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The Role of Resveratrol in Liver Disease: A Comprehensive Review from In Vitro to Clinical Trials. Nutrients 2021; 13:nu13030933. [PMID: 33805795 PMCID: PMC7999728 DOI: 10.3390/nu13030933] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/10/2021] [Accepted: 03/11/2021] [Indexed: 12/15/2022] Open
Abstract
Many studies have shown that resveratrol has a lot of therapeutic effects on liver disorders. Its administration can significantly increase the survival rate after liver transplantation, reduce fat deposition and ischemia-induced necrosis and apoptosis in Wistar rats. Resveratrol can provide Liver protection against chemical, cholestatic, and alcohol-mediated damage. It can improve glucose metabolism and lipid profile, reduce liver fibrosis, and steatosis. Additionally, it is capable of altering the fatty acid composition of the liver cells. Resveratrol may be a potential treatment option for the management of non-alcoholic fatty liver disease (NAFLD) due to its anti-inflammatory, antioxidant, and calorie-restricting effects. There are also studies that have evaluated the effect of resveratrol on lipid and liver enzyme profiles among patients with metabolic syndrome (MetS) and related disorders. Based on the extent of liver disease worldwide and the need to find new treatment possibilities, this review critically examines current in vitro and in vivo preclinical studies and human clinical studies related to liver protection.
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Cieciura T, Hryniewiecka E, Foroncewicz B, Strzelczyk Z, Ciszek M, Paczek L. Long-Term Follow-up of Liver Transplant Recipients Treated With Direct-Acting Antiviral Agents for Hepatitis C Recurrence After Transplantation. Transplant Proc 2020; 52:2468-2471. [PMID: 32241638 DOI: 10.1016/j.transproceed.2020.01.097] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Accepted: 01/26/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Treatment of hepatitis C virus (HCV) recurrence after liver transplantation (LTX) with direct-acting antiviral agents (DAA) is effective and leads to sustained viral response (SVR) in most cases. Long-term effect of HCV elimination on LTX function is not clear. The aim of the study was to evaluate the long-term influence of DAA with HCV on the liver function in LTX recipients. METHODS The study included 120 LTX patients with HCV recurrence. Before starting DAA therapy, all patients underwent liver biopsy and elastography. Biochemical tests and HCV viremia were assessed at baseline, 4, 12, and 24 weeks and 24 months after the end of treatment (EOT). The study protocol conformed with the Declaration of Helsinki. RESULTS In the HCV genotype 1 (G1) group, 106 patients were treated with ledipasvir/sofosbuvir with ribavirin (RBV), and 3 patients received paritaprevir/ritonavir/ombitasvir/dasabuvir/RBV. All HCV genotype 3 (G3) patients were treated with sofosbuvir/RBV; all HCV genotype 4 (G4) patients were treated with paritaprevir/ombitasvir/RBV. The efficacy of the treatment defined as SVR at week 12 after EOT (SVR12) was 97.3% in G1 group, 75% in G3, and 100% in G4 group. Median alanine (ALT) and aspartate (AST) transaminase before therapy were 44.0 IU/mL and 42.5 IU/mL, respectively. Median ALT and AST at 24 months after EOT were 17 IU/mL and 22 IU/mL, respectively. The lack of transaminases normalization was observed in 10 patients 24 months after EOT. CONCLUSION The efficacy of DAA therapy of HCV recurrence after LTX is as high as that reported in randomized clinical trials. It is also associated with the improvement of liver function tests during long-term follow-up.
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Affiliation(s)
- Tomasz Cieciura
- Department of Immunology, Transplant Medicine, and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Ewa Hryniewiecka
- Department of Immunology, Transplant Medicine, and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Bartosz Foroncewicz
- Department of Immunology, Transplant Medicine, and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Ziemowit Strzelczyk
- Department of Immunology, Transplant Medicine, and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Michal Ciszek
- Department of Immunology, Transplant Medicine, and Internal Diseases, Medical University of Warsaw, Warsaw, Poland.
| | - Leszek Paczek
- Department of Immunology, Transplant Medicine, and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
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Liver transplantation for hepatocellular carcinoma: outcomes and novel surgical approaches. Nat Rev Gastroenterol Hepatol 2017; 14:203-217. [PMID: 28053342 DOI: 10.1038/nrgastro.2016.193] [Citation(s) in RCA: 322] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Liver transplantation for hepatocellular carcinoma (HCC) is the best treatment option for patients with early-stage tumours and accounts for ∼20-40% of all liver transplantations performed at most centres worldwide. The Milan criteria are the most common criteria to select patients with HCC for transplantation but they can be seen as too restrictive. Several proposals have been made for a moderate expansion of the criteria, which result in good outcomes but with an increase in the risk of tumour recurrence. In this Review, we provide a comprehensive overview of the outcomes after liver transplantation for HCC, focusing on tumour recurrence in terms of surveillance, prevention and treatment. Additionally, novel surgical techniques have been developed to increase the available pool of organs for liver transplantation (such as living donor liver transplantation, donation after circulatory death and split livers), but the effect of these techniques on patients with HCC is still under debate. Thus, we will describe these techniques and expose the benefits and disadvantages of each surgical approach. Finally, we will comment on the limitations of the current priority policies for liver transplantation and the need to further refine them to better serve the population.
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Lim EJ, Chin R, Nachbur U, Silke J, Jia Z, Angus PW, Torresi J. Hepatitis C-induced hepatocyte apoptosis following liver transplantation is enhanced by immunosuppressive agents. J Viral Hepat 2016; 23:730-43. [PMID: 27167351 DOI: 10.1111/jvh.12541] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2015] [Accepted: 03/05/2016] [Indexed: 01/07/2023]
Abstract
In recurrent hepatitis C (HCV) post-liver transplantation (OLT), the combination of immunosuppressants and HCV is postulated to increase hepatocyte apoptosis and liver fibrosis. We evaluated hepatocyte apoptosis within the liver tissue of patients with postOLT HCV recurrence compared to HCV-negative individuals and correlated these findings with the effects of immunosuppressants on HCV-induced cell death and its inhibition in primary mouse hepatocytes (PMoH). Liver biopsies from patients with and without HCV were evaluated by immunohistochemistry for markers of apoptosis M30 CytoDEATH (M30) and cleaved PARP (clPARP). PMoH from C57BL/6 mice were infected with recombinant adenoviruses (rAdHCV) that expressed HCV proteins in hepatocytes. Infected cells were treated with cyclosporine, tacrolimus, sirolimus and/or MMF with or without pan-caspase inhibitor Q-VD-Oph. Cell viability and apoptosis were evaluated using crystal violet assays and Western immunoblots probed for cleaved caspase-3 (clCas3) and clPARP. Both M30 and clPARP were increased in the liver biopsies of patients with postOLT HCV recurrence compared to HCV-negative individuals. Treatment of rAdHCV-infected PMoH with cyclosporine, tacrolimus or sirolimus reduced cell viability and increased clCas3 and clPARP compared to rAdHCV infection alone. Addition of MMF to cyclosporine, tacrolimus or sirolimus further reduced cell viability and increased clCas3 and clPARP. Q-VD-Oph improved cell viability in HCV-infected PMoH treated with immunosuppressants alone and in combination and reduced clCas3 and clPARP by approximately 90%. Immunosuppressive agents, especially in combination, enhanced apoptosis in HCV-infected hepatocytes. The finding that Q-VD-Oph reversed hepatocyte death suggests that treatments utilizing apoptosis inhibition might reduce liver injury in postOLT HCV recurrence.
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Affiliation(s)
- E J Lim
- Liver Transplant Unit, Austin Hospital, Heidelberg, Vic., Australia.,Department of Medicine, The University of Melbourne, Austin Hospital, Heidelberg, Vic., Australia
| | - R Chin
- Department of Medicine, The University of Melbourne, Austin Hospital, Heidelberg, Vic., Australia
| | - U Nachbur
- Walter and Eliza Hall Institute, Parkville, Vic., Australia
| | - J Silke
- Walter and Eliza Hall Institute, Parkville, Vic., Australia
| | - Z Jia
- Department of Medicine, The University of Melbourne, Austin Hospital, Heidelberg, Vic., Australia
| | - P W Angus
- Liver Transplant Unit, Austin Hospital, Heidelberg, Vic., Australia.,Department of Medicine, The University of Melbourne, Austin Hospital, Heidelberg, Vic., Australia
| | - J Torresi
- Department of Medicine, The University of Melbourne, Austin Hospital, Heidelberg, Vic., Australia.,Department of Infectious Diseases, Austin Hospital, Heidelberg, Vic., Australia.,Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Vic., Australia
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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; 21:10760-10775. [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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Effect of Immunosuppressive Agents on Hepatocyte Apoptosis Post-Liver Transplantation. PLoS One 2015; 10:e0138522. [PMID: 26390404 PMCID: PMC4577231 DOI: 10.1371/journal.pone.0138522] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Accepted: 09/01/2015] [Indexed: 01/03/2023] Open
Abstract
INTRODUCTION Immunosuppressants are used ubiquitously post-liver transplantation to prevent allograft rejection. However their effects on hepatocytes are unknown. Experimental data from non-liver cells indicate that immunosuppressants may promote cell death thereby driving an inflammatory response that promotes fibrosis and raises concerns that a similar effect may occur within the liver. We evaluated apoptosis within the liver tissue of post-liver transplant patients and correlated these findings with in vitro experiments investigating the effects of immunosuppressants on apoptosis in primary hepatocytes. METHODS Hepatocyte apoptosis was assessed using immunohistochemistry for M30 CytoDEATH and cleaved PARP in human liver tissue. Primary mouse hepatocytes were treated with various combinations of cyclosporine, tacrolimus, sirolimus, or MMF. Cell viability and apoptosis were evaluated using crystal violet assays and Western immunoblots probed for cleaved PARP and cleaved caspase 3. RESULTS Post-liver transplant patients had a 4.9-fold and 1.7-fold increase in M30 CytoDEATH and cleaved PARP compared to normal subjects. Cyclosporine and tacrolimus at therapeutic concentrations did not affect hepatocyte apoptosis, however when they were combined with MMF, cell death was significantly enhanced. Cell viability was reduced by 46% and 41%, cleaved PARP was increased 2.6-fold and 2.2-fold, and cleaved caspase 3 increased 2.2-fold and 1.8-fold following treatment with Cyclosporine/MMF and Tacrolimus/MMF respectively. By contrast, the sirolimus/MMF combination did not significantly reduce hepatocyte viability or promote apoptosis. CONCLUSION Commonly used immunosuppressive drug regimens employed after liver transplantation enhance hepatocyte cell death and may thus contribute to the increased liver fibrosis that occurs in a proportion of liver transplant recipients.
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Abstract
INTRODUCTION Pegylated interferon and ribavirin (PEGIFN/RBV) therapy for recurrent hepatitis C after liver transplantation (LT) is associated with a lower sustained virological response (SVR) rate as well as more frequent side effects compared to non-transplant patients. We aimed to determine the incidence and clinical characteristics of LT recipients with recurrent hepatitis C who developed immunological dysfunction (ID) during or after PEG-IFN/RBV therapy and to assess its impact on patient and graft survival. METHODS Seventy-four deceased donor LT recipients with histological recurrence of hepatitis C were treated with PEG-IFN/RBV from 1/00 to 12/08. ID was defined as biopsy-proven rejection or moderate plasma cell hepatitis. Patients were followed up until death, re-LT or 30 September 2011. RESULTS Twelve patients (16 %) had ID, 8 (10.7 %) had cholestasis without ID, while 54 had no ID/cholestasis during or after discontinuation of PEG-IFN/RBV therapy. Biopsy-proven acute cellular rejection prior to (hazard ratio = 4.87, p = 0.009) and type of immunosuppression at the time of initiation of PEG-IFN/RBV were the only independent predictors of ID. Patients who were on tacrolimus at the time of initiation of PEG-IFN/RBV had a significantly lower risk of ID compared to those who were on cyclosporine (HR 0.254, p = 0.023). Patients with ID had a trend toward a lower SVR rate (25 vs. 54 %, p = 0.18) and a significantly higher rate of graft failure (33 vs. 4 %, p = 0.004) compared to patients with no ID/cholestasis. CONCLUSIONS ID is common during or after PEG-IFN/RBV therapy for recurrent hepatitis C and frequently associated with decreased graft survival, trending toward low rates of SVR. Careful monitoring of liver biochemistries during or after PEG-IFN/RBV therapy with a low threshold to biopsy patients and particularly those receiving cyclosporine-based immunosuppression may improve outcomes in these patients.
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de la Peña-Moral JM, Pons JA, Tome S, Gude F, Miras M, Bermejo J, Ramirez P, Berenguer M, Varo E, Forteza J, Parrilla P. Acute cellular rejection versus recurrent hepatitis C after liver transplantation: Clinical and pathological features driving a rational diagnostic approach. Hepatol Res 2015; 45:423-31. [PMID: 24906075 DOI: 10.1111/hepr.12369] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2013] [Revised: 05/20/2014] [Accepted: 06/02/2014] [Indexed: 02/08/2023]
Abstract
AIM The aim of our study was develop and validate an algorithm system based on morphological features for finding the differences between recurrent hepatitis C virus (HCV) and acute cellular rejection (ACR) in liver biopsies of HCV-transplanted patients. METHODS Two hundred and eighty-eight liver biopsies were analyzed from 121 patients transplanted for HCV. A diagnostic consensus was reached between clinicians and pathologists in 214 biopsies for the diagnosis of recurrent HCV or ACR. A random sample of 114 liver biopsies (derivation cohort) was taken to generate the diagnostic tree and was subsequently evaluated using the validation cohort in 100 liver biopsies by recursive partitioning analysis of morphological variables and time since transplantation. RESULTS The presence of endotheliitis together with a time of less than 6 weeks since LT definitely excluded recurrent HCV. After obtaining the regression tree, diagnostic accuracy was 96% and 93% in the derivation and validation cohort, respectively. Both cases surpassed the pathologist's original diagnosis, which had a diagnostic accuracy of 91% (P < 0.05, for both comparisons). CONCLUSION A recursive partitioning analysis of the morphological features in liver biopsies from HCV-transplanted patients may be useful for easily distinguishing between recurrent HCV and ACR.
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9
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Tanaka Y, Ohira M, Tashiro H, Imamura M, Chayama K, Ohdan H. Impact of alloimmune T cell responses on hepatitis C virus replication in liver transplant recipients. Hum Immunol 2014; 75:1259-67. [PMID: 25300999 DOI: 10.1016/j.humimm.2014.09.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Accepted: 08/09/2014] [Indexed: 12/16/2022]
Abstract
We investigated the influence of alloimmune T cell responses on hepatitis C virus (HCV) replication in HCV-infected patients after liver transplantation (LT). To monitor the immune-status in 27 HCV-infected LT recipients, we routinely performed mixed lymphocyte reaction (MLR) assays within 4 weeks after LT. HCV RNA titers in most patients fluctuated in inverse proportion to the stimulation index (SI) of anti-donor reactive T cells early after LT. Two weeks after LT, recipients with high HCV RNA titers (>1000 KIU/mL) displayed a significantly lower SI for anti-donor reactive T cells than recipients with low HCV RNA titers did (<1000 KIU/mL). An in vitro transwell assay mimicking the anatomical features of the interaction between HCV-infected hepatocytes and alloreactive T cells in allograft livers demonstrated that interferon (IFN)-γ was necessary to suppress HCV replication. This study proves the significant impact of alloimmune T cell responses on HCV replication in HCV-infected LT recipients.
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Affiliation(s)
- Yuka Tanaka
- Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Japan; Liver Research Project Center, Hiroshima University, Japan
| | - Masahiro Ohira
- Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Japan; Liver Research Project Center, Hiroshima University, Japan
| | - Hirotaka Tashiro
- Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Japan; Liver Research Project Center, Hiroshima University, Japan
| | - Michio Imamura
- Medicine and Molecular Science, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Japan; Liver Research Project Center, Hiroshima University, Japan
| | - Kazuaki Chayama
- Medicine and Molecular Science, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Japan; Liver Research Project Center, Hiroshima University, Japan
| | - Hideki Ohdan
- Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Japan; Liver Research Project Center, Hiroshima University, Japan.
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Campos-Varela I, Esteban JI, Bes M, Caralt M, Allende H, Rodríguez-Frías F, Salcedo MT, Sauleda S, Charco R, Guardia J, Esteban R, Castells L. Early predictors of antiviral treatment response in liver transplant recipients with recurrent hepatitis C genotype 1. J Viral Hepat 2014; 21:e118-e128. [PMID: 24620835 DOI: 10.1111/jvh.12246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2013] [Accepted: 01/14/2014] [Indexed: 12/09/2022]
Abstract
The success of current antiviral treatment for hepatitis C virus (HCV) recurrence in liver transplant (LT) recipients remains limited. We aimed at evaluating the value of IL28B genotype and early viral kinetics to predict response to standard treatment in the transplant setting. We retrospectively evaluated 104 LT recipients treated for HCV genotype 1 recurrence between 2001 and 2010. Baseline variables, including IL28B genotype, and early viral kinetics were compared among patients who did or did not achieve a sustained virological response (SVR). Logistic regression analyses of candidate variables were conducted to generate a reliable predictive model based on the minimum set of variables. Twenty-nine (28%) achieved an SVR. On multivariate analysis, the magnitude of HCV RNA decline at 4 weeks (OR: 3.74, 95% CI: 1.64-9.39; P = 0.003) and treatment compliance (OR: 35.27, 95% CI: 3.35-365.54; P = 0.003) were the only independent predictors of SVR. Favourable recipient IL28B genotype significantly correlates with virological response at week 4 (OR 3.23; 95% CI, 1.12-9.15; P = 0.03). By logistic regression analysis, a model including donor age, recipient rs12979860 genotype and viral load at 4 weeks showed the best predictive value for SVR with an area under the receiver operating curve of 0.861. Favourable recipient IL28B genotype strongly correlates with the viral response at week 4 which is the strongest predictor of response. The combination of recipient IL28B genotype and donor age with the week 4 response reliably estimates the probability of SVR early on-treatment and may facilitate therapeutic strategies incorporating new antiviral agents.
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Affiliation(s)
- I Campos-Varela
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
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Kakati B, Seetharam A. Hepatitis C Recurrence after Orthotopic Liver Transplantation: Mechanisms and Management. J Clin Transl Hepatol 2014; 2:189-96. [PMID: 26355427 PMCID: PMC4521242 DOI: 10.14218/jcth.2014.00016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Revised: 06/06/2014] [Accepted: 07/07/2014] [Indexed: 12/04/2022] Open
Abstract
Chronic Hepatitis C (HCV) infection is the leading indication for orthotopic liver transplantation and recurrence is nearly universal. Chronic HCV infection is frequently established through evasion of the innate immune system. Priming of adaptive immune responses modulate the severity and rate of fibrosis progression. Those with demonstrable viremia entering the transplant period uniformly suffer recurrence post-transplant. Progression to cirrhosis is accelerated post-transplant secondary to systemic immunosuppression. In addition, a number of factors, including donor, host, and viral characteristics, influence severity and rate of fibrosis progression. Interferon-based therapy, the previous standard of care, in those with advanced cirrhosis or post-transplant has been limited by a number of issues. These include a relative lack of efficacy and poor tolerability with higher incidence of infection and anemia. Recently, approval of direct acting antivirals have ushered in a new era in HCV therapeutics and have applicability in these special populations. Their use immediately prior to or post-transplant is expected to improve both morbidity and mortality.
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Affiliation(s)
- Bobby Kakati
- Banner Transplant and Advanced Liver Disease Center, Phoenix, AZ, USA
| | - Anil Seetharam
- Banner Transplant and Advanced Liver Disease Center, Phoenix, AZ, USA
- University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA
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Grassi A, Ballardini G. Post-liver transplant hepatitis C virus recurrence: an unresolved thorny problem. World J Gastroenterol 2014; 20:11095-11115. [PMID: 25170198 PMCID: PMC4145752 DOI: 10.3748/wjg.v20.i32.11095] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Revised: 02/15/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV)-related cirrhosis represents the leading cause of liver transplantation in developed, Western and Eastern countries. Unfortunately, liver transplantation does not cure recipient HCV infection: reinfection universally occurs and disease progression is faster after liver transplant. In this review we focus on what happens throughout the peri-transplant phase and in the first 6-12 mo after transplantation: during this crucial period a completely new balance between HCV, liver graft, the recipient's immune response and anti-rejection therapy is achieved that will deeply affect subsequent outcomes. Nearly all patients show an early graft reinfection, with HCV viremia reaching and exceeding pre-transplant levels; in this setting, histological assessment is essential to differentiate recurrent hepatitis C from acute or chronic rejection; however, differentiating the two patterns remains difficult. The host immune response (mainly cellular mediated) appears to be crucial both in the control of HCV infection and in the genesis of rejection, and it is also strongly influenced by immunosuppressive treatment. At present no clear immunosuppressive strategy could be strongly recommended in HCV-positive recipients to prevent HCV recurrence, even immunotherapy appears to be ineffective. Nonetheless it seems reasonable that episodes of rejection and over-immunosuppression are more likely to enhance the risk of HCV recurrence through immunological mechanisms. Both complete prevention of rejection and optimization of immunosuppression should represent the main goals towards reducing the rate of graft HCV reinfection. In conclusion, post-transplant HCV recurrence remains an unresolved, thorny problem because many factors remain obscure and need to be better determined.
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Gane EJ, Agarwal K. Directly acting antivirals (DAAs) for the treatment of chronic hepatitis C virus infection in liver transplant patients: "a flood of opportunity". Am J Transplant 2014; 14:994-1002. [PMID: 24730431 DOI: 10.1111/ajt.12714] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Revised: 01/24/2014] [Accepted: 01/26/2014] [Indexed: 02/06/2023]
Abstract
Chronic hepatitis C virus (HCV) is the leading cause of liver transplantation (LT) in adults. However, infection of the allograft is universal and associated with reduced graft and patient survival. Although successful eradication improves posttransplant outcome, current antiviral therapies have poor efficacy and tolerability. Direct acting antiviral agents (DAAs) provide new opportunities for treatment of HCV recurrence. The addition of a first-generation NS3/4A protease inhibitor (PI) has increased the efficacy of pegylated interferon and ribavirin in patients with chronic HCV genotype 1 infection. Preliminary efficacy results from open-labeled studies of PI-based triple therapy in LT recipients are encouraging. However, the tolerability of triple therapy is reduced following LT, because of increased anemia and drug-drug interactions. The use of PI-based triple therapy in LT recipients seems best suited to larger centers, experienced with management of PI toxicity. Fortunately, other classes of DAAs targeting different steps of HCV replication are in clinical trials, including nucleotide polymerase (NUC-NS5B) inhibitors, nonnucleotide polymerase (non-NUC-NS5B) inhibitors and NS5A inhibitors. Several dual and triple DAA regimens are in clinical development. Phase II studies conducted in patients before and after LT suggest that these regimens will dramatically reduce the impact of recurrent HCV. There is a tide in the affairs of men. Which, taken at the flood, leads on to fortune (Shakespeare: J Caesar Act 4, scene 3).
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Affiliation(s)
- E J Gane
- New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand
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Ho CM, Hu RH, Lee PH. Perspective of antiviral therapeutics for hepatitis C after liver transplantation. World J Pharmacol 2014; 3:193. [DOI: 10.5497/wjp.v3.i4.193] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Revised: 09/22/2014] [Accepted: 10/10/2014] [Indexed: 02/06/2023] Open
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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: 14] [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: 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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New insights in recurrent HCV infection after liver transplantation. Clin Dev Immunol 2013; 2013:890517. [PMID: 23710205 PMCID: PMC3655463 DOI: 10.1155/2013/890517] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Revised: 03/17/2013] [Accepted: 03/31/2013] [Indexed: 12/15/2022]
Abstract
Hepatitis C virus (HCV) is a small-enveloped RNA virus belonging to the Flaviviridae family. Since first identified in 1989, HCV has been estimated to infect 170 million people worldwide. Mostly chronic hepatitis C virus has a uniform natural history, from liver cirrhosis to the development of hepatocellular carcinoma. The current therapy for HCV infection consists of a combination of Pegylated interferon and ribavirin. On the other hand, HCV-related liver disease is also the leading indication for liver transplantation. However, posttransplant HCV re-infection of the graft has been reported to be universal. Furthermore, the graft after HCV re-infection often results in accelerated progression to liver failure. In addition, treatment of recurrent HCV infection after liver transplantation is often compromised by enhanced adverse effects and limited efficacy of interferon-based therapies. Taken together, poor outcome after HCV re-infection, regardless of grafts or recipients, poses a major issue for the hepatologists and transplant surgeons. The aim of this paper is to review several specific aspects regarding HCV re-infection after transplant: risk factors, current therapeutics for HCV in different stages of liver transplantation, cellular function of HCV proteins, and molecular mechanisms of HCV entry. Hopefully, this paper will inspire new strategies and novel inhibitors against recurrent HCV infection after liver transplantation and greatly improve its overall outcome.
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17
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Donor-recipient matching: myths and realities. J Hepatol 2013; 58:811-20. [PMID: 23104164 DOI: 10.1016/j.jhep.2012.10.020] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2012] [Revised: 09/17/2012] [Accepted: 10/13/2012] [Indexed: 12/23/2022]
Abstract
Liver transplant outcomes keep improving, with refinements of surgical technique, immunosuppression and post-transplant care. However, these excellent results and the limited number of organs available have led to an increasing number of potential recipients with end-stage liver disease worldwide. Deaths on waiting lists have led liver transplant teams maximize every organ offered and used in terms of pre and post-transplant benefit. Donor-recipient (D-R) matching could be defined as the technique to check D-R pairs adequately associated by the presence of the constituents of some patterns from donor and patient variables. D-R matching has been strongly analysed and policies in donor allocation have tried to maximize organ utilization whilst still protecting individual interests. However, D-R matching has been written through trial and error and the development of each new score has been followed by strong discrepancies and controversies. Current allocation systems are based on isolated or combined donor or recipient characteristics. This review intends to analyze current knowledge about D-R matching methods, focusing on three main categories: patient-based policies, donor-based policies and combined donor-recipient systems. All of them lay on three mainstays that support three different concepts of D-R matching: prioritarianism (favouring the worst-off), utilitarianism (maximising total benefit) and social benefit (cost-effectiveness). All of them, with their pros and cons, offer an exciting controversial topic to be discussed. All of them together define D-R matching today, turning into myth what we considered a reality in the past.
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Abstract
GOALS To evaluate the safety and efficacy of peginterferon-α-2b plus ribavirin in patients with recurrent hepatitis C after orthotopic liver transplant. BACKGROUND Reinfection of liver allografts in hepatitis C virus -infected transplant recipients begins immediately after transplantation. Treatment of these patients is challenging because of poor tolerability. STUDY A multicenter, open-label study enrolling patients with persistent viremia after primary orthotopic liver transplant for cirrhosis related to hepatitis C virus infection. Patients received peginterferon-α-2b (1.5 µg/kg/wk) plus ribavirin (400 to 1200 mg/d administered using a dose-escalating regimen and according to body weight) for 48 weeks. The primary endpoint was sustained virologic response (SVR). RESULTS In total, 125 patients started treatment and 58.4% completed 48 weeks. SVR rate was 28.8% (G1, 23.8%; G2/3, 55.0%), end-of-treatment response rate was 40.8%, and relapse rate was 18.2%. SVR was 55% among patients who completed treatment. Genotype 2/3 infection, male sex, baseline hemoglobin>14 g/dL, 80:80:80 compliance, rapid virologic response (RVR), and complete early virologic response (cEVR) were predictors of SVR. SVR was higher among patients with RVR compared with those without RVR (83.3% vs. 25.7%; P=0.0098), and among patients with cEVR compared with those without EVR (66.7% vs. 1.8%; P<0.0001). Thirty-eight patients discontinued because of an adverse event and 69 required dose reduction or interruption. Anemia (74%) and neutropenia (30%) were common, and rejection was low (3.2%). CONCLUSIONS SVR was low in this study. Anemia was a particular challenge in achieving maximal ribavirin therapeutic exposure and may account in part for the lower SVR.
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Picascia A, Grimaldi V, Napoli C. HLA match in operational tolerance after pediatric living-donor liver transplantation. Transpl Int 2012; 25:e106-7. [PMID: 22775465 DOI: 10.1111/j.1432-2277.2012.01527.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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A Randomized Multicenter Study Comparing a Tacrolimus-Based Protocol with and without Steroids in HCV-Positive Liver Allograft Recipients. J Transplant 2012; 2012:894215. [PMID: 22690326 PMCID: PMC3368368 DOI: 10.1155/2012/894215] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2011] [Accepted: 02/06/2012] [Indexed: 02/06/2023] Open
Abstract
Allograft reinfection with hepatitis C virus (HCV) occurs universally in liver transplant recipients. Corticosteroids can contribute to HCV recurrence.
This randomized study evaluated HCV recurrence in HCV-positive liver allograft recipients using steroid-free immunosuppression. All patients received tacrolimus (TAC) at an initial dose of 0.10–0.15 mg/kg. The steroid-free arm (TAC/daclizumab (TAC/DAC, n = 67)) received daclizumab induction, and the steroid arm (TAC/steroid (TAC/STR, n = 68)) received a steroid bolus (≤ 500mg) followed by 15–20 mg/day with discontinuation after month 3. Median HCV viral load at month 12, the primary endpoint, was similar at 5.46 (0.95–6.54) IU/mL with TAC/DAC and 5.91 (0.95–6.89) IU/mL with TAC/STR. Small numerical differences in the estimated rate of freedom from HCV recurrence (19.1 versus 13.8%) and freedom from biopsy proven rejection (78.4 versus 66.1%) were observed between TAC/DAC and TAC/STR. Patient survival estimates were significantly lower with TAC/DAC than with TAC/STR (83.1 versus 95.5%; 95% CI, −0.227 to −0.019%), and graft survival was numerically lower (80.1 versus 91.1%, P = NS). Completion rates (45 versus 82%) indicated poorer tolerability with TAC/DAC than with TAC/STR. Steroid-free immunosuppression had no real impact on HCV viral load. HCV recurrence was higher with TAC/STR. Results are inconclusive due to the unexpected lower completion rates in the TAC/DAC arm.
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21
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Lim EJ, Chin R, Angus PW, Torresi J. Enhanced apoptosis in post-liver transplant hepatitis C: Effects of virus and immunosuppressants. World J Gastroenterol 2012; 18:2172-9. [PMID: 22611309 PMCID: PMC3351766 DOI: 10.3748/wjg.v18.i18.2172] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2012] [Revised: 03/29/2012] [Accepted: 04/09/2012] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C (HCV)-infected patients have a poorer survival post-liver transplantation compared to patients transplanted for other indications, since HCV recurrence post-transplant is universal and commonly follows an aggressive course. There is increasing evidence that in the non-transplant setting, induction of hepatocyte apoptosis is one of the main mechanisms by which HCV drives liver inflammation and fibrosis, and that HCV proteins directly promote apoptosis. Recent studies have shown that post-liver transplant, there is a link between high levels of HCV replication, enhanced hepatocyte apoptosis and the subsequent development of rapidly progressive liver fibrosis. Although the responsible mechanisms remain unclear, it is likely that immunosuppressive drugs play an important role. It is well known that immunosuppressants impair immune control of HCV, thereby allowing increased viral replication. However there is also evidence that immunosuppressants may directly induce apoptosis and this may be facilitated by the presence of high levels of HCV replication. Thus HCV and immunosuppressants may synergistically interact to further enhance apoptosis and drive more rapid fibrosis. These findings suggest that modulation of apoptosis within the liver either by changing immunosuppressive therapy or the use of apoptosis inhibitors may help prevent fibrosis progression in patients with post-transplant HCV disease.
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22
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Yosry A, Said M, Esmat G, Al-Serafy M, Omar A, Doss W, Omran D, Saad Y, Kamel S, Abdel-Bary A, Hatata Y, Hosny A. HLA tissue typing has no effect on the outcome of patients undergoing a living-donor liver transplant: a single-center experience in Egypt. EXP CLIN TRANSPLANT 2012; 10:136-40. [PMID: 22432757 DOI: 10.6002/ect.2011.0066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES To analyze the effect of human leukocyte antigen tissue typing on outcome of live-donor liver transplant. MATERIALS AND METHODS Fifty recipients underwent live-donor liver transplant in the Dar Al-Fouad Hospital in Egypt and were retrospectively evaluated. Patients were classified into 2 groups: those with human leukocyte antigen +ve, and those with human leukocyte antigen -ve and donors. Hepatitis C virus-related end-stage liver disease was the main indication for transplant. Demographic data, preoperative laboratory data, results of human leukocyte antigen tissue typing, Child score, model for end-stage liver disease score, graft/recipient weight-ratio, ischemia times, surgical complications, postoperative laboratory data, liver biopsy, immunosuppression, and pulse steroids were collected. Graft and patient survivals were studied using Kaplan-Meier curves. RESULTS The mean model end-stage liver disease score was 18 ± 3.61 in group 1 and 17.73 ± 3.72 in group 2, with no significant difference. Graft/recipient weight ratio, ischemia times, and postoperative complications showed P = NS. Cyclosporine and tacrolimus were used in 5/9, 8/41, and 4/9 in group 1, and 32/41 in group 2 (P = NS). Rejection and pulse steroids were reported in 3/9 and 12/41 of group 1, and 3/12 and 11/41 of group 2 (P = NS). Hepatitis C virus-recurrence was diagnosed in 5/9 of patients (55%) and 8/41 of patients (29.5%) in groups 1 and 2 (P < .05). No statistical difference was found regarding mortality; 5-year patient and graft survival was 35/50 (70% in group 1 [human leukocyte antigen +ve]), 7/9 (77.8%), and 28/41 in group 2 (68.3%) (human leukocyte antigen -ve). CONCLUSIONS Positive human leukocyte antigen typing before live-donor liver transplant has no effect on the incidence of postoperative complications, rejection episodes, and patient or graft survival. Recipients with positive human leukocyte antigen typing may have increased risk of hepatitis C virus-recurrence after live-donor liver transplant.
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Affiliation(s)
- Ayman Yosry
- Department of Endemic Medicine and Hepatology, Cairo University, Giza, Egypt
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McKenna GJ, Trotter JF, Klintmalm E, Onaca N, Ruiz R, Jennings LW, Neri M, O'Leary JG, Davis GL, Levy MF, Goldstein RM, Klintmalm GB. Limiting hepatitis C virus progression in liver transplant recipients using sirolimus-based immunosuppression. Am J Transplant 2011; 11:2379-87. [PMID: 21967703 DOI: 10.1111/j.1600-6143.2011.03767.x] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Hepatitis C virus (HCV) causes progressive liver fibrosis in liver transplant recipients and is the principal cause of long-term allograft failure. The antifibrotic effects of sirolimus are seen in animal models but have not been described in liver transplant recipients. We reviewed 1274 liver recipients from 2002 to 2010 and identified a cohort of HCV recipients exposed to sirolimus as primary immunosuppression (SRL Cohort) and an HCV Control Group of recipients who had never received sirolimus. Yearly protocol biopsies were done recording fibrosis stage (METAVIR score) with biopsy compliance of >80% at both year one and two. In an intent-to-treat analysis, the SRL Cohort had significantly less advanced fibrosis (stage ≥2) compared to the HCV Control Group at year one (15.3% vs. 36.2%, p < 0.0001) and year two (30.1% vs. 50.5%, p = 0.001). Because sirolimus is sometimes discontinued for side effects, the SRL Cohort was subgroup stratified for sirolimus duration, showing progressively less fibrosis with longer sirolimus duration. Multivariate analysis demonstrated sirolimus as an independent predictor of minimal fibrosis at year one, and year two. This is the first study among liver transplant recipients with recurrent HCV to describe the positive impact of sirolimus in respect of reduced fibrosis extent and rate of progression.
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Affiliation(s)
- G J McKenna
- Surgery Medicine, Baylor Transplant Institute, Baylor University Medical Center, Dallas, TX, USA.
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24
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Distinctive gene expression profiles characterize donor biopsies from HCV-positive kidney donors. Transplantation 2011; 90:1172-9. [PMID: 20935597 DOI: 10.1097/tp.0b013e3181f9ca6c] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Because of the shortage of organs for transplantation, procurement of kidneys from extended criteria donors is inevitable. Frequently, donors infected with hepatitis C virus (HCV) are used. To elucidate an initial compromise of molecular pathways in HCV graft, gene expression profiles were evaluated. METHODS Twenty-four donor allograft biopsies (n=12 HCV positive (+) and n=12 HCV negative (-)) were collected at preimplantation time and profiled using microarrays. Donors were age, race, gender, and cold and warm ischemia time matched between groups. Probe level data were read into the R programming environment using the affy Bioconductor package, and the robust multiarray average method was used to obtain probe set expression summaries. To identify probe sets exhibiting differential expression, a two sample t test was performed. Molecular and biologic functions were analyzed using Interaction Networks and Functional Analysis. RESULTS Fifty-eight probe sets were differentially expressed between HCV (+) versus HCV (-) donors (P<0.001). The molecular functions associated with the two top scored networks from the analysis of the differentially expressed genes were connective tissue development and function and tissue morphology (score 34), cell death, cell signaling, cellular assembly, and organization (score 32). Among the differentially affected top canonical pathways, we found the role of RIG1-like receptors in antiviral innate immunity (P<0.001), natural killer cell signaling (P=0.007), interleukin-8 signaling (P=0.048), interferon signaling (P=0.0 11; INFA21, INFGR1, and MED14), ILK signaling (P=0.001), and apoptosis signaling. CONCLUSIONS A unique gene expression pattern was identified in HCV (+) kidney grafts. Innate immune system and inflammatory pathways were the most affected.
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Gutierrez JA, Klepper AL, Garber J, Walewski JL, Bateman K, Khaitova V, Syder A, Tscherne DM, Gauthier A, Jefferson D, Rice CM, Schiano TD, Branch AD. Cross-genotypic polyclonal anti-HCV antibodies from human ascitic fluid. J Virol Methods 2011; 171:169-75. [PMID: 21034775 PMCID: PMC3018694 DOI: 10.1016/j.jviromet.2010.10.020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2010] [Revised: 10/17/2010] [Accepted: 10/19/2010] [Indexed: 12/31/2022]
Abstract
Many anti-HCV antibodies are available, but more are needed for research and clinical applications. This study examines whether ascitic fluid from cirrhotic patients could be a source of reagent-grade antibodies. Ascitic fluid from 29 HCV patients was screened by ELISA for anti-HCV antibodies against three viral proteins: core, NS4B, and NS5A. Significant patient-to-patient variability in anti-HCV antibody titers was observed. Total ascitic fluid IgG purified by Protein-A chromatography reacted with HCV proteins in immunoblots, cell extracts, and replicon-expressing cells. Affinity-purification using synthetic peptides as bait allowed the preparation of cross-genotypic antibodies directed against pre-selected regions of HCV core, NS4B, and NS5A proteins. The performance of the polyclonal antibodies was comparable to that of monoclonal antibodies. Anti-NS4B antibody preparations reacted with genotype 1a, 1b, and 2a NS4B proteins in immunoblots and allowed NS4B to be localized in replicon-expressing cells. Ascitic fluid is an abundant source of human polyclonal cross-genotypic antibodies that can be used as an alternative to blood. This study shows the utility of selectively purifying human polyclonal antibodies from ascitic fluid. Affinity purification allows antibodies to be selected that are comparable to monoclonal antibodies in their ability to react with targeted regions of viral proteins.
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Affiliation(s)
- Julio A Gutierrez
- Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY 10029, USA
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26
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Rowe IA, Barber KM, Birch R, Curnow E, Neuberger JM. Retransplantation for graft failure in chronic hepatitis C infection: a good use of a scarce resource? World J Gastroenterol 2010; 16:5070-6. [PMID: 20976844 PMCID: PMC2965284 DOI: 10.3748/wjg.v16.i40.5070] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2010] [Revised: 06/16/2010] [Accepted: 06/23/2010] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the outcome of patients with hepatitis C virus (HCV) infection undergoing liver retransplantation. METHODS Using the UK National Registry, patients undergoing liver transplantation for HCV-related liver disease were identified. Data on patient and graft characteristics, as well as transplant and graft survival were collected to determine the outcome of HCV patients undergoing retransplantation and in order to identify factors associated with transplant survival. RESULTS Between March 1994 and December 2007, 944 adult patients were transplanted for HCV-related liver disease. At the end of follow-up, 617 of these patients were alive. In total, 194 (21%) patients had first graft failure and of these, 80 underwent liver retransplantation, including 34 patients where the first graft failed due to recurrent disease. For those transplanted for HCV-related disease, the 5-year graft survival in those retransplanted for recurrent HCV was 45% [95% confidence interval (CI): 24%-64%] compared with 80% (95% CI: 62%-90%) for those retransplanted for other indications (P = 0.01 log-rank test); the 5-year transplant survival after retransplantation was 43% (95% CI: 23%-62%) and 46% (95% CI: 31%-60%), respectively (P = 0.8, log-rank test). In univariate analysis of all patients retransplanted, no factor analyzed was significantly associated with transplant survival. CONCLUSION Outcomes for retransplantation in patients with HCV infection approach agreed criteria for minimum transplant benefit. These data support selective liver retransplantation in patients with HCV infection.
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27
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Takada Y, Ozawa K, Egawa H, Teramukai S, Mori A, Kaido T, Kasahara M, Ogawa K, Ono M, Sato H, Tanaka K, Uemoto S. Initial burst of viremia related to CD8 effector memory T cells after living donor liver transplantation in hepatitis C virus-infected recipients. Transl Res 2010; 156:68-79. [PMID: 20627191 DOI: 10.1016/j.trsl.2010.06.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2009] [Revised: 06/06/2010] [Accepted: 06/08/2010] [Indexed: 10/19/2022]
Abstract
The post-transplant immune responses, viremia, and allograft histology after living donor liver transplantation were studied in 39 hepatitis C virus (HCV)-infected recipients. The recipients were classified into the following groups according to a hierarchical clustering of their preoperative CD8CD45 T-cell isoforms: group I, naive-dominant; group II, effector memory-dominant; and group III, effector-dominant. Plasma HCV-RNA rapidly increased and then peaked as an initial burst around postoperative day (POD) 25 in group I, on POD 40 in group II, and on POD 55 in group III. The initial burst of viremia was suppressed by the high expression of CD8+CD28-CD27- subsets. The progression of fibrosis > or =F2 was significantly more frequent for those patients with the highest viremia levels. Moreover, the initial T-cell immune response became less important throughout time, and new immune responses emerged after 2 months that modified the host-virus interaction. It is suggested that the interferon (IFN)-alpha/ribavirin therapy starting 2 months may be an effective option and now is undertaken.
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Affiliation(s)
- Yasutsugu Takada
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Simonin Y, Disson O, Lerat H, Antoine E, Binamé F, Rosenberg AR, Desagher S, Lassus P, Bioulac-Sage P, Hibner U. Calpain activation by hepatitis C virus proteins inhibits the extrinsic apoptotic signaling pathway. Hepatology 2009; 50:1370-9. [PMID: 19711428 DOI: 10.1002/hep.23169] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
UNLABELLED An unresolved question regarding the physiopathology of hepatitis C virus (HCV) infection is the remarkable efficiency with which host defenses are neutralized to establish chronic infection. Modulation of an apoptotic response is one strategy used by viruses to escape immune surveillance. We previously showed that HCV proteins down-regulate expression of BH3-only Bcl2 interacting domain (Bid) in hepatocytes of HCV transgenic mice. As a consequence, cells acquire resistance to Fas-mediated apoptosis, which in turn leads to increased persistence of experimental viral infections in vivo. This mechanism might participate in the establishment of chronic infections and the resulting pathologies, including hepatocellular carcinoma. We now report that Bid is also down-regulated in patients in the context of noncirrhotic HCV-linked tumorigenesis and in the HCV RNA replicon system. We show that the nonstructural HCV viral protein NS5A is sufficient to activate a calpain cysteine protease, leading to degradation of Bid. Moreover, pharmacological inhibitors of calpains restore both the physiological levels of Bid and the sensitivity of cells toward a death receptor-mediated apoptotic signal. Finally, human HCV-related tumors and hepatocytes from HCV transgenic mice that display low Bid expression contain activated calpains. CONCLUSION Calpains activated by HCV proteins degrade Bid and thus dampen apoptotic signaling. These results suggest that inhibiting calpains could lead to an improved efficiency of immune-mediated elimination of HCV-infected cells.
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Affiliation(s)
- Yannick Simonin
- Centre National de la Recherche Scientifique (CNRS), UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France
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29
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Hughes MG, Rosen HR. Human liver transplantation as a model to study hepatitis C virus pathogenesis. Liver Transpl 2009; 15:1395-411. [PMID: 19877210 PMCID: PMC2954677 DOI: 10.1002/lt.21866] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Hepatitis C is a leading etiology of liver cancer and a leading reason for liver transplantation. Although new therapies have improved the rates of sustained response, a large proportion of patients (approximately 50%) fail to respond to antiviral treatment, thus remaining at risk for disease progression. Although chimpanzees have been used to study hepatitis C virus biology and treatments, their cost is quite high, and their use is strictly regulated; indeed, the National Institutes of Health no longer supports the breeding of chimpanzees for study. The development of hepatitis C virus therapies has been hindered by the relative paucity of small animal models for studying hepatitis C virus pathogenesis. This review presents the strengths of human liver transplantation and highlights the advances derived from this model, including insights into viral kinetics and quasispecies, viral receptor binding and entry, and innate and adaptive immunity. Moreover, consideration is given to current and emerging antiviral therapeutic approaches based on translational research results.
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Affiliation(s)
- Michael G. Hughes
- Department of Surgery, Medical University of South Carolina, Charleston, SC
| | - Hugo R. Rosen
- Department of Medicine, Divisions of Gastroenterology & Hepatology and Liver Transplantation; University of Colorado Health Sciences Center & National Jewish Hospital, and Denver VA
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Ferri S, Muratori L, Quarneti C, Muratori P, Menichella R, Pappas G, Granito A, Ballardini G, Bianchi FB, Lenzi M. Clinical features and effect of antiviral therapy on anti-liver/kidney microsomal antibody type 1 positive chronic hepatitis C. J Hepatol 2009; 50:1093-1101. [PMID: 19398235 DOI: 10.1016/j.jhep.2009.02.020] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2008] [Revised: 01/31/2009] [Accepted: 02/03/2009] [Indexed: 12/11/2022]
Abstract
BACKGROUND/AIMS Anti-liver/kidney microsomal antibody type 1 (anti-LKM1), a serological marker of type 2 autoimmune hepatitis, is also detected in a small proportion of patients with hepatitis C. This study aimed to evaluate clinical features and effect of antiviral therapy in patients with hepatitis C who are anti-LKM1 positive. METHODS Sixty consecutive anti-LKM1 positive and 120 age and sex-matched anti-LKM1 negative chronic hepatitis C patients were assessed at diagnosis and during follow-up. Of these, 26 anti-LKM1 positive and 72 anti-LKM1 negative received antiviral therapy. Anti-LKM1 was detected by indirect immunofluorescence and immunoblot. Number of HCV-infected hepatocytes and intrahepatic CD8+ lymphocytes was determined by immunohistochemistry. RESULTS At diagnosis anti-LKM1 positive patients had higher IgG levels and more intrahepatic CD8+ lymphocytes (p 0.022 and 0.046, respectively). Viral genotypes distribution and response to therapy were identical. Hepatic flares during antiviral treatment only occurred in a minority of patients in concomitance with anti-LKM1 positivity. CONCLUSIONS Immune system activation is more pronounced in anti-LKM1 positive patients with hepatitis C, possibly representing the expression of autoimmune mechanisms of liver damage. Antiviral treatment is as beneficial in these patients as in anti-LKM1 negative patients, and the rare necroinflammatory flares are effectively controlled by corticosteroids, allowing subsequent resumption of antiviral therapy.
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Affiliation(s)
- Silvia Ferri
- Department of Clinical Medicine, University of Bologna, S. Orsola-Malpighi Hospital, Via Massarenti 9, 40138 Bologna, Italy.
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Molecular and cellular aspects of hepatitis C virus reinfection after liver transplantation: how the early phase impacts on outcomes. Transplantation 2009; 87:1105-11. [PMID: 19384153 DOI: 10.1097/tp.0b013e31819dfa83] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatitis C virus (HCV)-related liver disease postliver transplantation is associated with an accelerated course in comparison with that observed in the nonimmunosuppressed individual. Outcomes in transplantation for this indication have, therefore, been a major area of clinical interest in the field of liver transplantation. The factors underlying the rapid progression of HCV-related liver disease posttransplantation are complex and multifactorial. Nevertheless, recent data indicate a range of parameters assessable early posttransplantation that may be useful in the prediction of outcome of transplantation for this condition. This overview, therefore, concentrates on the early events occurring postliver transplantation in the HCV-infected patient, and the implications of these recent observations for the pathogenesis of the various forms of HCV-related allograft injury.
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Abstract
Recurrent hepatitis C after liver transplantation is a universal phenomenon. Graft reinfection occurs rapidly; once it is established, allograft cirrhosis and decompensation rapidly ensue in many patients. Treatment with pegylated interferon plus ribavirin is the standard of care among nontransplant patients with hepatitis C; however, the applicability of these therapies in liver transplant patients is severely limited. Before transplantation, many patients are simply too ill to endure the long treatment duration necessary to achieve viral eradication; thus, treatment-related toxicity is a frequent barrier to success. Clinical trials in the pretransplantation population have yielded poor outcomes, with sustained virologic response rates only as high as 25%. Early after transplantation, treatment may be initiated prophylactically, or it may be initiated therapeutically in patients with evidence of recurrent disease. In small studies, prophylactic therapy has been associated with sustained virologic response rates lower than 20%, whereas in therapeutic intervention studies, sustained virologic response rates have ranged from 20% to 37%. In the setting of therapeutic intervention, preliminary indications suggest that rapid and early virologic response may become important clinical tools enabling the early identification of patients likely to respond to treatment. Two important clinical trials, PHOENIX (Pegasys and Copegus Administered After Liver Transplantation for Hepatitis C) in the prophylactic setting and PROTECT (Pegylated Interferon Alpha-2b and Ribavirin After Orthotopic Liver Transplantation: Efficacy and Safety in Hepatitis C Recurrence Therapy) in the therapeutic setting, are under way and should further advance our understanding of the management of hepatitis C in patients undergoing liver transplantation.
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Fujimoto M, Ichikawa T, Nakao K, Miyaaki H, Shibata H, Eguchi S, Takatsuki M, Nagaoka S, Yatsuhashi H, Kanematsu T, Eguchi K. The significance of enzyme immunoassay for the assessment of hepatitis B virus core-related antigen following liver transplantation. Intern Med 2009; 48:1577-83. [PMID: 19755758 DOI: 10.2169/internalmedicine.48.2000] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
PURPOSE Recently, a new enzyme immunoassay for the detection of hepatitis B virus (HBV) core-related antigen (HBcrAg) has been reported. In this study, we proposed to account for feasibility of HBcrAg assay, and discuss the dynamics of HBV seen in patients following HBV-related living donor liver transplantation (LDLT). METHODS AND RESULTS This study involved 12 patients; 11 patients had positive serum HBcrAg, and 6 patients had negative HBV-DNA. In the post-operation period, all cases were negative for HBV-DNA and HBsAg in sera under prophylaxis therapy. At post-operation, 5 of the 12 had positive serum HBcrAg, and at stable state, 6 had positive serum HBcrAg postoperatively. The mean levels of HBcrAg following LDLT were significantly lower than those seen in the preoperative-operation stage. CONCLUSION This enzyme immunoassay is a readily utilizable marker of HBV replication in the post transplantation stage. Furthermore, the evaluation of HBV activity by HBcrAg assay must be studied to determine the appropriate prophylaxis for controlling replication of HBV following LDLT.
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Affiliation(s)
- Masumi Fujimoto
- The First Department of Internal Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
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34
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Abstract
1. Liver failure and liver cancer from chronic hepatitis C are the most common indications for liver transplantation and numbers of both are projected to double over the next 20 years. 2. Recurrent hepatitis C infection of the allograft is universal and immediate following liver transplantation and associated with accelerated progression to cirrhosis, graft loss and death. 3. Graft and patient survival is reduced in liver transplant recipients with recurrent HCV infection compared to HCV-negative recipients. 4. The natural history of chronic hepatitis C is accelerated following liver transplantation compared C, with 20% progressing to cirrhosis by 5 years. However, the rate of fibrosis progression is not uniform and may increase over time. 5. The rates of progression from cirrhosis to decompensation and from decompensation to death are also accelerated following liver transplantation. 6. Multiple host, donor and viral factors are associated with rapid fibrosis progression and HCV-related graft failure. 7. Over the last decade, graft and patient survival rates have improved following liver transplantation for non-HCV disease but not for HCV-cirrhosis. This may reflect worsening donor quality and changes in immunosuppression strategies over recent years. 8. Viral eradication by antiviral therapy prevents disease progression and improves survival. 9. The severity of recurrent hepatitis C at one year post-transplant predicts subsequent progression to cirrhosis. Annual protocol biopsies are recommended to help determine need for antiviral therapy. 10. The projected impact of recurrent hepatitis C on graft and patient survival can only be avoided by the development of safe and effective antiviral strategies which can both prevent initial graft infection and eradicate established hepatitis C recurrence.
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Affiliation(s)
- Edward J Gane
- New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand.
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Pessôa MG, Alves VAF, Wakamatsu A, Gomes JG, Maertens G, van der Borght B, Kim M, Ferrell L, Wright TL. Post-transplant recurrent hepatitis C: immunohistochemical detection of hepatitis C virus core antigen and possible pathogenic implications. Liver Int 2008; 28:807-13. [PMID: 18422936 DOI: 10.1111/j.1478-3231.2008.01739.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
INTRODUCTION The mechanisms by which severe cholestatic hepatitis develops after liver transplantation are not fully understood. Reports on immunohistochemical distribution of hepatitis C virus (HCV) antigens are still scarce, but recently, HCV immunostaining was suggested for early diagnosis of cholestatic forms of recurrent hepatitis C in liver grafts. After purification, Rb246 pab anticore (aa1-68) yielded specific, granular cytoplasmic staining in hepatocytes. Signal amplification through the Envision-Alkaline Phosphatase System avoided endogenous biotin and peroxidase. AIMS/METHODS Rb246 was applied to liver samples of explants of 12 transplant recipients, six with the most severe form of post-transplantation recurrence, severe cholestatic hepatitis (group 1) and six with mild recurrence (group 2). We also assessed immuno-reactivity at two time-points post-transplantation (median 4 and 22 months) in both groups. HCV-core Ag was semiquantified from 0 to 3+ in each time point. Serum HCV-RNA was also measured on the different time points by branched DNA. RESULTS In the early post-transplant time point, one patient had a mild staining (1+), two patients had a moderate staining (2+) and the other three had no staining in group 1, compared with five patients with no staining (0) and one patient with mild staining (1+) in group 2. Late post-transplant liver samples were available in nine patients, and two out of four samples in group 1 showed a mild staining, compared with no staining patients in five patients in group 2. Strikingly, on the explant samples, HCV immunostaining was strongly positive in group 1, and mildly positive in group 2. Two out of five samples showed 3+ staining, and three samples showed 2+ staining in group 1; two out of five samples showed no staining, two samples showed 1+ staining and one sample showed 2+ staining in group 2. Serum HCV-RNA was significantly higher in group 1, on both time-points post-transplantation. HCV-core Ag was not directly associated with serum HCV-RNA on the different time points. CONCLUSION These preliminary results suggest that strong HCV immunostaining in the explant is predictive of more severe disease recurrence.
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Affiliation(s)
- Mário G Pessôa
- Department of Pathology, São Paulo University School of Medicine, São Paulo, Brazil.
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36
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D'Errico-Grigioni A, Fiorentino M, Vasuri F, Gruppioni E, Fabbrizio B, Zucchini N, Ballardini G, Morelli C, Pinna AD, Grigioni WF. Tissue hepatitis C virus RNA quantification and protein expression help identify early hepatitis C virus recurrence after liver transplantation. Liver Transpl 2008; 14:313-20. [PMID: 18306349 DOI: 10.1002/lt.21375] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
We compared tissue hepatitis C virus (HCV) RNA polymerase chain reaction quantification and HCV immunohistochemistry (IHC) to histology in biopsy tissues in order to differentiate between acute rejection and HCV hepatitis recurrence early after orthotopic liver transplantation (OLT). We analyzed the first biopsy performed because of alteration of serum aminotransferases in 65 consecutive OLT patients with HCV genotype 1b. In the histological analysis, we quantified the portal tracts, Councilman bodies, Councilman body/portal tract (CP) ratio, steatosis, and Knodell and Ishak scores. The 52 patients (80%) with histological HCV recurrence [recurrence-positive (Rec+)] were separated from the 6 (9%) with acute rejection and the 7 (11%) with undetermined pathological features [recurrence-negative (Rec-)]. HCV RNA strongly correlated with HCV IHC, regardless of the histological diagnosis (P < 0.001). Both HCV RNA and HCV IHC were significantly associated with CP ratio (P = 0.041 and P = 0.008). No statistical correlation was found between HCV RNA, HCV IHC, and the other histopathologic features or the hepatitis scores. HCV RNA, HCV IHC, and CP ratio were the only variables able to discriminate between Rec+ and Rec- patients (Mann-Whitney test P < 0.001, P < 0.001, P = 0.014). In conclusion, a combined evaluation of histology, tissue HCV RNA, and HCV IHC significantly discriminated between OLT patients with or without HCV recurrence.
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Fishman SL, Murray JM, Eng FJ, Walewski JL, Morgello S, Branch AD. Molecular and bioinformatic evidence of hepatitis C virus evolution in brain. J Infect Dis 2008; 197:597-607. [PMID: 18275278 PMCID: PMC2736634 DOI: 10.1086/526519] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Neurocognitive deficits in patients with hepatitis C virus (HCV) infection prompted a search for HCV in brain. RESULTS HCV was present in the brains of 7 (54%) of 13 patients with viremia, as determined by 5' UTR and E1 (envelope 1) gene analysis. Brain HCV RNA consensus sequences differed from those in plasma and liver in 4 (57%) of 7 patients. The quality of HCV RNA from postmortem brain and liver was assessed and demonstrated to be suitable for sequence analysis. Quasispecies analysis revealed that several mutations present in clones from >1 brain region were absent in clones from liver and plasma. Brain-specific mutations defined several families of related sequences. The patterns of brain-specific mutations in these families were consistent with the evolution of HCV RNA from a common ancestor. Single-nucleotide-polymorphism analysis confirmed that a prominent brain-specific mutation constituted approximately 10% of HCV RNA in cerebellum and medulla but that this mutation was undetectable in the liver and plasma of the same patient. CONCLUSIONS This study introduces novel methods for assessing RNA from postmortem samples. It increases the reported cases of HCV in the brain, provides the first E1 sequences from the brain, and contributes to the growing evidence that HCV replicates and evolves within the brain.
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Affiliation(s)
- Sarah L Fishman
- Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA
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Neff GW, Kemmer N, Kaiser T, Zacharias V, Majoras N, Safdar K. Outcomes in adult and pediatric liver transplantation among various ethnic groups. Transplant Proc 2007; 39:3204-6. [PMID: 18089354 DOI: 10.1016/j.transproceed.2007.09.031] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2007] [Accepted: 09/02/2007] [Indexed: 10/22/2022]
Abstract
BACKGROUND The reported patient and graft survivals among adults post-orthotopic liver transplantation (OLT) are variable, with an apparent discrepancy between ethnic groups. The aim of this study was to evaluate the impact of ethnicity on patient and graft survivals among adult and pediatric patients. METHODS A retrospective analysis from the UNOS/OPTN databank between January 1995 and December 2006 was performed on adult and pediatric liver transplant recipients. Patients were divided into 4 groups based on ethnicity: African Americans, Hispanic, Caucasians, and other. Kaplan-Meier (KM) analysis was used to calculate patient and graft survival. Log-rank tests were used to compare survival rates between groups. RESULTS In our study 42,710 OLT patients were included in the analysis, 90% of whom were adults. Of the 38,639 adult recipients, 29,432 (76.1%) were Caucasian, 4369 (11.3%) were Hispanic, 2963 (7.7%) were African American, and the remaining 1875 (4.9%) were of other ethnicities. KM estimates and Cox regression analyses demonstrated that there was a significant ethnic difference in both patient and graft survivals at 1, 3, 5, and 10 years. African Americans showed a lower rate (P<.001). Of the 4341 pediatric recipients, 2461 (56.7%) were Caucasian, 797 (18.4%) were Hispanic, 824 (18.9%) were African American, and the remaining 259 (5.9%) were of other ethnicities. Unlike the adults, there were no significant differences among ethnic groups in terms of patient (P=.31) and graft (P=.33) survival at 1, 3, 5, and 10 years after OLT. CONCLUSION These results showed that adult African American OLT patients have a reduced transplantation rate and a worse survival rate when compared with other ethnicities in the adult but not in the pediatric population. This information suggests that further studies are indicated to identify the causes of racial differences in transplant access and outcomes in the adult patient population.
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Affiliation(s)
- G W Neff
- Department of Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0595, USA
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Sharma P, Marrero JA, Fontana RJ, Greenson JK, Conjeevaram H, Su GL, Askari F, Sullivan P, Lok AS. Sustained virologic response to therapy of recurrent hepatitis C after liver transplantation is related to early virologic response and dose adherence. Liver Transpl 2007; 13:1100-8. [PMID: 17377914 DOI: 10.1002/lt.21121] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Sustained virologic response (SVR) after antiviral therapy for recurrent hepatitis C virus (HCV) infection in liver transplant (LT) recipients is consistently lower than that achieved in non-LT patients. We evaluated efficacy and safety of pegylated interferon (IFN) and ribavirin (RBV) therapy in LT recipients with recurrent HCV and factors associated with SVR. All subjects with histologic evidence of recurrent HCV were intended to be treated for 48 weeks with full-dose pegylated IFN; target dose of RBV was 800 mg/day. Thirty-five LT recipients with recurrent HCV, median age 48.5 years, 77% genotype 1, and median pretreatment HCV RNA 6.4 log10 IU/mL were treated between January 2000 and February 2006. Antiviral therapy was discontinued prematurely in 15 subjects as a result of adverse events. Median overall treatment duration was 46 weeks. Early virologic response at week 12 was seen in 17 (49%) and an end-of-treatment virological response in 19 (54%) patients. SVR was achieved in 13 patients (37%), and all 9 patients followed for >1 year after treatment had durable response. Patients with SVR had significantly lower pretreatment HCV RNA (5.7 vs. 6.5 log10 IU/mL, P=0.003), more likely to have a week 12 virological response (85% vs. 27%, P=0.0009) and received higher cumulative doses of pegylated IFN (75% vs. 33%, P=0.029) and RBV (90% vs. 26%, P=0.016) compared with patients whose disease did not respond to therapy. In conclusion, SVR was achieved in 37% of patients with recurrent hepatitis C after LT. Similar to non-LT patients, those with lower pretreatment HCV RNA, a week 12 virological response, and pegylated IFN and RBV dose adherence were more likely to achieve SVR.
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Affiliation(s)
- Pratima Sharma
- University of Michigan Health Systems, Division of Gastroenterology and Department of Pathology, Ann Arbor, MI 48109-0362, USA
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40
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Funk GA, Gosert R, Hirsch HH. Viral dynamics in transplant patients: implications for disease. THE LANCET. INFECTIOUS DISEASES 2007; 7:460-72. [PMID: 17597570 DOI: 10.1016/s1473-3099(07)70159-7] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Viral infections cause substantial morbidity and mortality in transplant patients. Quantifying viral loads is widely appreciated as a direct means to diagnose and monitor the course of viral infections. Recent studies indicate that the kinetics of viral load changes rather than single viral load measurements better correlate with organ involvement. In this Review, we will summarise the current knowledge regarding the kinetics of viruses relevant to transplantation including cytomegalovirus, Epstein-Barr virus, the herpes viruses 6 and 7, hepatitis C virus, GB virus C, adenovirus, and the emerging human polyomavirus type BK. We discuss the implications of viral kinetics for organ pathology as well as for the evaluation of antiviral interventions in transplant patients.
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Affiliation(s)
- Georg A Funk
- Transplantation Virology, Institute for Medical Microbiology, University of Basel, Basel, Switzerland
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41
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McCaughan GW, Omata M, Amarapurkar D, Bowden S, Chow WC, Chutaputti A, Dore G, Gane E, Guan R, Hamid SS, Hardikar W, Hui CK, Jafri W, Jia JD, Lai MY, Wei L, Leung N, Piratvisuth T, Sarin S, Sollano J, Tateishi R. Asian Pacific Association for the Study of the Liver consensus statements on the diagnosis, management and treatment of hepatitis C virus infection. J Gastroenterol Hepatol 2007; 22:615-33. [PMID: 17444847 DOI: 10.1111/j.1440-1746.2007.04883.x] [Citation(s) in RCA: 119] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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42
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Sprinzl MF, Otto G, Galle PR, Schuchmann M. Hepatitis C virus re-infection: new perspectives. Clin Transplant 2007; 20 Suppl 17:117-23. [PMID: 17100711 DOI: 10.1111/j.1399-0012.2006.00610.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Hepatitis C virus (HCV) re-infection of the liver graft has been recognized to be one of the most important factors that determines prognosis and outcome after liver transplantation in HCV-positive patients. Graft loss due to recurrent HCV re-cirrhosis and subsequent hepatic decompensation, which is the predominant cause of death among transplant recipients, reflects the prognostic significance of HCV re-infection. Despite better overall outcome after liver transplantation, the prognosis of HCV-infected patients has not improved during the last two decades. Recent data suggest that increased liver donor age and intensified immunosuppression of transplant patients are the most important contributors to this situation. Other prognostic factors need further confirmation to stratify risk constellations. As HCV cirrhosis has also become the leading indication for orthotopic liver transplantation, the therapeutic management of HCV re-infection is a central issue of liver transplantation. The antiviral approaches based on interferon (IFN) alpha and ribavirin combinations are still hampered by high toxicity and low efficacy. Sustained viral response rates are still as low as approximately 10-30% and further prospective clinical trials are mandatory to identify the best time point and schedule of antiviral treatment in transplant patients.
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Affiliation(s)
- Martin F Sprinzl
- Department of Internal Medicine, Johannes Gutenberg University Mainz, Mainz, Germany
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43
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Hepatitis C virus in liver transplantation: impact and treatment of hepatitis C virus recurrence. Curr Opin Organ Transplant 2006. [DOI: 10.1097/mot.0b013e3280106c3d] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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44
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Grassi A, Quarneti C, Ravaioli M, Bianchini F, Susca M, D'Errico A, Piscaglia F, Tamè MR, Andreone P, Grazi G, Galli S, Zauli D, Pinna AD, Bianchi FB, Ballardini G. Detection of HCV antigens in liver graft: relevance to the management of recurrent post-liver transplant hepatitis C. Liver Transpl 2006; 12:1673-1681. [PMID: 17031825 DOI: 10.1002/lt.20882] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
The aim of this study was to evaluate how the immunohistochemical detection of liver hepatitis C virus (HCV) antigens (HCV-Ag) could support the histologic diagnosis and influence the clinical management of post-liver transplantation (LT) liver disease. A total of 215 liver specimens from 152 HCV-positive patients with post-LT liver disease were studied. Histologic coding was: hepatitis (126), rejection (34), undefined (24; coexisting rejection grade I and hepatitis), or other (31). The percentage of HCV-Ag infected hepatocytes were evaluated, on frozen sections, by an immunoperoxidase technique. HCV-Ag were detectable early in 57% of cases within 30 days post-LT, 92% of cases between 31 and 180 days, and 74% of cases after more than 180 days. Overall, HCV-Ag were detected more frequently in histologic hepatitis as compared to rejection (P < 0.0001) with a higher percentage of positive hepatocytes (P < 0.00001). In 16 patients with a high number of HCV-Ag-positive hepatocytes (65%; range 40-90%) a clinical diagnosis of recurrent hepatitis (RHC) was made despite inconclusive histopathologic diagnosis. Multivariate analysis identified the percentage of HCV-Ag-positive hepatocytes and the time post-LT as independent predictors for RHC (P = 0.008 and P = 0.041, respectively) and the number of HCV-Ag-positive hepatocytes >/=50% as the only independent predictor for nonresponse (P < 0.001) in 26 patients treated with alpha-interferon plus ribavirin. In conclusion, HCV reinfection occurs early post-LT, reaching its peak within 6 months. Immunohistochemical detection of post-LT HCV reinfection support the diagnosis of hepatitis when the histologic features are not conclusive. A high number of infected cells, independently from the genotype, represents a negative predictive factor of response to antiviral treatment.
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Affiliation(s)
- Alberto Grassi
- Department of Internal Medicine, Cardioangiology, Hepatology, University of Bologna-Sant'Orsola-Malpighi Hospital, Bologna, Italy.
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45
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Minguela A, Miras M, Bermejo J, Sánchez-Bueno F, López-Alvarez MR, Moya-Quiles MR, Muro M, Ontañón J, Garía-Alonso AM, Parrilla P, Alvarez-López MR. HBV and HCV infections and acute rejection differentially modulate CD95 and CD28 expression on peripheral blood lymphocytes after liver transplantation. Hum Immunol 2006; 67:884-93. [PMID: 17145368 DOI: 10.1016/j.humimm.2006.06.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2005] [Revised: 06/20/2006] [Accepted: 06/29/2006] [Indexed: 12/21/2022]
Abstract
Hepatitis B virus (HBV) and hepatitis C virus (HCV) generally reinfect liver graft early posttransplantation and lead to poorer graft and patient survivals. In the present study the influence of acute rejection (AR), HBV and HCV infections, and human leukocyte antigen (HLA) class-I compatibility on the expression of CD28 (in 237 liver recipients) and CD95 (in 114 liver recipients) on peripheral blood cells were evaluated by flow cytometry during the first month after transplantation. HBV/HCV infections induced strong CD95 upregulation on CD3+ lymphocytes. Maximal CD95 upmodulation was found in infected recipients showing partial HLA class-I compatibility. AR and virus reinfection could be distinguished because CD28 was upregulated on CD4+ lymphocytes only in recipients with AR, irrespective of their status regarding HBV/HCV infections. In conclusion, cytometric co-evaluation of CD95 and CD28 expression on peripheral blood lymphocytes could be useful to discriminate AR from cellular activation induced by viral reinfection of the liver graft.
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Affiliation(s)
- Alfredo Minguela
- Immunology Services, Virgen de la Arrixaca University Hospital, Murcia, Spain.
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46
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Burra P, Targhetta S, Pevere S, Boninsegna S, Guido M, Canova D, Brolese A, Masier A, D'Aloiso C, Germani G, Tomat S, Fagiuoli S. Antiviral Therapy for Hepatitis C Virus Recurrence Following Liver Transplantation: Long-Term Results From a Single Center Experience. Transplant Proc 2006; 38:1127-30. [PMID: 16757285 DOI: 10.1016/j.transproceed.2006.02.135] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Hepatitis C virus (HCV) reinfection after liver transplantation is a virtually constant finding and leads to chronic hepatitis and cirrhosis in variable proportions. This study aimed to assess the safety and efficacy of alpha-interferon (IFN) plus ribavirin for recurrent HCV following liver transplantation. PATIENTS AND METHODS Thirty of 55 patients (54.5%) with histologically proven HCV recurrence after liver transplantation were given antiviral therapy (alpha-IFN at a dose of 6 MU x 3 x week IM associated with oral ribavirin 1 g/d for 12 months) and followed up for a further 12 months after the end of the treatment. Liver and renal function tests, hemocytometric values, and HCV-RNA were assessed every 3 months throughout the therapy and follow-up. Liver biopsy was performed before and after the treatment and after another 12 months of follow-up. RESULTS Eight patients (26.7%) were withdrawn from the treatment due to adverse events and another 8 (26.7%) needed a dosage reduction. Eleven patients (36.7%) had a biochemical and virological response, becoming aminotransferase and HCV-RNA negative at the end of the treatment; 6 patients (20%) still had a sustained response after 12 months of follow-up. All 6 patients are clinically stable at 6 years after completing the antiviral therapy. A low viral load before therapy was a positive predictor of sustained response. No histologically significant improvement was seen at the end of the therapy or after the follow-up. CONCLUSIONS The combination of alpha-IFN plus ribavirin induced a sustained virologic response in 20% of liver transplant recipients with recurrent HCV, but intolerance of the therapy prompted its discontinuation or a dosage reduction in a large proportion of patients. However, we have observed a long-term efficacy of the antiviral therapy in the sustained responders.
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Affiliation(s)
- P Burra
- Department of Surgical and Gastroenterological Sciences, University Hospital, Padova, Italy.
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47
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Langrehr JM, Puhl G, Bahra M, Schmeding M, Spinelli A, Berg T, Schönemann C, Krenn V, Neuhaus P, Neumann UP. Influence of donor/recipient HLA-matching on outcome and recurrence of hepatitis C after liver transplantation. Liver Transpl 2006; 12:644-51. [PMID: 16555324 DOI: 10.1002/lt.20648] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The aim of this study was to analyze the effect of human leukocyte antigen (HLA) matching on outcome, severity of recurrent hepatitis C and risk of rejection in hepatitis C positive patients after liver transplantation (LT). In a retrospective analysis, 165 liver transplants in patients positive for hepatitis C virus (HCV) with complete donor/recipient HLA typing were reviewed for recurrence of HCV and outcome. Follow-up ranged from 1 to 158 months (median, 74.5 months). Immunosuppression consisted of either cyclosporine-A- or tacrolimus-based quadruple induction therapy including or an interleukin 2-receptor antagonist. Protocol liver biopsies were performed after 1, 3, 5, 7, and 10 years and staged according to the Scheuer scoring system. The overall 1-, 5-, and 10-year graft survival figures were 81.8%, 69.11 and 62%, respectively. There was no correlation in the study population between number of HLA mismatches and graft survival. The number of rejection episodes increased significantly in patients with more HLA mismatches (P < 0.05). In contrast to this, the fibrosis progression was significantly faster in patients with 0-5 HLA mismatches compared to patients with a complete HLA mismatch. In conclusion, HLA matching did not influence graft survival in patients after LT for end-stage HCV infection, however, despite less rejection episodes, the fibrosis progression increased in patients with less HLA mismatches within the first year after LT.
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Affiliation(s)
- Jan Michael Langrehr
- Department of Surgery, Charité, Campus Virchow-Clinic, Humboldt University, Berlin, Germany.
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48
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Cescon M, Grazi GL, Grassi A, Ravaioli M, Vetrone G, Ercolani G, Varotti G, D'Errico A, Ballardini G, Pinna AD. Effect of ischemic preconditioning in whole liver transplantation from deceased donors. A pilot study. Liver Transpl 2006; 12:628-635. [PMID: 16555338 DOI: 10.1002/lt.20640] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The effect of ischemic preconditioning (IPC) in orthotopic liver transplantation (OLT) has not yet been clarified. We performed a pilot study to evaluate the effects of IPC in OLT by comparing the outcomes of recipients of grafts from deceased donors randomly assigned to receive (IPC+ group, n = 23) or not (IPC- group, n = 24) IPC (10-min ischemia + 15-min reperfusion). In 10 cases in the IPC+ group and in 12 in the IPC- group, the expression of inducible nitric oxide synthase (iNOS), neutrophil infiltration, and hepatocellular apoptosis were tested by immunohistochemistry in prereperfusion and postreperfusion biopsies. Median aspartate aminotransferase (AST) levels were lower in the IPC+ group vs. the IPC- group on postoperative days 1 and 2 (398 vs. 1,234 U/L, P = 0.002; and 283 vs. 685 U/L, P = 0.009). Alanine aminotransferases were lower in the IPC+ vs. the IPC- group on postoperative days 1, 2, and 3 (333 vs. 934 U/L, P = 0.016; 492 vs. 1,040 U/L, P = 0.008; and 386 vs. 735 U/L, P = 0.022). Bilirubin levels and prothrombin activity throughout the first 3 postoperative weeks, incidence of graft nonfunction and graft and patient survival rates were similar between groups. Prereperfusion and postreperfusion immunohistochemical parameters did not differ between groups. iNOS was higher postreperfusion vs. prereperfusion in the IPC- group (P = 0.008). Neutrophil infiltration was higher postreperfusion vs. prereperfusion in both groups (IPC+, P = 0.007; IPC-, P = 0.003). Prereperfusion and postreperfusion apoptosis was minimal in both groups. In conclusion, IPC reduced ischemia/reperfusion injury through a decrease of hepatocellular necrosis, but it showed no clinical benefits.
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Affiliation(s)
- Matteo Cescon
- Liver and Multiorgan Transplant Unit, Department of Surgery and Transplantation, University of Bologna, Bologna, Italy
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Powers KA, Ribeiro RM, Patel K, Pianko S, Nyberg L, Pockros P, Conrad AJ, McHutchison J, Perelson AS. Kinetics of hepatitis C virus reinfection after liver transplantation. Liver Transpl 2006; 12:207-16. [PMID: 16447184 DOI: 10.1002/lt.20572] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Improved understanding of hepatitis C virus (HCV) dynamics during and after liver transplantation can be useful in optimizing antiviral therapy in transplant recipients. We analyzed serum HCV ribonucleic acid (RNA) levels during and after cadaveric liver transplantation in 6 HCV patients. After removal of the liver and before the new liver started producing virions, HCV RNA levels dropped with an average half-life (t(1/2)) of 0.8 hours. Viral loads then continued to drop up to 23 hours postimplantation (t(1/2) = 3.4 hours), and began to rise (doubling-time = 2.0 days) as soon as 15 hours after the anhepatic phase. In 3 patients the viral load reached a plateau before rising, suggesting that a nonhepatic source supplied virions and balanced their intrinsic clearance. However, from the decline in viral load over the first 24 hours of the postanhepatic phase, we estimate that nonhepatic sources can at most correspond to 4% of total viral production, 96% of which occurs in the liver, even after we corrected for fluid exchanges during surgery. As the new liver was reinfected, production increased and viral load rose to a new steady state. Using nonlinear regression, we were able to fit the patients' HCV RNA data to a viral dynamic model and estimate the de novo infection rate (mean 1.5 x 10(-6) mL/virion/day), as well as the average percentage of hepatocytes infected at the posttransplantation steady state (19%). In conclusion, we have quantified liver reinfection dynamics in the absence of posttransplantation antiviral therapy. Our findings support the notion that early antiviral therapy may delay or prevent reinfection.
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Affiliation(s)
- Kimberly A Powers
- Theoretical Biology & Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545, USA
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Schiano TD, Gutierrez JA, Walewski JL, Fiel MI, Cheng B, Bodenheimer H, Thung SN, Chung RT, Schwartz ME, Bodian C, Branch AD. Accelerated hepatitis C virus kinetics but similar survival rates in recipients of liver grafts from living versus deceased donors. Hepatology 2005; 42:1420-8. [PMID: 16317672 DOI: 10.1002/hep.20947] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
This study tested the hypothesis that hepatitis C virus (HCV) RNA and core antigen levels rise more rapidly after liver transplantation (LT) in recipients of grafts from living donors (LD) versus deceased donors (DD). Eleven consecutive LD and 15 DD recipients were followed prospectively. Before LT, median HCV RNA levels were similar: 5.42 (LDLT) and 5.07 (DDLT) log(10) IU/mL (P = NS). During the first 7 hours after LT a trend toward a greater HCV RNA decrease in LDLT patients was seen, although they received fewer blood replacement products during surgery. HCV RNA levels rose more rapidly in LDLT patients between days 1 and 3 (P = .0059) and were higher in this group on days 2, 3, 4, and 5. Core antigen levels were significantly higher in LDLT patients on days 3 and 5, although they were similar before LT (P = NS). Alanine aminotransferase (ALT) values were higher among LDLT patients from 8 to 14 days and from 4 to 24 months. Two-year graft and patient survival were 73% for LDLT patients and 80% for DDLT patients (P = NS). In conclusion, viral load rose more rapidly in LD recipients and reached higher levels shortly after surgery. Greater ALT elevations were evident in the LDLT group, but survival rates were similar. The trend toward a greater initial viral load decrease in patients with LD grafts and the significantly sharper increase suggest that the liver plays a predominant role in both HCV clearance and replication.
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Affiliation(s)
- Thomas D Schiano
- The Recanati/Miller Transplantation Institute, The Mount Sinai Hospital, New York, NY, USA
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