conclusion, HCV patients who have undetectable RNA at the time of liver transplantation experience improved long-term graft and patient outcomes. We speculate that the post-transplant survival of HCV recipients could be improved by safe and tolerable pretransplant antiviral strategies.
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Affiliation(s)
- Brett E Fortune
- Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
| | | | - Sarah Kreidler
- Department of Radiology, University of Colorado Denver, Aurora, CO, USA
| | - Jane Gralla
- Department of Pediatrics, University of Colorado Denver, Aurora, CO, USA
| | - Gregory T Everson
- Division of Gastroenterology and Hepatology, University of Colorado Denver, Aurora, CO, USA
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24
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Optimizing outcome of recurrent hepatitis C virus genotype 4 after living donor liver transplantation: moving forward by looking back. Transplant Proc 2015; 46:822-7. [PMID: 24767357 DOI: 10.1016/j.transproceed.2013.11.152] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2013] [Revised: 11/08/2013] [Accepted: 11/27/2013] [Indexed: 12/16/2022]
Abstract
PURPOSE Recurrence of HCV after LDLT is almost universal. Different factors affect response to treatment. Few data are available regarding outcome of recurrent HCV genotype 4. The purpose of this study is to improve outcome of recurrent HCV genotype 4 after LDLT. METHODS An IRB approved chart review of 243 patients transplanted for ESLD, HCV genotype 4 over 4 years were reviewed. Protocol liver biopsies were taken 6 months after transplant. Patients received pegylated interferon and ribavirin in case of histological recurrence. Five patients had FCH were excluded. RESULTS Thirty-seven patients were included. Sustained Virological Response (SVR) was achieved in 29 (78.3%). Patients with Metavir fibrosis stage (F0) and (F1) had SVR in 5/5 (100%) and 20/24 (83.3%). Two patients with F1 had to stop treatment because of thrombocytopenia and 2 were non responders. Three out of 6 patients (50%) with (F2) had SVR, 2 were non responders and one had to discontinue treatment because of severe depression. One of 2 patients (50%) with F3 had SVR and the other patient decompensated within 4 months before treatment and died. CONCLUSION Protocol biopsies allow early detection of inflammatory changes in the graft before fibrosis occurs. Early treatment of recurrent HCV genotype 4 after LDLT results in better response.
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25
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Verna EC, Shetty K, Lukose T, Terry N, Mentore K, Olsen SK, Fox AN, Dove LM, Brown RS. High post-transplant virological response in hepatitis C virus infected patients treated with pretransplant protease inhibitor-based triple therapy. Liver Int 2015; 35:510-7. [PMID: 24905624 DOI: 10.1111/liv.12616] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Accepted: 05/25/2014] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Prevention of recurrent hepatitis C virus (HCV) following liver transplant (LT) with pre-LT antiviral therapy is limited by poor tolerability and efficacy. We aimed to evaluate the safety and efficacy of NS3/4A protease inhibitor (PI)-based triple therapy in patients awaiting LT. METHODS Consecutive patients treated with triple therapy pre-LT from two centers were prospectively enrolled in an observational cohort. Overall 12 week sustained virological response (SVR12) was the primary outcome. Pre- and post-LT (pTVR) virological response rates and safety were secondary outcomes. RESULTS Twenty-nine patients (mean age 57.9, 79% male, 66% prior non-responders) were treated with telaprevir (93%) or boceprevir-based (7%) triple therapy for a median (range) of 27 (3-50) weeks, including a pegylated-interferon and ribavirin lead-in in 18%. Median (range) MELD at treatment was 8 (6-16), 39% had hepatocellular carcinoma and all patients were Child-Turcotte-Pugh class A (62%) or B (38%). Twelve patients underwent LT, 75% with undetectable viral load. The overall SVR12 rate was 52%, including pre-LT SVR12 of 41% in patients who completed treatment and follow-up on the wait list and pTVR12 of 67% among transplanted patients. The pTVR12 rate was 89% among those patients with undetectable viral load at LT. Serious adverse events occurred in nine (31%) patients including one (3%) on-treatment death and eight (28%) hospitalizations. CONCLUSIONS Overall SVR12 and pTVR12 rates are high among patients treated with PI-based triple therapy while awaiting LT, even in this difficult to treat population. However, caution is needed as early discontinuation and serious adverse events are common.
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Affiliation(s)
- Elizabeth C Verna
- Division of Digestive and Liver Diseases, Center for Liver Disease and Transplantation, Columbia University College of Physicians and Surgeons, New York, NY, USA
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26
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Curry MP, Forns X, Chung RT, Terrault NA, Brown R, Fenkel JM, Gordon F, O'Leary J, Kuo A, Schiano T, Everson G, Schiff E, Befeler A, Gane E, Saab S, McHutchison JG, Subramanian GM, Symonds WT, Denning J, McNair L, Arterburn S, Svarovskaia E, Moonka D, Afdhal N. Sofosbuvir and ribavirin prevent recurrence of HCV infection after liver transplantation: an open-label study. Gastroenterology 2015; 148:100-107.e1. [PMID: 25261839 DOI: 10.1053/j.gastro.2014.09.023] [Citation(s) in RCA: 249] [Impact Index Per Article: 24.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Revised: 08/26/2014] [Accepted: 09/17/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Patients with detectable hepatitis C virus (HCV) RNA at the time of liver transplantation universally experience recurrent HCV infection. Antiviral treatment before transplantation can prevent HCV recurrence, but existing interferon-based regimens are poorly tolerated and are either ineffective or contraindicated in most patients. We performed a trial to determine whether sofosbuvir and ribavirin treatment before liver transplantation could prevent HCV recurrence afterward. METHODS In a phase 2, open-label study, 61 patients with HCV of any genotype and cirrhosis (Child-Turcotte-Pugh score, ≤7) who were on waitlists for liver transplantation for hepatocellular carcinoma, received up to 48 weeks of sofosbuvir (400 mg) and ribavirin before liver transplantation. The primary end point was the proportion of patients with HCV-RNA levels less than 25 IU/mL at 12 weeks after transplantation among patients with this HCV-RNA level at their last measurement before transplantation. RESULTS Sixty-one patients received sofosbuvir and ribavirin, and 46 received transplanted livers. The per-protocol efficacy population consisted of 43 patients who had HCV-RNA level less than 25 IU/mL at the time of transplantation. Of these 43 patients, 30 (70%) had a post-transplantation virologic response at 12 weeks, 10 (23%) had recurrent infection, and 3 (7%) died (2 from nonfunction of the primary graft and 1 from complications of hepatic artery thrombosis). Of all 61 patients given sofosbuvir and ribavirin, 49% had a post-transplantation virologic response. Recurrence was related inversely to the number of consecutive days of undetectable HCV RNA before transplantation. The most frequently reported adverse events were fatigue (in 38% of patients), headache (23%), and anemia (21%). CONCLUSIONS Administration of sofosbuvir and ribavirin before liver transplantation can prevent post-transplant HCV recurrence. ClinicalTrials.gov: NCT01559844.
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Affiliation(s)
- Michael P Curry
- Transplant Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
| | - Xavier Forns
- Liver Unit, Hospital Clínic, Institut d'Investigacions Biomédiques August Pi i Sunyer and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
| | - Raymond T Chung
- GI Unit, Massachusetts General Hospital, Boston, Massachusetts
| | - Norah A Terrault
- Division of Gastroenterology, University of California San Francisco, San Francisco, California
| | - Robert Brown
- Center for Liver Diseases and Transplantation, Columbia University, New York, New York
| | - Jonathan M Fenkel
- Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania
| | - Fredric Gordon
- Liver Transplantation & Hepatology, Lahey Clinic, Burlington, Massachusetts
| | | | - Alexander Kuo
- Liver Transplantation, University of California, San Diego, La Jolla, California
| | - Thomas Schiano
- Liver Diseases, Mount Sinai School of Medicine, New York, New York
| | - Gregory Everson
- Section of Hepatology, University of Colorado, Denver, Colorado
| | - Eugene Schiff
- Center for Liver Disease, University of Miami, Miami, Florida
| | - Alex Befeler
- Division of Gastroenterology and Hepatology, Saint Louis University, St. Louis, Missouri
| | - Edward Gane
- New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand
| | - Sammy Saab
- Department of Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | | | | | | | | | | | | | | | - Dilip Moonka
- Gastroenterology, Henry Ford Health System, Detroit, Michigan
| | - Nezam Afdhal
- Transplant Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts
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27
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Jiménez-Pérez M, González-Grande R, Rando-Muñoz FJ. Management of recurrent hepatitis C virus after liver transplantation. World J Gastroenterol 2014; 20:16409-16417. [PMID: 25469009 PMCID: PMC4248184 DOI: 10.3748/wjg.v20.i44.16409] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Revised: 08/27/2014] [Accepted: 10/15/2014] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection is the leading cause of death from liver disease and the leading indication for liver transplantation (LT) in the United States and Western Europe. LT represents the best therapeutic alternative for patients with advanced chronic liver disease caused by HCV or those who develop hepatocarcinoma. Reinfection by HCV of the graft is universal and occurs in 95% of transplant patients. This reinfection can compromise graft function and patient survival. In a few cases, the histological recurrence is minimal and non-progressive; however, in most patients it follows a more rapid course than in immunocompetent persons, and frequently evolves into cirrhosis with graft loss. In fact, the five-year and ten-year survival of patients transplanted because of HCV are 75% and 68%, respectively, compared with 85% and 78% in patients transplanted for other reasons. There is also a pattern of recurrence that is very severe, but rare (< 10%), called fibrosing cholestatic hepatitis, which often involves rapid graft loss. Patients who present a negative HCV viremia after antiviral treatment have better survival. Many studies published over recent years have shown that antiviral treatment of post-transplant HCV hepatitis carried out during the late phase is the best option for improving the prognosis of these patients. Until 2011, PEGylated interferon plus ribavirin was the standard of care, resulting in a sustained virological response in around 30% of recipients. The addition of protease inhibitors, such as boceprevir or telaprevir, to the standard of care, or the use of other direct-acting antiviral drugs may involve therapeutic changes in the context of HCV recurrence. This may result a better prognosis for these patients, particularly those with severe recurrence or factors predicting rapid progression of fibrosis. However, the use of these agents in LT still requires clarification in terms of safety and efficacy.
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MESH Headings
- Antiviral Agents/adverse effects
- Antiviral Agents/therapeutic use
- Carcinoma, Hepatocellular/diagnosis
- Carcinoma, Hepatocellular/mortality
- Carcinoma, Hepatocellular/surgery
- Carcinoma, Hepatocellular/virology
- Drug Therapy, Combination
- End Stage Liver Disease/diagnosis
- End Stage Liver Disease/mortality
- End Stage Liver Disease/surgery
- End Stage Liver Disease/virology
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/diagnosis
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/immunology
- Hepatitis C, Chronic/mortality
- Humans
- Immunocompromised Host
- Immunosuppressive Agents/adverse effects
- Liver Neoplasms/diagnosis
- Liver Neoplasms/mortality
- Liver Neoplasms/surgery
- Liver Neoplasms/virology
- Liver Transplantation/adverse effects
- Liver Transplantation/mortality
- Recurrence
- Risk Factors
- Time Factors
- Treatment Outcome
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Xu Y, Qi W, Wang X, Zhao P, Zhang Y, Zhang Q, Qin S, Wang J. Pegylated interferon α-2a plus ribavirin for decompensated hepatitis C virus-related cirrhosis: relationship between efficacy and cumulative dose. Liver Int 2014; 34:1522-31. [PMID: 25453135 DOI: 10.1111/liv.12417] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND & AIMS A combination of pegylated interferon alpha-2a (Peg-IFNα-2a) and ribavirin (RBV) achieves a sustained virological response (SVR) in 40-50% of patients infected with genotype 1 hepatitis C virus (HCV), but efficacy rates are significantly lower in patients with decompensated HCV-induced cirrhosis. The efficacy and tolerability of Peg-IFNα-2a and RBV, the cumulative dose effect, time to achieve planned cumulative dose and role of HCV phenotype on treatment response were determined in patients with decompensated HCV-induced cirrhosis. METHODS In this case-controlled study, 257 patients with decompensated HCV-induced cirrhosis were enrolled, including patients treated with partial splenic embolization for leukopaenia. Of patients with sufficient blood cell counts, 130 patients opted for antiviral therapy (treatment group) consisting of 180 μg/kg Peg-IFNα-2a for 48 weeks with 800-1200 mg/day RBV; the remaining 127 were considered the control group. Primary endpoints were SVR and absence of relapse; the secondary end point was assessment of disease progression. RESULTS Sustained virological response was highest and relapse rates were lowest when cumulative doses of Peg-IFNα-2a and RBV were both ≥80% of the prescribed dose. Patients achieving ≥80% of the planned cumulative doses in 48 weeks had a significantly higher SVR compared with patients achieving this in 72 weeks. Patients with HCV genotype 1 had significantly lower SVR compared with patients with HCV genotype 2 (19.7% vs. 42.9%, respectively; P = 0.008). Treatment group patients had a significantly lower rate of SVR-independent liver disease-related mortality. CONCLUSIONS Our findings provide additional evidence to support the use of Peg-IFNα-2a and RBV therapy for decompensated HCV-induced cirrhosis.
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Affiliation(s)
- Yan Xu
- Department of Digestive; China-Japan Union Hospital affiliated to Jilin University; Changchun China
| | - Wenqian Qi
- Department of Digestive; China-Japan Union Hospital affiliated to Jilin University; Changchun China
| | - Xu Wang
- Department of Digestive; China-Japan Union Hospital affiliated to Jilin University; Changchun China
| | - Ping Zhao
- Department of Digestive; China-Japan Union Hospital affiliated to Jilin University; Changchun China
| | - Yonggui Zhang
- Department of Digestive; China-Japan Union Hospital affiliated to Jilin University; Changchun China
| | - Qian Zhang
- Department of Digestive; China-Japan Union Hospital affiliated to Jilin University; Changchun China
| | - Shaoyou Qin
- Department of Digestive; China-Japan Union Hospital affiliated to Jilin University; Changchun China
| | - Jiangbin Wang
- Department of Digestive; China-Japan Union Hospital affiliated to Jilin University; Changchun China
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Abstract
INTRODUCTION Cirrhosis is a major milestone in patients with chronic liver disease because of its impact on patient morbidity and mortality. Chronic hepatitis B (CHB) and hepatitis C (CHC) are important causes of cirrhosis. This systematic review examines the relevant literature and evidence to assess whether cirrhosis can be reversible in patients with cirrhosis from viral hepatitis through long viral suppression. METHODS A MEDLINE and Cochrane Library search was conducted to identify all articles pertinent to the subject matter. Fourteen publications were included in the final analysis: 4 hepatitis B studies and 10 hepatitis C studies. Data abstracted from individual studies included patient demographics, antiviral therapy used, length of treatment, liver biopsy scoring system, length of biopsy, and time between biopsies. RESULTS In CHB, the 7 studies reviewed included a total of 463 cirrhotic patients. Regression of cirrhosis was noted in a median of 70% (range, 33% to 80%) of patients. In CHC, the 13 studies reviewed included a total of 58 cirrhotic patients. Regression of cirrhosis was seen in a median of 64% (range, 33% to 100%) of patients with sustained viral response. CONCLUSIONS The results of our review suggest that viral suppression in CHB and sustained virologic response in CHC can be associated with histologic regression of cirrhosis in select patients.
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Chen CL, Tsukamoto H, Machida K. Oncogenic signaling pathways and origins of tumor-initiating stem-like cells of hepatocellular carcinomas induced by hepatitis C virus, alcohol and/or obesity. Hepatol Int 2014; 8:330-8. [PMID: 26202636 PMCID: PMC10560513 DOI: 10.1007/s12072-014-9545-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Accepted: 05/13/2014] [Indexed: 12/21/2022]
Abstract
This review article discusses the importance and oncogenic signaling pathways of tumor-initiating cells (TICs) in several etiologies of hepatocellular carcinomas (HCCs) induced by hepatitis C virus (HCV), alcohol, obesity and/or chemicals. Stem cells may be present in cancer tissue, and a hierarchy of cells is formed, as is the case for normal tissue. Tumor formation, growth and propagation are maintained by a small proportion of cells with stem cell-like properties. TICs are present in alcohol-fed HCV transgenic mice, diethylnitrosamine/phenobarbital-treated mice (chemical carcinogenesis) and Spnb2 +/- mice (defective TGF-β signal). Alcohol/obesity-associated endotoxemia induces the stem cell marker Nanog through TLR4 signaling to generate TICs and liver tumors in several HCC models. The oncogenic pathway (such as the STAT3 and TLR4-NANOG pathway) and mechanism of generation of TICs of HCCs associated with HCV, alcohol and obesity are discussed. Understanding the molecular stemness signaling and cellular hierarchy and defining key TIC-specific genes will accelerate the development of novel biomarkers and treatment strategies. This review highlights recent advances in understanding the pathogenesis of liver TICs and discusses unanswered questions about the concept of liver TICs. (This project was supported by NIH grants 1R01AA018857 and P50AA11999).
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Affiliation(s)
- Chia-Lin Chen
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Hidekazu Tsukamoto
- Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, USA
- Department of Pathology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Keigo Machida
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, 90033, USA.
- Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, USA.
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Iacobellis A, Cozzolongo R, Minerva N, Valvano MR, Niro GA, Fontana R, Palmieri O, Ippolito A, Andriulli A. Feasibility of pegylated interferon and ribavirin in hepatitis C-related cirrhosis with neutropenia or thrombocytopenia. Dig Liver Dis 2014; 46:621-4. [PMID: 24675038 DOI: 10.1016/j.dld.2014.02.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2013] [Revised: 01/19/2014] [Accepted: 02/04/2014] [Indexed: 12/11/2022]
Abstract
AIM To investigate the feasibility of pegylated interferon plus ribavirin treatment in cirrhotic patients who presented with, or developed while on-treatment, platelet counts ≤ 80,000/μL and/or neutrophil counts ≤ 1,500/μL. METHODS A retrospective analysis of prospectively gathered data on 123 cirrhotic patients treated with pegylated interferon and ribavirin. Adverse effects and haematological changes were monitored: bleeding and infectious events were registered and related to platelet and absolute neutrophil counts. RESULTS Among the 58 patients (47.2%) with nadir platelets ≤ 50,000/μL during therapy, 6 (10.3%) experienced a bleeding episode; of the remaining 65 patients with platelets constantly >50,000/μL, 3 (4.6%) bled. Of the 11 bleedings, 3 manifested during an infection, while patients had platelets >50,000/μL. Nadir neutrophils ≤ 750/μL occurred in 45 patients (38.2%) during treatment, and 14 of them (29.8%) had an infectious event. Infections were also documented in 18 of the 76 patients (23.7%) with neutrophils constantly >750/μL. CONCLUSIONS The study reveals the feasibility of treating cirrhotic patients with cytopenia with pegylated interferon and ribavirin, as bleeding or infectious events under therapy were unrelated to platelet and neutrophil counts. Withdrawal of therapy or variations in the pre-assigned dosages of either pegylated interferon or ribavirin owing to abnormally low haematological parameters seems to no longer be tenable.
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Affiliation(s)
- Angelo Iacobellis
- Division of Gastroenterology, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo 71013, Italy.
| | - Raffaele Cozzolongo
- Division of Gastroenterology, De Bellis Hospital, IRCCS, Castellana Grotte 70013, Italy
| | - Nicola Minerva
- Division of Internal Medicine, General Hospital, Canosa 76012, Italy
| | - Maria Rosa Valvano
- Division of Gastroenterology, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo 71013, Italy
| | - Grazia Anna Niro
- Division of Gastroenterology, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo 71013, Italy
| | - Rosanna Fontana
- Division of Gastroenterology, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo 71013, Italy
| | - Orazio Palmieri
- Division of Gastroenterology, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo 71013, Italy
| | - Antonio Ippolito
- Division of Gastroenterology, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo 71013, Italy
| | - Angelo Andriulli
- Division of Gastroenterology, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo 71013, Italy
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Section 13. Short-course pretransplant antiviral therapy is a feasible and effective strategy to prevent hepatitis C recurrence after liver transplantation in genotype 2 patients. Transplantation 2014; 97 Suppl 8:S47-53. [PMID: 24849835 DOI: 10.1097/01.tp.0000446277.36181.e7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
BACKGROUND Hepatitis C virus (HCV) recurrence in recipients who are viremic at time of liver transplantation (LT) is universal and carries poor prognosis. Pretransplant antiviral therapy to eradicate HCV reduces recurrence, but withdrawal rate is high. We conducted a short-course (4 weeks) of pegylated interferon alpha-2a (Peg-IFN-α2a) plus ribavirin (RBV) to prevent of HCV recurrence. PATIENTS AND METHODS From October 2009 to December 2011, eighty-eight consecutive HCV patients for living donor LT with potential living donor at Kaohsiung Chang Gung Memorial Hospital were included. Patients were divided into treatment and nontreatment group depending on presence of HCV-RNA. Fixed dosage of Peg-IFN-α2a (135 μg/week) plus RBV (10 mg/kg per day) were given for 4 weeks to treatment group who passed the 4-week waiting time according to clinical safety assessment. RESULTS Forty-eight patients with genotypes 1, 2, and 3 (n=29/18/1) were treated with IFN and RBV combination for 4 (range, 1-9) weeks. Serum HCV RNA became undetectable at transplantation in 26 (54%) patients. No difference between genotypes 1 (n= 14, 48%) and 2/3(n=12, 63%, P=0.25) was observed. Most patients experienced cytopenia during treatment, but no mortality was noted. In the treatment group, 13 patients remained free of HCV infection 6 months after transplant. Virologic response at transplantation (48% vs. 100%, P=0.015) and genotype 2/3 (50% vs. 84%, P=0.01) are strong predictors of lower HCV recurrence rate. Multivariate analysis showed that genotype 2/3 was the only independent predictive factor affecting HCV RNA negativity 6 months after liver transplantation (OR:11.25; P=0.014). CONCLUSIONS Short-term pretransplant antiviral therapy is a feasible strategy in preventing HCV recurrence after LDLT especially in genotypes 2 and 3 recipients.
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Gurusamy KS, Tsochatzis E, Toon CD, Xirouchakis E, Burroughs AK, Davidson BR. Antiviral interventions for liver transplant patients with recurrent graft infection due to hepatitis C virus. Cochrane Database Syst Rev 2013; 2013:CD006803. [PMID: 24307460 PMCID: PMC8930021 DOI: 10.1002/14651858.cd006803.pub4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
BACKGROUND Antiviral therapy for recurrent hepatitis C infection after liver transplantation is controversial due to unresolved balance between benefits and harms. OBJECTIVES To compare the therapeutic benefits and harms of different antiviral regimens in patients with hepatitis C re-infected grafts after liver transplantation. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 1, 2013), MEDLINE, EMBASE, and Science Citation Index Expanded to February 2013. SELECTION CRITERIA We considered only randomised clinical trials (irrespective of language, blinding, or publication status) comparing various antiviral therapies (alone or in combination) in the treatment of hepatitis C virus recurrence in liver transplantation for the review. DATA COLLECTION AND ANALYSIS Two authors collected the data independently. We calculated the risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI) using the fixed-effect and the random-effects models based on available case-analysis. In the presence of only trials for a dichotomous outcome, we performed the Fisher's exact test. MAIN RESULTS Overall, 17 trials with 736 patients met the inclusion criteria for this review. All trials had high risk of bias. Five hundred and one patients randomised in 11 trials provided information for various comparisons in this systematic review after excluding post-randomisation drop-outs and patients from trials that did not report any of the outcomes of interest for this review. The comparisons for which outcomes were available included pegylated (peg) interferon versus control; peg interferon plus ribavirin versus control; ribavirin plus peg interferon versus peg interferon; peg interferon (1.5 μg/kg/week) plus ribavirin versus peg interferon (0.5 μg/kg/week) plus ribavirin; amantadine plus peg interferon plus ribavirin versus peg interferon plus ribavirin; interferon versus control; interferon plus ribavirin versus control; ribavirin versus interferon; and ribavirin versus placebo. Long-term follow-up was not available in these trials. There were no significant differences in mortality, retransplantation, graft rejections requiring retransplantation or medical treatment, or fibrosis worsening between the groups in any of the comparisons in which these outcomes were reported. Quality of life and liver decompensation were not reported in any of the trials. There was a significantly higher proportion of participants who developed serious adverse events in the ribavirin plus peg interferon combination therapy group than in the peg interferon monotherapy group (1 trial; 56 participants; 17/28 (60.7%) in the intervention group versus 5/28 (17.9%) in the control group; RR 3.40; 95% CI 1.46 to 7.94). There was no significant difference in proportion of participants who developed serious adverse events or in the number of serious adverse events between the intervention and control groups in the other comparisons that reported serious adverse events. AUTHORS' CONCLUSIONS Considering the lack of clinical benefit, there is currently no evidence to recommend or refute antiviral treatment for recurrent liver graft infection with hepatitis C virus. Further randomised clinical trials with low risk of bias and low risk of random errors with adequate duration of follow-up are necessary.
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Affiliation(s)
- Kurinchi Selvan Gurusamy
- Royal Free Campus, UCL Medical SchoolDepartment of SurgeryRoyal Free HospitalRowland Hill StreetLondonUKNW3 2PF
| | - Emmanuel Tsochatzis
- Royal Free Hampstead NHS Foundation Trust and UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentrePond StreetHampsteadLondonUKNW3 2QG
| | - Clare D Toon
- University College LondonDivision of Surgery & Interventional Science9th Floor, Royal Free HospitalRowland Hill StreetLondonLondonUKNW3 2PF
| | - Elias Xirouchakis
- Athens Medical Group, Hospital P. FaliroGI and Hepatology36 Areos str.AthensGreece17562
| | - Andrew K Burroughs
- Royal Free Hampstead NHS Foundation TrustSheila Sherlock Liver CentrePond StreetHampsteadLondonUKNW3 2QG
| | - Brian R Davidson
- Royal Free Campus, UCL Medical SchoolDepartment of SurgeryRoyal Free HospitalRowland Hill StreetLondonUKNW3 2PF
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Agarwal K, Barnabas A. Treatment of chronic hepatitis C virus infection after liver transplantation. Dig Liver Dis 2013; 45 Suppl 5:S349-54. [PMID: 24091115 DOI: 10.1016/j.dld.2013.07.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Accepted: 07/01/2013] [Indexed: 12/11/2022]
Abstract
Chronic hepatitis C virus infection is a leading cause of end stage liver disease and one of the leading indications for liver transplantation. Furthermore, hepatitis C virus recurrence is universal post-transplant leading to decreased graft and patient survival. Recurrent disease related to hepatitis C virus can lead to between 20 and 30% of patients developing recurrent cirrhosis within 5 years. Treatment options with antiviral therapy are limited and are associated with a significant side-effect profile, suboptimal tolerability and inferior response rates. Attention has therefore turned to strategies that can reduce hepatitis C virus recurrence rates post-transplant. Approximately only 30% of patients will achieve a sustained virologic response with current therapy with pegylated interferon and ribavirin. Successful hepatitis C virus eradication is the only factor associated with improved graft and patient survival post liver transplantation. Here we provide an overview of antiviral treatment in patients in the transplant arena and the potential opportunities and challenges with the introduction of new directly acting antivirals in G1 patients.
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Affiliation(s)
- Kosh Agarwal
- Institute of Liver Studies, King's College Hospital, London, UK.
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Baseline MELD score predicts hepatic decompensation during antiviral therapy in patients with chronic hepatitis C and advanced cirrhosis. PLoS One 2013; 8:e71262. [PMID: 23936497 PMCID: PMC3731309 DOI: 10.1371/journal.pone.0071262] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Accepted: 06/27/2013] [Indexed: 02/07/2023] Open
Abstract
Background and Aims In patients with advanced liver cirrhosis due to chronic hepatitis C virus (HCV) infection antiviral therapy with peginterferon and ribavirin is feasible in selected cases only due to potentially life-threatening side effects. However, predictive factors associated with hepatic decompensation during antiviral therapy are poorly defined. Methods In a retrospective cohort study, 68 patients with HCV-associated liver cirrhosis (mean MELD score 9.18±2.72) were treated with peginterferon and ribavirin. Clinical events indicating hepatic decompensation (onset of ascites, hepatic encephalopathy, upper gastrointestinal bleeding, hospitalization) as well as laboratory data were recorded at baseline and during a follow up period of 72 weeks after initiation of antiviral therapy. To monitor long term sequelae of end stage liver disease an extended follow up for HCC development, transplantation and death was applied (240weeks, ±SD 136weeks). Results Eighteen patients (26.5%) achieved a sustained virologic response. During the observational period a hepatic decompensation was observed in 36.8%. Patients with hepatic decompensation had higher MELD scores (10.84 vs. 8.23, p<0.001) and higher mean bilirubin levels (26.74 vs. 14.63 µmol/l, p<0.001), as well as lower serum albumin levels (38.2 vs. 41.1 g/l, p = 0.015), mean platelets (102.64 vs. 138.95/nl, p = 0.014) and mean leukocytes (4.02 vs. 5.68/nl, p = 0.002) at baseline as compared to those without decompensation. In the multivariate analysis the MELD score remained independently associated with hepatic decompensation (OR 1.56, 1.18–2.07; p = 0.002). When the patients were grouped according to their baseline MELD scores, hepatic decompensation occurred in 22%, 59%, and 83% of patients with MELD scores of 6–9, 10–13, and >14, respectively. Baseline MELD score was significantly associated with the risk for transplantation/death (p<0.001). Conclusions Our data suggest that the baseline MELD score predicts the risk of hepatic decompensation during antiviral therapy and thus contributes to decision making when antiviral therapy is discussed in HCV patients with advanced liver cirrhosis.
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Pretransplant and posttransplant treatment of hepatitis C virus infection with protease inhibitors. Curr Opin Organ Transplant 2013; 18:271-8. [PMID: 23665543 DOI: 10.1097/mot.0b013e3283614aca] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW Considering the impact of recurrent hepatitis C after liver transplantation on patient and graft survival, we examine the current and potential use of protease inhibitors in the prevention and treatment of recurrent hepatitis C. RECENT FINDINGS In genotype-1-infected patients in the waiting list, triple therapy with boceprevir or telaprevir should be considered in compensated cirrhotics. However, tolerability of therapy is low, and side effects are frequent and potentially life-threatening. In posttransplant hepatitis C, available data suggest that triple therapy substantially increases the virological response. Interactions of protease inhibitors with immunosuppressants are considerable, especially between tacrolimus and telaprevir. Anemia seems to be particularly frequent with triple therapy after liver transplantation. Interferon (IFN)-free regimens seem to achieve a high antiviral effect with an excellent safety profile and will probably replace the current IFN-based treatments in a few years from now. SUMMARY Antiviral therapy with protease inhibitors will substantially increase the number of patients achieving sustained hepatitis C virus eradication, either before or after liver transplantation. However, side effects and drug-drug interactions will possibly hamper their applicability in both settings; thus, a careful selection and management of patients will be crucial. In the near future, combination of direct-acting antivirals will allow shorter, safer, and more effective IFN-free regimens.
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Ponziani FR, Annicchiarico EB, Siciliano M, D’Aversa F, Pompili M, Gasbarrini A. Treatment of hepatitis C in compensated cirrhotic patients is equally effective before and after liver transplantation. World J Gastroenterol 2013; 19:3255-3262. [PMID: 23745027 PMCID: PMC3671077 DOI: 10.3748/wjg.v19.i21.3255] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Revised: 03/07/2013] [Accepted: 04/28/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate differences in tolerability and response to treatment in compensated cirrhotic patients affected by hepatitis C virus (HCV) infection before and after liver transplantation.
METHODS: Forty-three HCV non-liver transplanted (LT) cirrhotics (mean age 55 ± 8 years, 65.1% male, Child-Pugh-A, genotype 1-4: 65.1%, 2-3: 34.9%) and 17 LT recipients with recurrent HCV-related cirrhosis (mean age 57 ± 9 years, 88.2% male, Child-Pugh-A, genotype 1-4: 76.5%, 2-3: 23.5%) were included in the analysis from retrospective series. All patients received recombinant or pegylated interferon plus ribavirin at a standard dose and duration. Adverse events were recorded and classified according to the Common Terminology Criteria for Adverse Events. The mean duration of follow-up was of 4.3 ± 1.8 years after the end of the treatment.
RESULTS: An early virological response (EVR) was achieved in 30/43 (69.8%) non-LT and in 8/17 (47.1%) LT cirrhotics, a sustained virological response (SVR) in 18/43 (41.9%) and 5/17 (29.4 %), respectively. No statistical difference was observed in EVR and SVR rates between the two groups. Among HCV non-LT cirrhotics, 6/43 (13.9%) discontinued the treatment prematurely, 11.6% of them receiving ≤ 80% of treatment; 8/17 (47%) LT cirrhotics withdrew the treatment, 35.2% of them receiving ≤ 80% of treatment. If compared with LT-ones (P = 0.015), an higher risk of treatment discontinuation could affect LT cirrhotics, who undergo more frequently ≤ 80% of treatment (P = 0.05). None of the non-LT cirrhotics died after the end of the treatment. With no regards to the achievement of SVR, LT cirrhotic patients showed a reduced survival in respect to non-LT ones (87% at 1 year, 76% at 3 and 5 years after the end of treatment).
CONCLUSION: HCV antiviral treatment is equally effective in compensated cirrhotics both before and after LT, which patients show a higher risk of premature treatment withdrawal and a reduced survival, independently of the achievement of SVR.
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García-Reyne A, Lumbreras C, Fernández I, Colina F, Abradelo M, Magan P, San-Juan R, Manrique A, López-Medrano F, Fuertes A, Lizasoain M, Moreno E, Aguado JM. Influence of antiviral therapy in the long-term outcome of recurrent hepatitis C virus infection following liver transplantation. Transpl Infect Dis 2013; 15:405-15. [PMID: 23725370 DOI: 10.1111/tid.12097] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2012] [Revised: 12/03/2012] [Accepted: 12/19/2012] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Severity of recurrent hepatitis C virus (HCV) infection in liver transplant recipients (LTR) is variable and the influence of different factors, including the administration of antiviral therapy in the long-term outcome is controversial. METHODS We analyzed the outcome of a cohort of HCV-infected LTR who were transplanted in our institution. Patients were divided into 2 groups (severe and non-severe HCV disease) depending on the presence of a fibrosis score of F ≥ 2 in the Scheuer index and/or fibrosing cholestasic hepatitis (FCH) in a graft biopsy. Risk factors were studied using logistic regression analysis. Survival of patients was estimated using Kaplan-Meier plots. A total of 146 patients were followed for a mean of 58 months. RESULTS Fifty-six (34%) patients developed severe HCV disease and showed shorter survival (P < 0.024). Donor age (odds ratio [OR]: 1.04; 95% confidence interval [CI]: 1.02-1.06) and pre-transplant viral load (VL) >10(6) UI/mL (OR: 3.5; 95% CI: 1.42-10.61) were the only factors associated with severe HCV infection. Over-immunosuppression (OR: 2.3; 95% CI: 1.2-4.41) was specifically associated with the development of FCH. Overall, patient survival in recipients who received a full course of anti-HCV therapy was higher than in patients who did not complete antiviral therapy (P = 0.004) or received no treatment (P = 0.007). Patients with non-severe HCV infection have a higher probability of receiving a full course of antiviral therapy (P = 0.033). CONCLUSION In conclusion, donor age, pre-transplant VL, and over-immunosuppression were associated with the long-term development of severe HCV recurrence in liver grafts. Administration of a full course of antiviral therapy was associated with better survival.
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Affiliation(s)
- A García-Reyne
- Infectious Diseases Unit, University Hospital 12 de Octubre, Instituto de Investigación Hospital 12 de Octubre, Madrid, Spain.
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Ciria R, Pleguezuelo M, Khorsandi SE, Davila D, Suddle A, Vilca-Melendez H, Rufian S, de la Mata M, Briceño J, Cillero PL, Heaton N. Strategies to reduce hepatitis C virus recurrence after liver transplantation. World J Hepatol 2013; 5:237-50. [PMID: 23717735 PMCID: PMC3664282 DOI: 10.4254/wjh.v5.i5.237] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2012] [Revised: 11/16/2012] [Accepted: 12/01/2012] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is a major health problem that leads to chronic hepatitis, cirrhosis and hepatocellular carcinoma, being the most frequent indication for liver transplantation in several countries. Unfortunately, HCV re-infects the liver graft almost invariably following reperfusion, with an accelerated history of recurrence, leading to 10%-30% of patients progressing to cirrhosis within 5 years of transplantation. In this sense, some groups have even advocated for not re-transplanting this patients, as lower patient and graft outcomes have been reported. However, the management of HCV recurrence is being optimized and several strategies to reduce post-transplant recurrence could improve outcomes, decrease the rate of re-transplantation and optimize the use of available grafts. Three moments may be the focus of potential actions in order to decrease the impact of viral recurrence: the pre-transplant moment, the transplant environment and the post-transplant management. In the pre-transplant setting, it is not well established if reducing the pre transplant viral load affects the risk for HCV progression after transplant. Obviously, antiviral treatment can render the patient HCV RNA negative post transplant but the long-term benefit has not yet been fully established to justify the cost and clinical risk. In the transplant moment, factors as donor age, cold ischemia time, graft steatosis and ischemia/reperfusion injury may lead to a higher and more aggressive viral recurrence. After the transplant, discussion about immunosuppression and the moment to start the treatment (prophylactic, pre-emptive or once-confirmed) together with new antiviral drugs are of interest. This review aims to help clinicians have a global overview of post-transplant HCV recurrence and strategies to reduce its impact on our patients.
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Affiliation(s)
- Ruben Ciria
- Ruben Ciria, Shirin Elizabeth Khorsandi, Diego Davila, Abid Suddle, Hector Vilca-Melendez, Nigel Heaton, Institute of Liver Studies, King's College Hospital, London SE5 9RS, United Kingdom
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Everson GT, Terrault NA, Lok AS, Rodrigo DR, Brown RS, Saab S, Shiffman ML, Al-Osaimi AMS, Kulik LM, Gillespie BW, Everhart JE. A randomized controlled trial of pretransplant antiviral therapy to prevent recurrence of hepatitis C after liver transplantation. Hepatology 2013; 57:1752-62. [PMID: 22821361 PMCID: PMC3510348 DOI: 10.1002/hep.25976] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2012] [Accepted: 06/11/2012] [Indexed: 12/13/2022]
Abstract
UNLABELLED Hepatitis C virus (HCV) infection recurs in liver recipients who are viremic at transplantation. We conducted a randomized, controlled trial to test the efficacy and safety of pretransplant pegylated interferon alpha-2b plus ribavirin (Peg-IFN-α2b/RBV) for prevention of post-transplant HCV recurrence. Enrollees had HCV and were listed for liver transplantation, with either potential living donors or Model for End-Stage Liver Disease upgrade for hepatocellular carcinoma. Patients with HCV genotypes (G) 1/4/6 (n = 44/2/1) were randomized 2:1 to treatment (n = 31) or untreated control (n = 16); HCV G2/3 (n=32) were assigned to treatment. Overall, 59 were treated and 20 were not. Peg-IFN-α2b, starting at 0.75 μg/kg/week, and RBV, starting at 600 mg/day, were escalated as tolerated. Patients assigned to treatment versus control had similar baseline characteristics. Combined virologic response (CVR) included pretransplant sustained virologic response and post-transplant virologic response (pTVR), defined as undetectable HCV RNA 12 weeks after end of treatment or transplant, respectively. In intent-to-treat analyses, 12 (19%) assigned to treatment and 1 (6%) assigned to control achieved CVR (P = 0.29); per-protocol values were 13 (22%) and 0 (0%) (P = 0.03). Among treated G1/4/6 patients, 23 of 30 received transplant, of whom 22% had pTVR; among treated G2/3 patients 21 of 29 received transplant, of whom 29% had pTVR. pTVR was 0%, 18%, and 50% in patients treated for <8, 8-16, and >16 weeks, respectively (P = 0.01). Serious adverse events (SAEs) occurred with similar frequency in treated versus untreated patients (68% versus 55%; P = 0.30), but the number of SAEs per patient was higher in the treated group (2.7 versus 1.3; P = 0.003). CONCLUSION Pretransplant treatment with Peg-IFN-α2b/RBV prevents post-transplant recurrence of HCV in selected patients. Efficacy is higher with >16 weeks of treatment, but treatment is associated with increased risk of potentially serious complications.
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Affiliation(s)
| | - Norah A. Terrault
- Division of Gastroenterology, University of California, San Francisco, CA
| | - Anna S. Lok
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI
| | - Del R. Rodrigo
- Department of Surgery, University of Michigan, Ann Arbor, MI
| | - Robert S. Brown
- Department of Medicine and Surgery, Columbia University College of Physicians and Surgeons, New York, NY
| | - Sammy Saab
- Department of Medicine and Surgery, University of California, Los Angeles, CA
| | | | | | - Laura M. Kulik
- Department of Medicine and Surgery, Northwestern University, Chicago, IL
| | | | - James E. Everhart
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - the Adult-to-Adult Living Donor Liver Transplantation Cohort Study
- The A2ALL Study Group includes Northwestern University, Chicago, IL; University of California – Los Angeles, CA; University of California – San Francisco, CA; University of Colorado Health Sciences Center, Denver, CO; University of North Carolina, Chapel Hill, NC; Epidemiology and Clinical Trials Branch, Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; University of Michigan, Ann Arbor, MI; Department of Surgery, Columbia Presbyterian Medical Center, New York, NY; University of Pennsylvania, Philadelphia, PA; Department of Internal Medicine, University of Virginia, Charlottesville, VA; Virginia Commonwealth University, Richmond, VA
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Hepatitis C virus treatment and liver transplantation in the era of new antiviral therapies. Curr Opin Organ Transplant 2013; 17:216-24. [PMID: 22476221 DOI: 10.1097/mot.0b013e3283534d64] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW The new standard-of-care treatment for genotype 1 hepatitis C virus infection is a combination of PEG-interferon (PEG-IFN), ribavirin (RBV) and a protease inhibitor - telaprevir or boceprevir. As triple therapy is not yet approved for use in decompensated cirrhotics and liver transplant recipients, we examine the efficacy and safety of PEG-IFN, RBV and protease inhibitors in nontransplant populations to inform the current and future treatment paradigms for transplant candidates and recipients. RECENT FINDINGS Protease inhibitor-based triple therapy is more efficacious than PEG-IFN and RBV in nontransplant genotype 1 patients, so sustained virologic response rates are predicted to be higher in waitlisted candidates and transplant recipients treated with protease inhibitor-triple therapy. Because of the need to use a backbone of PEG-IFN and RBV, tolerability of therapy will remain a major challenge. Anemia, a well recognized side-effect with PEG-IFN and RBV, will be especially common with protease inhibitor-triple therapy. Both protease inhibitors can modify the levels of drugs metabolized by the CYP3A/4 pathway, and in posttransplant patients, the protease inhibitors increase the levels of cyclosporine and tacrolimus, with the magnitude of the drug-drug interactions varying with protease inhibitor and type of calcineurin inhibitor (CNI). SUMMARY Given the complexities of treatment, it is best undertaken by experienced clinicians and only after a detailed discussion of risks-benefits with the patient. To maximize the benefit while minimizing risk, only Child-Turcott-Pugh A (CPT-A) cirrhotics should be considered for pretransplant protease inhibitor-triple therapy. For transplant recipients, very close monitoring and adjustment of CNI levels is critical during protease inhibitor-triple therapy. Cytopenias, especially anemia, will require aggressive management.
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Joshi D, Carey I, Agarwal K. Review article: the treatment of genotype 1 chronic hepatitis C virus infection in liver transplant candidates and recipients. Aliment Pharmacol Ther 2013; 37:659-71. [PMID: 23432320 DOI: 10.1111/apt.12260] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Revised: 12/20/2012] [Accepted: 02/03/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND Recently, the therapeutic landscape with regard to anti-HCV therapy has changed dramatically. The new directly acting anti-virals (DAAs) have demonstrated improved sustained virological response (SVR) compared with pegylated-interferon and ribavirin. AIM To examine and present the latest data with regard to anti-viral therapy in genotype 1 HCV-positive transplant candidates and recipients. METHODS An electronic search using Medline was performed. Search terms included 'HCV, DAA and protease inhibitor' in combination with 'treatment pre-transplantation' and 'treatment post-transplantation'. RESULTS Patients with advanced fibrosis and cirrhosis have inferior SVR rates compared with patients with minimal fibrosis. A low accelerating dose regimen (LADR) of pegylated interferon and ribavirin (PR) appears to be a safe therapeutic option. Side effects also appear to be more pronounced in patients with advanced disease. Data from the large registration studies with triple therapy (boceprevir or telaprevir plus PR) demonstrated improved SVR rates even in patients with advanced disease, although virological relapse rates were highest amongst these patients. In transplant recipients, initial data are being reported on the use of triple therapy, and although no SVR data are available, promising results are accruing. The drug-drug interactions appear to be manageable. Side effects in particular anaemia appear to be markedly increased in the posttransplant setting. CONCLUSIONS The use of the new DAAs in patients with advanced fibrosis/cirrhosis pretransplant and posttransplant appears possible, with manageable side effects and drug-drug interactions, and improved early virological response rates. We recommend that these patients are managed in centres with the appropriate expertise.
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Affiliation(s)
- D Joshi
- Institute of Liver Studies, King's College Hospital, London, UK.
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Machida K. Tumor-initiating stem-like cells and drug resistance: carcinogenesis through Toll-like receptors, environmental factors, and virus. Drug Deliv Transl Res 2013; 3:152-64. [PMID: 25787983 PMCID: PMC10578060 DOI: 10.1007/s13346-012-0115-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Neoplasms contain distinct subpopulations of cells known as tumor-initiating stem-like cells (TICs) that have been identified as key drivers of tumor growth and malignant progression with drug resistance. Stem cells normally proliferate through self-renewing divisions in which the two daughter cells differ markedly in their proliferative potential, with one displaying the differentiation phenotypes and another retaining self-renewing activity. Therefore, understanding the molecular mechanisms of hepatocarcinogenesis will be required for the eventual development of improved therapeutic modalities for treating hepatocellular carcinoma (HCC). Hepatitis C virus (HCV) and hepatitis B virus is a major cause of HCC. Compelling epidemiologic evidence identifies obesity and alcohol as co-morbidity factors that can increase the risk of HCV patients for HCC, especially in alcoholics or obese patients. The mechanisms underlying liver oncogenesis, and how environmental factors contribute to this process, are not yet understood. The HCV-Toll-like receptor 4 (TLR4)-Nanog signaling network is established since alcohol/obesity-associated endotoxemia then activates TLR4 signaling, resulting in the induction of the stem cell marker Nanog expression and liver tumors. Liver TICs are highly sensitized to leptin and exposure of TICs to leptin increases the expression and activity of an intrinsic pluripotency-associated transcriptional network comprised of signal transducer and activator of transcription 3, SOX2, OCT4, and Nanog. Stimulation of the pluripotency network may have significant implications for hepatocellular oncogenesis via genesis and maintenance of TICs. It is important to understand how HCV induces liver cancer through genesis of TICs so that better prevention and treatment can be found. This article reviews the oncogenic pathways to generate TICs.
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Affiliation(s)
- Keigo Machida
- Department of Molecular Microbiology and Immunology, Research Center for ALPD and Cirrhosis, University of Southern California School of Medicine, 503C-HMR, Los Angeles, CA, 90033, USA,
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Lee SW, Bae SH. Management of Hepatitis C Viral Infection Pre- and Post-liver Transplantation. KOREAN JOURNAL OF TRANSPLANTATION 2013. [DOI: 10.4285/jkstn.2013.27.1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Affiliation(s)
- Sung Won Lee
- Department of Internal Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Si Hyun Bae
- Department of Internal Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
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Bota S, Sporea I, Sirli R, Popescu A, Neghină AM, Dănilă M, Străin M. Severe adverse events during antiviral therapy in hepatitis C virus cirrhotic patients: A systematic review. World J Hepatol 2013; 5:120-6. [PMID: 23556044 PMCID: PMC3612570 DOI: 10.4254/wjh.v5.i3.120] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2012] [Revised: 11/26/2012] [Accepted: 01/17/2013] [Indexed: 02/06/2023] Open
Abstract
AIM To identify severe adverse events (SAEs) leading to treatment discontinuation that occur during antiviral therapy in hepatitis C virus (HCV)-infected cirrhotic patients. METHODS We identified all the articles published prior to December 2011 in the PubMed, Medline, Lilacs, Scopus, Ovid, EMBASE, Cochrane and Medscape databases that presented these data in cirrhotic patients. These studies evaluated the rate of SAEs leading to discontinuation of standard care treatment: Pegylated interferon (PegIFN) alpha 2a (135-180 μg/wk) or PegIFN alpha 2b (1 or 1.5 μg/kg per week) and ribavirin (800-1200 mg/d). Patients with genotype 1 + 4 underwent treatment for 48 wk, whereas those with genotypes 2 + 3 were treated for 24 wk. RESULTS We included 17 papers in this review, comprising of 1133 patients. Treatment was discontinued due to SAEs in 14.5% of the patients. The most common SAEs were: severe thrombocytopenia and/or neutropenia (23.2%), psychiatric disorders (15.5%), decompensation of liver cirrhosis (12.1%) and severe anemia (11.2%). The proportion of patients who needed to discontinue their therapy due to SAEs was significantly higher in patients with Child-Pugh class B and C vs those with Child-Pugh class A: 22% vs 11.4% (P = 0.003). A similar discontinuation rate was found in cirrhotic patients treated with PegIFN alpha 2a and those treated with PegIFN alpha 2b, in combination with ribavirin: 14.2% vs 13.7% (P = 0.96). The overall sustained virological response rate in cirrhotic patients was 37% (95%CI: 33.5-43.1) but was significantly lower in patients with genotype 1 + 4 than in those with genotype 2 + 3: 20.5% (95%CI: 17.9-24.8) vs 56.5% (95%CI: 51.5-63.2), (P < 0.0001). CONCLUSION Fourteen point five percent of HCV cirrhotic patients treated with PegIFN and ribavirin needed early discontinuation of therapy due to SAEs, the most common cause being hematological disorders.
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Affiliation(s)
- Simona Bota
- Simona Bota, Ioan Sporea, Roxana Şirli, Alina Popescu, Mirela Dănilă, Mihnea Străin, Department of Gastroenterology and Hepatology, University of Medicine and Pharmacy, 300736 Timişoara, Romania
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An update on the management of hepatitis C: guidelines for protease inhibitor-based triple therapy from the Latin American Association for the Study of the Liver. Ann Hepatol 2013. [PMID: 23559487 DOI: 10.1016/s1665-2681(19)31404-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2025]
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Levitsky J, Doucette K. Viral hepatitis in solid organ transplantation. Am J Transplant 2013; 13 Suppl 4:147-68. [PMID: 23465008 DOI: 10.1111/ajt.12108] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Affiliation(s)
- J Levitsky
- Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
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Safety and anti-HCV effect of prolonged intravenous silibinin in HCV genotype 1 subjects in the immediate liver transplant period. J Hepatol 2013; 58:421-6. [PMID: 23073223 DOI: 10.1016/j.jhep.2012.10.009] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Revised: 10/01/2012] [Accepted: 10/08/2012] [Indexed: 01/16/2023]
Abstract
BACKGROUND & AIMS Reinfection of the graft is the rule in patients with HCV cirrhosis undergoing liver transplantation, and HCV-RNA reaches pre-transplantation levels within the first month. Short-term intravenous silibinin monotherapy is safe and shows a potent in vivo anti-HCV effect. We aimed at evaluating the safety and antiviral effect of prolonged intravenous silibinin, started immediately before liver transplantation. METHODS Single centre, prospective, pilot study, to assess the safety and effect on HCV-RNA kinetics during at least 21 days of intravenous silibinin monotherapy (20 mg/kg/day) in 9 consecutive HCV genotype 1 subjects, in comparison to a control, non-treated group of 7 consecutive prior transplanted subjects under the same immunosuppressive regimen (basiliximab, steroids, delayed tacrolimus, micophenolate). RESULTS Intravenous silibinin led to significant, maintained and progressive HCV-RNA decreases (mean HCV-RNA drop at week 3, -4.1 ± 1.3 log(10)IU/ml), and lack of viral breakthrough during administration. Four patients (44%) reached negative HCV-RNA, maintained during silibinin treatment, vs. none in the control group, but HCV-RNA relapsed in all of them after a median of 21 days (16-28), following silibinin withdrawal. Partial responders to silibinin showed marked decreases in HCV-RNA when compared to controls, but lower than complete responders. There were no clinical adverse effects, and silibinin led to asymptomatic transient hyperbilirubinemia (week 2, 4.2 ± 2.2 vs. 2.5 ± 3.6 mg/dl; p=0.02). CONCLUSIONS Prolonged intravenous silibinin monotherapy was safe in the immediate liver transplantation period, leading to a potent and time dependent antiviral effect and lack of HCV-RNA breakthrough during administration. However, HCV-RNA rebounded after withdrawal, and silibinin monotherapy did not avoid reinfection of the graft.
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Abstract
More than one-third of listed potential liver recipients in the US are infected with the hepatitis C virus (HCV). Recurrence of infection with HCV after liver transplantation is associated with accelerated graft loss and diminished patient survival. Current HCV treatments using peginterferon and ribavirin either alone or with first generation protease inhibitors (telaprevir, boceprevir) are limited by suboptimal viral response, drug-drug interaction, and side effects, some of which may be graft- or life-threatening. Rapid advances in new drug therapy for HCV promise to improve outcomes, reduce side effects and drug-drug interaction, shorten treatment duration, and simplify treatment regimens.
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Affiliation(s)
- James R Burton
- Department of Medicine, University of Colorado Denver, Aurora, 80045, USA
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50
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Living-donor liver transplantation and hepatitis C. HPB SURGERY : A WORLD JOURNAL OF HEPATIC, PANCREATIC AND BILIARY SURGERY 2013; 2013:985972. [PMID: 23401640 PMCID: PMC3564275 DOI: 10.1155/2013/985972] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/17/2012] [Accepted: 01/01/2013] [Indexed: 12/19/2022]
Abstract
Hepatitis-C-virus- (HCV-) related end-stage cirrhosis is the primary indication for liver transplantation in many countries. Unfortunately, however, HCV is not eliminated by transplantation and graft reinfection is universal, resulting in fibrosis, cirrhosis, and finally graft decompression. In areas with low deceased-donor organ availability like Japan, living-donor liver transplantation (LDLT) is similarly indicated for HCV cirrhosis as deceased-donor liver transplantation (DDLT) in Western countries and accepted as an established treatment for HCV-cirrhosis, and the results are equivalent to those of DDLT. To prevent graft failure due to recurrent hepatitis C, antiviral treatment with pegylated-interferon and ribavirin is currently considered the most promising regimen with a sustained viral response rate of around 30% to 35%, although the survival benefit of this regimen remains to be investigated. In contrast to DDLT, many Japanese LDLT centers have reported modified treatment regimens as best efforts to secure first graft, such as aggressive preemptive antiviral treatment, escalation of dosages, and elongation of treatment duration.
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