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Xue W, Liu K, Qiu K, Shen Y, Pan Z, Hu P, Peng M, Chen M, Ren H. A systematic review with meta-analysis: Is ribavirin necessary in sofosbuvir-based direct-acting antiviral therapies for patients with HCV recurrence after liver transplantation? Int J Infect Dis 2019; 83:56-63. [PMID: 30959250 DOI: 10.1016/j.ijid.2019.03.038] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 03/29/2019] [Accepted: 03/30/2019] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVES With the appearance of direct-acting antiviral agents (DAAs), sofosbuvir (SOF)-based DAAs are recommended for patients with hepatitis C virus (HCV) recurrence after liver transplantation (LT). Whether ribavirin (RBV) is needed by patients after LT in combination with SOF-based DAAs remains to be determined. This meta-analysis was conducted to evaluate the necessity of RBV with SOF-based DAAs for post-LT patients. METHODS PubMed, Web of Science, Cochrane Library and EMBASE databases were systematically searched for eligible studies from the databases' inceptions until November 2018. We accepted the studies that included HCV recurrence in post-LT patients who were treated with SOF-based DAAs ± RBV, and evaluated the rate of sustained virological response 12 weeks (SVR12) after the end of treatment. RESULTS Twelve studies, comprising a total of 1466 LT recipients, were included in this study. The pooled SVR12 of these patients was 91% (95% CI: 84% to 95%). There was no statistical difference of SVR12 in the patients treated with SOF-based DAAs + RBV versus -RBV group (risk ratio [RR] = 0.97; 95% CI: 0.92 to 1.03; P = 0.35) by different therapy duration (P = 0.26), with different targets of DAAs (P = 0.13) and in different regions (P = 0.34) but a tendency for a higher incidence of anemia in the +RBV group than in the -RBV group (RR = 5.18; 95% CI: 3.41 to 7.86; p < 0.00001). CONCLUSION The addition of RBV may not contribute to a higher SVR rate and could increase the incidence of anemia, so RBV is not necessary in SOF-based DAAs for patients with HCV recurrence after LT.
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Affiliation(s)
- Wei Xue
- The Key Laboratory of Molecular Biology for Infectious Diseases, Department of Infectious Diseases, Institute for Viral Hepatitis, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Kai Liu
- The Key Laboratory of Molecular Biology for Infectious Diseases, Department of Infectious Diseases, Institute for Viral Hepatitis, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China; Department of Medical Laboratory, The People's Hospital of Leshan, Leshan, China
| | - Ke Qiu
- The Key Laboratory of Molecular Biology for Infectious Diseases, Department of Infectious Diseases, Institute for Viral Hepatitis, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China; West China Hospital, Sichuan University, Chengdu, China
| | - Yanxi Shen
- The Key Laboratory of Molecular Biology for Infectious Diseases, Department of Infectious Diseases, Institute for Viral Hepatitis, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhaojun Pan
- Department of Infectious Diseases, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Peng Hu
- The Key Laboratory of Molecular Biology for Infectious Diseases, Department of Infectious Diseases, Institute for Viral Hepatitis, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Mingli Peng
- The Key Laboratory of Molecular Biology for Infectious Diseases, Department of Infectious Diseases, Institute for Viral Hepatitis, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Min Chen
- The Key Laboratory of Molecular Biology for Infectious Diseases, Department of Infectious Diseases, Institute for Viral Hepatitis, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| | - Hong Ren
- The Key Laboratory of Molecular Biology for Infectious Diseases, Department of Infectious Diseases, Institute for Viral Hepatitis, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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McCarty TR, Lim JK. Developing therapies to treat hepatitis C infection in post-liver transplant recipients. Expert Opin Pharmacother 2017; 18:165-174. [PMID: 28024124 DOI: 10.1080/14656566.2016.1276564] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Currently, hepatitis C virus (HCV) infection remains the most common indication for liver transplant in the United States (US) with almost universal HCV recurrence in the post-liver transplant setting. Previous interferon (IFN)-related efficacy and tolerability concerns about worsening liver function have limited treatment options for many patients with HCV-associated decompensated liver disease and post-liver transplant recipients. However, the last decade has seen a seen a radical shift in the management of HCV with multiple direct-acting antiviral (DAA) treatments that provide more effective, all-oral, IFN-free alternatives. Areas covered: This review will serve to highlight the various pharmacotherapies available to clinicians for patients with HCV recurrence post-liver transplant. A brief history of prior regimens is provided with evidence for newer treatments presented. Also detailed are updated guidelines from societal organizations. Finally, timing of HCV treatment is discussed as the decision to treat patients in a pre or post-liver transplant setting remains challenging. Expert opinion: While there are many potential available therapies for HCV recurrence in the post-liver transplant setting, daclatasvir/sofosbuvir and ledipasvir/sofosbuvir have been the most extensively studied. Newer, pangenotypic generation drugs require more evidence before routine utilization in post-liver transplant recipients.
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Affiliation(s)
- Thomas R McCarty
- a Department of Internal Medicine , Yale University School of Medicine , New Haven , CT , USA
| | - Joseph K Lim
- b Section of Digestive Diseases , Yale University School of Medicine , New Haven , CT , USA
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Njei B, McCarty TR, Fortune BE, Lim JK. Optimal timing for hepatitis C therapy in US patients eligible for liver transplantation: a cost-effectiveness analysis. Aliment Pharmacol Ther 2016; 44:1090-1101. [PMID: 27640785 DOI: 10.1111/apt.13798] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2016] [Revised: 08/12/2016] [Accepted: 08/20/2016] [Indexed: 12/14/2022]
Abstract
BACKGROUND Recurrence of hepatitis C virus (HCV) following liver transplantation (LT) is universal for those with ongoing viraemia and is associated with higher rates of allograft failure and death. However, the optimal timing of HCV treatment for patients awaiting transplant remains unclear. AIM To evaluate the comparative cost-effectiveness of treating HCV pre-LT vs. post-LT (pre-emptive or after HCV recurrence). METHODS A Markov state-transition model was created to simulate the progression of a cohort of HCV-genotype 1 or 4 cirrhotic patients from the time of transplant listing until death. We then used this model to study the cost-effectiveness of ledipasvir-sofosbuvir (LDV/SOF) with ribavirin for 12 weeks, administered for three separate treatment strategies: (i) pre-LT; (ii) post-LT preemptively prior to HCV recurrence; or (iii) post-LT after HCV recurrence. RESULTS In the base-case analysis using a median model for end-stage liver disease (MELD) score <25 at the time of transplant, we found that pre-LT treatment of HCV led to more QALYs for fewer dollars compared to other strategies. Analysis limited to living donor LT recipients revealed that pre-LT treatment was also the most cost-effective strategy. When the analysis was repeated for MELD ≥25, decompensated disease (Child-Pugh class B or C), and hepatocellular carcinoma cases, preemptive post-LT strategy was more cost-effective. CONCLUSIONS Treatment of HCV prior to liver transplantation appears to be the most cost-effective strategy for patients with a MELD score <25. For patients with a MELD ≥25 or decompensated cirrhosis, preemptive post-liver transplantation treatment before HCV recurrence is the most cost-effective strategy.
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Affiliation(s)
- B Njei
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
- Investigative Medicine Program, Yale Center of Clinical Investigation, New Haven, CT, USA
| | - T R McCarty
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - B E Fortune
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
| | - J K Lim
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA.
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Seifert LL, Heinzow H, Kabar I, Christensen S, Hüsing A, Schmidt HHJ. Successful Anti-HCV Therapy of a Former Intravenous Drug User with Sofosbuvir and Daclatasvir in a Peritranspant Setting: A Case Report. AMERICAN JOURNAL OF CASE REPORTS 2016; 17:605-10. [PMID: 27554644 PMCID: PMC4999016 DOI: 10.12659/ajcr.895839] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Accepted: 04/22/2016] [Indexed: 02/02/2023]
Abstract
BACKGROUND Direct-acting antivirals (DAAs) represent a new hallmark in antiviral therapy of hepatitis C virus (HCV). DAAs have been shown to be safe and effective after liver transplantation (LT), but there is little information about their use in peritransplant settings. Former intravenous drug users represent an increasing group seeking HCV treatment. This case report demonstrates the successful peritransplant antiviral treatment of a former intravenous drug user who had been treated in a methadone maintenance program. CASE REPORT The patient was diagnosed with Child B cirrhosis for the first time in 2009. He had a Model for End-stage Liver Disease (MELD) score of 21 and started antiviral therapy with sofosbuvir (SOF) and daclatasvir (DCV) in March 2014. Due to hepatic decompensation, he received a LT in April 2014. Immunosuppression was performed with tacrolimus (TAC) and mycophenolate-mofetil (MMF), and boosted with prednisolone in the initial stage. Four weeks after his LT, the patient presented with an acute renal injury. The patient was discharged one week later after sufficient hydration, discontinuation of non-steroidal anti-phlogistics therapy, and adjustments to his immunosuppressive regimen. At the beginning of his therapy, the number of RNA copies was 13,000 IU/mL. He received 24 weeks of anti-HCV treatment with SOF and DCV; the antiviral treatment was successful and his LT was well tolerated. CONCLUSIONS Treatment of HCV is feasible in a peritransplant setting. The antiviral regimen we used did not seem to have any relevant interactions with the patient's immunosuppressive regimens. Still, the peritransplant setting is a very demanding environment for anti-HCV therapy, and further studies are needed.
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Affiliation(s)
- Leon Louis Seifert
- Department of Transplantation Medicine, University Hospital Münster, Münster, Germany
| | - Hauke Heinzow
- Department of Transplantation Medicine, University Hospital Münster, Münster, Germany
| | - Iyad Kabar
- Department of Transplantation Medicine, University Hospital Münster, Münster, Germany
| | - Stefan Christensen
- Center for Interdisciplinary Medicine (CIM) Infectious Diseases, Münster, Germany
| | - Anna Hüsing
- Department of Transplantation Medicine, University Hospital Münster, Münster, Germany
| | - Hartmut H.-J. Schmidt
- Department of Transplantation Medicine, University Hospital Münster, Münster, Germany
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Burra P, De Martin E, Zanetto A, Senzolo M, Russo FP, Zanus G, Fagiuoli S. Hepatitis C virus and liver transplantation: where do we stand? Transpl Int 2016; 29:135-152. [PMID: 26199060 DOI: 10.1111/tri.12642] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Revised: 03/06/2015] [Accepted: 07/15/2015] [Indexed: 12/14/2022]
Abstract
The hepatitis C virus (HCV) infects more than 180 million people globally, with increasing incidence, especially in developing countries. HCV infection frequently progresses to liver cirrhosis leading to liver transplantation or death, and HCV recurrence still constitutes a major challenge for the transplant team. Antiviral therapy is the only available instrument to slow down this process, although its actual impact on liver histology, in responders and nonresponders, is still controversial. We are now facing a "new era" of direct antiviral agents that is already changing the approach to HCV burden both in the pre- and in the post-liver transplantation settings. Available data on sofosbuvir/ledipasvir and sofosbuvir/simeprevir in patients with decompensated cirrhosis sustain a SVR12 of 89% , but one-third of patients do not clinically improved. The sofosbuvir/ribavirin treatment in stable cirrhotic patients with HCC before liver transplantation is associated with 2% recurrence rate if liver transplantation is performed at least one month after undetectable HCV-RNA is achieved. The treatment of recurrence with the new antiviral drugs is associated with a SVR that ranges between 60 and 90%. In this review, we have focused on the evolution of antiviral therapy for HCV recurrence from the "old" interferon-based therapy to the "new" interferon-free regimens, highlighting useful information to aid the transplant hepatologist in the clinical practice.
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Affiliation(s)
- Patrizia Burra
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Eleonora De Martin
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
- Centre Hepato-Biliaire Paul Brousse, Villejuif, France
| | - Alberto Zanetto
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Marco Senzolo
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Francesco Paolo Russo
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Giacomo Zanus
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Stefano Fagiuoli
- Gastroenterology and Transplant Hepatology, Papa Giovanni XXIII Hospital, Bergamo, Italy
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EXP CLIN TRANSPLANTExp Clin Transplant 2015; 13. [DOI: 10.6002/ect.2015.0061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
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Habib S, Meister E, Habib S, Murakami T, Walker C, Rana A, Shaikh OS. Slower Fibrosis Progression Among Liver Transplant Recipients With Sustained Virological Response After Hepatitis C Treatment. Gastroenterology Res 2015; 8:237-246. [PMID: 27785303 PMCID: PMC5051041 DOI: 10.14740/gr686w] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/24/2015] [Indexed: 12/20/2022] Open
Abstract
Background The natural course of hepatic fibrosis in HCV allograft recipients with sustained virological response (SVR) after anti-HCV therapy remains debatable. The aim of this study was to examine the progression of fibrosis in a cohort of patients who achieved SVR compared with those without treatment. Methods The 167 patients who met the inclusion and exclusion criteria were chosen from a transplant database. All patients were required to have histological evidence of recurrent HCV infection post-liver transplantation and a follow-up biopsy. The 140 of these patients had received anti-viral therapy. Twenty-seven patients were identified as controls and were matched with the treatment group in all respects. The patients were categorized into four groups based on treatment response: 1) no treatment (control) (n = 27); 2) non-responders (n = 81); 3) relapsers (n = 32); and 4) SVR (n = 27). The endpoint was the stage of fibrosis on the follow-up liver biopsy. Results The treated and untreated groups were similar in clinical characteristics at the time of transplantation and prior to the initiation of treatment. The 72% of the cohort showed a fibrosis progression of ≥ 1 stage; this change did not significantly differ between the patient groups. Nonetheless, the fibrosis progression rate was the highest in the untreated group and lowest in the patients who achieved SVR. A coefficient of determination was used. Improvements in fibrosis scores were found with greater treatment duration. These improvements were most evident with the achievement of SVR. Conclusions In conclusion, SVR after anti-viral therapy for recurrent hepatitis C infection post-transplantation was associated with slower fibrosis progression and significantly improved graft survival.
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Affiliation(s)
- Shahid Habib
- Liver Institute, Department of Internal Medicine, Divisions of Gastroenterology, Hepatology and Transplantation, University of Arizona, AZ, USA
| | | | - Sana Habib
- Liver Institute, Department of Internal Medicine, Divisions of Gastroenterology, Hepatology and Transplantation, University of Arizona, AZ, USA
| | - Traci Murakami
- Liver Institute, Department of Internal Medicine, Divisions of Gastroenterology, Hepatology and Transplantation, University of Arizona, AZ, USA
| | - Courtney Walker
- Liver Institute, Department of Internal Medicine, Divisions of Gastroenterology, Hepatology and Transplantation, University of Arizona, AZ, USA
| | - Abbas Rana
- Division of Transplantation Surgery, Department of Surgery, Baylor College of Medicine, TX, USA
| | - Obaid S Shaikh
- Division of Transplantation Surgery and Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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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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Lim KBL, Sima HR, Fiel MI, Khaitova V, Doucette JT, Chernyiak M, Ahmad J, Bach N, Chang C, Grewal P, Kim-Schluger L, Liu L, Odin J, Perumalswami P, Florman SS, Schiano TD. Utility of the low-accelerating-dose regimen in 182 liver recipients with recurrent hepatitis C virus. World J Gastroenterol 2015; 21:6236-45. [PMID: 26034358 PMCID: PMC4445100 DOI: 10.3748/wjg.v21.i20.6236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2014] [Revised: 02/09/2015] [Accepted: 03/12/2015] [Indexed: 02/06/2023] Open
Abstract
AIM To describe our experience using a low-accelerating-dose regimen (LADR) with pegylated interferon alpha-2a and ribavirin in treatment of hepatitis C virus (HCV) recurrence. METHODS From 2003, a protocolized LADR strategy was employed to treat liver transplant (LT) recipients with recurrent HCV at our institution. Medical records of 182 adult patients with recurrent HCV treated with LADR between 1/2003 and 1/2011 were reviewed. Histopathology from all post-LT liver biopsies were reviewed in a blinded fashion. Paired recipient and donor IL28B status were assessed. A novel technique was employed to ascertain recipient and donor IL28B (rs12979860) Gt data using DNA extracted from archival FFPE tissue from explanted native livers and donor gallbladders respectively. The primary endpoint was SVR; secondary endpoints examined include (1) patient and graft survival; (2) effect of anti-viral therapy on liver histology (fibrosis and inflammation); (3) incidence of on-treatment development of ACR, CDR, or PCH; (4) association of recipient and donor IL28B genotype with SVR; and (5) incidence of anti-viral therapy-associated adverse events (anemia, leukopenia, thrombocytopenia, depression) and hepatic decompensation. RESULTS The overall SVR rate was 38% (29% Gt1, 67% Gt2, 86% Gt3 and 58% Gt4). HCV Gt (P < 0.0001), donor age (P = 0.003), cytomegalovirus mismatch (P = 0.001), baseline serum bilirubin (P = 0.002), and baseline viral load (P = 0.04) were independent predictors for SVR. SVR rates were significantly higher in the recipient-CC/donor-non CC pairs (P = 0.007). Neither baseline fibrosis nor change in fibrosis stage after anti-viral therapy were associated with SVR. Fibrosis progressed in 72% of patients despite SVR. Median graft survival was 91 mo. Five-year patient survival was superior in patients who achieved SVR (97% vs 82%, P = 0.001). Pre-treatment ALP ≥ 150 U/L (P = 0.01), total bilirubin ≥ 1.5 mg/dL (P = 0.001) and creatinine ≥ 2 mg/dL (P = 0.001) were independently associated with patient survival. Only 13% of patients achieving SVR died during the follow-up period. Treatment discontinuation and treatment-related mortality occurred in 35% and 2.2% of patients, respectively. EPO, G-CSF and blood transfusion were needed in 89%, 40% and 23% of patients, respectively. Overall hospitalization rate for treatment-related serious adverse events was 21%. Forty-six (25%) of the patients were deceased; among those who died, 25 (54%) were due to liver-related complications, and 4 deaths (9%) occurred while receiving therapy (2 patients experienced hepatic decompensation and 2 sepsis). CONCLUSION LADR strategy remains relevant in managing post-LT recurrent HCV where access to DAAs is limited. SVR is associated with improved survival, but fibrosis progression still occurs.
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Faisal N, Mumtaz K, Marquez M, Renner EL, Lilly LB. High sustained virological response to pegylated interferon and ribavirin for recurrent genotype 3 hepatitis C infection post-liver transplantation. Hepatol Int 2014; 9:76-83. [PMID: 25788382 DOI: 10.1007/s12072-014-9589-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Accepted: 10/20/2014] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Treatment outcomes of recurrent HCV genotype 3 (GT-3) after liver transplantation (LT) are ill-defined. AIMS To determine efficacy, predictors, and long-term survival after treatment of recurrent HCV GT-3 infection, post-LT, with a combination of pegylated interferon (PEG) and ribavirin (RBV). METHODS We studied all LT recipients (LTR) in our program treated with PEG and RBV for recurrent HCV GT-3 between Jan 1st 2002 and Dec 31st 2013. Antiviral therapy (AVT) was started if histology showed recurrent HCV with ≥ stage 2 fibrosis. Treatment was intended for 24 or 36 weeks, depending on early virologic response, and/or 24 weeks consolidation. Primary endpoint was sustained virological response (SVR). We also studied predictors of SVR and long-term patient survival. RESULTS Among 492 LT for HCV-related cirrhosis and/or hepatocellular carcinoma performed during the study period, 110 (22%) had HCV GT-3 infection. Fifty-two (10.5%) HCV GT-3 patients had indications for AVT. Six were unable to complete the AVT, three because of clinical decompensation and one each because of metastatic disease involving the brain, lung cancer, and ductopenic rejection. Forty-seven (90%) patients achieved early virological response (EVR) and 37 (71%) achieved SVR. Predictors of SVR were EVR (p < 0.001), stage ≤ 3 fibrosis (p = 0.008), and 36 weeks treatment duration (p < 0.001). Less advanced fibrosis ≤ 3 was independent predictor of SVR (OR 0.18, 95% CI 0.05-0.67). SVR patients had actuarial (Kaplan-Meier) 1, 3, and 10 year post-treatment survival of 100, 100, and 95%, compared with 87, 78, and 20% for non-SVR patients (p < 0.001, log rank test). CONCLUSION Efficacy of AVT for recurrent HCV GT-3 post-LT is high, and comparable with that for non-transplant patients. Less advanced fibrosis is an independent predictor of SVR. SVR improves long-term survival.
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Affiliation(s)
- Nabiha Faisal
- Liver Transplant Program/Multi-Organ Transplant Program, University Health, Network/Toronto General Hospital, University of Toronto, Toronto, ON, Canada
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Dumortier J, Boillot O, Scoazec JY. Natural history, treatment and prevention of hepatitis C recurrence after liver transplantation: Past, present and future. World J Gastroenterol 2014; 20:11069-11079. [PMID: 25170196 PMCID: PMC4145750 DOI: 10.3748/wjg.v20.i32.11069] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 03/07/2014] [Accepted: 06/23/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV)-related liver disease, including cirrhosis and hepatocellular carcinoma is the main indication for liver transplantation (LT) worldwide. Post-transplant HCV re-infection is almost universal and results in accelerated progression from acute hepatitis to chronic hepatitis, and liver cirrhosis. Comprehension and treatment of recurrent HCV infection after LT have been major issues for all transplant hepatologists and transplant surgeons for the last decades. The aim of this paper is to review the evolution of our knowledge on the natural history of HCV recurrence after LT, including risk factors for disease progression, and antiviral therapy. We will focus our attention on possible ways (present and future) to improve the final long-term results of LT for HCV-related liver disease.
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Dall’Agata M, Gramenzi A, Biselli M, Bernardi M. Hepatitis C virus reinfection after liver transplantation: Is there a role for direct antiviral agents? World J Gastroenterol 2014; 20:9253-9260. [PMID: 25071318 PMCID: PMC4110555 DOI: 10.3748/wjg.v20.i28.9253] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Revised: 03/27/2014] [Accepted: 06/05/2014] [Indexed: 02/06/2023] Open
Abstract
Recurrence of hepatitis C virus (HCV) infection following liver transplantation (LT) is almost universal and can accelerate graft cirrhosis in up to 30% of patients. The development of effective strategies to treat or prevent HCV recurrence after LT remains a major challenge, considering the shortage of donor organs and the accelerated progression of HCV in LT recipients. Standard antiviral therapy with pegylated-interferon plus ribavirin is the current treatment of choice for HCV LT recipients, even though the combination is not as effective as it is in immunocompetent patients. A sustained virological response in the setting of LT improves patient and graft survival, but this is only achieved in 30%-45% of patients and the treatment is poorly tolerated. To improve the efficacy of pre- and post-transplant antiviral therapy, a new class of potent direct-acting antiviral agents (DAAs) has been developed. The aim of this review is to summarize the use of DAAs in LT HCV patients. PubMed, Cochrane Library, MEDLINE, EMBASE, Web of Science and clinical trial databases were searched for this purpose. To date, only three clinical studies on the topic have been published and most of the available data are in abstract form. Although a moderately successful early virological response has been reported, DAA treatment regimens were associated with severe toxicity mitigating their potential usefulness. Moreover, the ongoing nature of data, the lack of randomized studies, the small number of enrolled patients and the heterogeneity of these studies make the results largely anecdotal and questionable. In conclusion, large well-designed clinical studies on DAAs in HCV LT patients are required before these drugs can be recommended after transplantation.
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Ponziani FR, Viganò R, Iemmolo RM, Donato MF, Rendina M, Toniutto P, Pasulo L, Morelli MC, Burra P, Miglioresi L, Merli M, Di Paolo D, Fagiuoli S, Gasbarrini A, Pompili M, Belli L, Gerunda GE, Marino M, Montalti R, Di Benedetto F, De Ruvo N, Rigamonti C, Colombo M, Rossi G, Di Leo A, Lupo L, Memeo V, Bringiotti R, Zappimbulso M, Bitetto D, Vero V, Colpani M, Fornasiere E, Pinna AD, Morelli MC, Bertuzzo V, De Martin E, Senzolo M, Ettorre GM, Visco-Comandini U, Antonucci G, Angelico M, Tisone G, Giannelli V, Giusto M. Long-term maintenance of sustained virological response in liver transplant recipients treated for recurrent hepatitis C. Dig Liver Dis 2014; 46:440-5. [PMID: 24635906 DOI: 10.1016/j.dld.2014.01.157] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2013] [Revised: 01/13/2014] [Accepted: 01/25/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND The recurrence of hepatitis C viral infection is common after liver transplant, and achieving a sustained virological response to antiviral treatment is desirable for reducing the risk of graft loss and improving patients' survival. AIM To investigate the long-term maintenance of sustained virological response in liver transplant recipients with hepatitis C recurrence. METHODS 436 Liver transplant recipients (74.1% genotype 1) who underwent combined antiviral therapy for hepatitis C recurrence were retrospectively evaluated. RESULTS The overall sustained virological response rate was 40% (173/436 patients), and the mean follow-up after liver transplantation was 11±3.5 years (range, 5-24). Patients with a sustained virological response demonstrated a 5-year survival rate of 97% and a 10-year survival rate of 93%; all but 6 (3%) patients remained hepatitis C virus RNA-negative during follow-up. Genotype non-1 (p=0.007), treatment duration >80% of the scheduled period (p=0.027), and early virological response (p=0.002), were associated with the maintenance of sustained virological response as indicated by univariate analysis. Early virological response was the only independent predictor of sustained virological response maintenance (p=0.008). CONCLUSIONS Sustained virological response achieved after combined antiviral treatment is maintained in liver transplant patients with recurrent hepatitis C and is associated with an excellent 5-year survival.
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14
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Dabbous HM, Elmeteini MS, Sakr MA, Montasser IF, Bahaa M, Abdelaal A, Fathy M, Refaie R, Seyam M, Abdelmonem A, Mukhtar A, Hegazy N, Almoneiri M. Optimizing outcome of recurrent hepatitis C virus genotype 4 after living donor liver transplantation: moving forward by looking back. Transplant Proc 2014; 46:822-827. [PMID: 24767357 DOI: 10.1016/j.transproceed.2013.11.152] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2013] [Revised: 11/08/2013] [Accepted: 11/27/2013] [Indexed: 12/16/2022]
Abstract
PURPOSE Recurrence of HCV after LDLT is almost universal. Different factors affect response to treatment. Few data are available regarding outcome of recurrent HCV genotype 4. The purpose of this study is to improve outcome of recurrent HCV genotype 4 after LDLT. METHODS An IRB approved chart review of 243 patients transplanted for ESLD, HCV genotype 4 over 4 years were reviewed. Protocol liver biopsies were taken 6 months after transplant. Patients received pegylated interferon and ribavirin in case of histological recurrence. Five patients had FCH were excluded. RESULTS Thirty-seven patients were included. Sustained Virological Response (SVR) was achieved in 29 (78.3%). Patients with Metavir fibrosis stage (F0) and (F1) had SVR in 5/5 (100%) and 20/24 (83.3%). Two patients with F1 had to stop treatment because of thrombocytopenia and 2 were non responders. Three out of 6 patients (50%) with (F2) had SVR, 2 were non responders and one had to discontinue treatment because of severe depression. One of 2 patients (50%) with F3 had SVR and the other patient decompensated within 4 months before treatment and died. CONCLUSION Protocol biopsies allow early detection of inflammatory changes in the graft before fibrosis occurs. Early treatment of recurrent HCV genotype 4 after LDLT results in better response.
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Affiliation(s)
- H M Dabbous
- Ain Shams Center for Organ Transplant, Cairo, Egypt.
| | | | - M A Sakr
- Ain Shams Center for Organ Transplant, Cairo, Egypt
| | | | - M Bahaa
- Ain Shams Center for Organ Transplant, Cairo, Egypt
| | - A Abdelaal
- Ain Shams Center for Organ Transplant, Cairo, Egypt
| | - M Fathy
- Ain Shams Center for Organ Transplant, Cairo, Egypt
| | - R Refaie
- Ain Shams Center for Organ Transplant, Cairo, Egypt
| | - M Seyam
- Ain Shams Center for Organ Transplant, Cairo, Egypt
| | - A Abdelmonem
- Ain Shams Center for Organ Transplant, Cairo, Egypt
| | - A Mukhtar
- Ain Shams Center for Organ Transplant, Cairo, Egypt
| | - N Hegazy
- Ain Shams Center for Organ Transplant, Cairo, Egypt
| | - M Almoneiri
- Ain Shams Center for Organ Transplant, Cairo, Egypt
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15
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CD49b, a major marker of regulatory T-cells type 1, predicts the response to antiviral therapy of recurrent hepatitis C after liver transplantation. BIOMED RESEARCH INTERNATIONAL 2014; 2014:290878. [PMID: 24575405 PMCID: PMC3915765 DOI: 10.1155/2014/290878] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Revised: 10/08/2013] [Accepted: 10/14/2013] [Indexed: 01/22/2023]
Abstract
The TRANSPEG study was a prospective study to assess the efficacy of antiviral therapy in patients with a recurrent hepatitis C virus (HCV) after liver transplantation. The influence of regulatory T-cells (Tregs) on the response to antiviral therapy was analyzed. Patients were considered as a function of their sustained virological response (SVR) at 18 months after treatment initiation. A transcriptomic analysis was performed to assess Treg markers (Tr1 and FoxP3+) in serum, PBMC, and liver biopsies. 100 patients had been included in the TRANSPEG study. Data from 27 of these patients were available. The results showed that the expression of CD49b (a predominant marker of Tr1) before the introduction of antiviral therapy was significantly associated with SVR. Responders displayed lower serum levels of CD49b than nonresponders (P < 0.02). These findings were confirmed in PBMC and liver biopsies even if in a nonsignificant manner for the limited number of samples. The assessment of CD49b levels is thus predictive of the response to antiviral therapy. This data suggests that CD49b may be a marker of the failure of the immune response and antiviral therapy during HCV recurrence. The assessment of CD49b could help to select patients who require earlier and more intensive antiviral therapy.
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16
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Streeck H, Rockstroh JK. Challenges in the treatment of HIV and HCV coinfection. Expert Rev Clin Immunol 2014; 2:811-22. [DOI: 10.1586/1744666x.2.5.811] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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17
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Bitetto D, De Feo T, Mantovani M, Falleti E, Fabris C, Belli LS, Fagiuoli S, Burra P, Piccolo G, Donato MF, Toniutto P, Cmet S, Cussigh A, Viganò R, Airoldi A, Pasulo L, Colpanij M, De Martin E, Gambato M, Rigamonti C. Interaction between calcineurin inhibitors and IL-28B rs12979860 C>T polymorphism and response to treatment for post-transplant recurrent hepatitis C. Dig Liver Dis 2013; 45:927-32. [PMID: 23722013 DOI: 10.1016/j.dld.2013.04.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2013] [Revised: 03/14/2013] [Accepted: 04/21/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND The impact of calcineurin inhibitors on achievement of sustained virological response to antiviral therapy for post-transplant recurrent hepatitis C is controversial. This study aimed at investigating the interactions between calcineurin inhibitors and interleukin-28B (IL-28B) gene polymorphisms and sustained virological response. METHODS Retrospective study of 147 liver transplant recipients with recurrent hepatitis C, who received 48 weeks of peg-interferon-α (N=113) or standard interferon (N=34), in association with ribavirin. Cyclosporine and tacrolimus were administered in 68 and 79 patients, respectively. IL-28B rs12979860 allele frequency was assessed in both donors and recipients. RESULTS Overall, 57 patients (38.8%) obtained sustained virological response; no difference was found between cyclosporine and tacrolimus-treated patients (42.6% vs. 35.4%, p=0.371). Recipient and donor IL-28B genotypic frequencies were C/C=30.6%, C/T=51.7%, T/T=17.7% and C/C=44.9%, C/T=50.3%, T/T=4.8%, respectively. Combining donor and recipient alleles, response rates decreased from cyclosporine-treated patients carrying ≤ 1 T allele (56.1%) to tacrolimus-treated patients carrying ≤ 1 T allele (44.7%) to patients carrying ≥ 2 T alleles (25.0%, p=0.0009). CONCLUSIONS Donor and recipient rs12979860 alleles synergistically influence sustained virological response rate to antiviral treatment for recurrent hepatitis C. In patients carrying <2 T alleles cyclosporine favours a better response than tacrolimus, while no difference was found in the presence of ≥ 2 T alleles.
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Affiliation(s)
- Davide Bitetto
- Medical Liver Transplant Unit, Department of Medical Sciences Experimental and Clinical, University of Udine, Italy
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18
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Agarwal K, Barnabas A. Treatment of chronic hepatitis C virus infection after liver transplantation. Dig Liver Dis 2013; 45 Suppl 5:S349-54. [PMID: 24091115 DOI: 10.1016/j.dld.2013.07.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Accepted: 07/01/2013] [Indexed: 12/11/2022]
Abstract
Chronic hepatitis C virus infection is a leading cause of end stage liver disease and one of the leading indications for liver transplantation. Furthermore, hepatitis C virus recurrence is universal post-transplant leading to decreased graft and patient survival. Recurrent disease related to hepatitis C virus can lead to between 20 and 30% of patients developing recurrent cirrhosis within 5 years. Treatment options with antiviral therapy are limited and are associated with a significant side-effect profile, suboptimal tolerability and inferior response rates. Attention has therefore turned to strategies that can reduce hepatitis C virus recurrence rates post-transplant. Approximately only 30% of patients will achieve a sustained virologic response with current therapy with pegylated interferon and ribavirin. Successful hepatitis C virus eradication is the only factor associated with improved graft and patient survival post liver transplantation. Here we provide an overview of antiviral treatment in patients in the transplant arena and the potential opportunities and challenges with the introduction of new directly acting antivirals in G1 patients.
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Affiliation(s)
- Kosh Agarwal
- Institute of Liver Studies, King's College Hospital, London, UK.
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19
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Ponziani FR, Annicchiarico EB, Siciliano M, D’Aversa F, Pompili M, Gasbarrini A. Treatment of hepatitis C in compensated cirrhotic patients is equally effective before and after liver transplantation. World J Gastroenterol 2013; 19:3255-3262. [PMID: 23745027 PMCID: PMC3671077 DOI: 10.3748/wjg.v19.i21.3255] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Revised: 03/07/2013] [Accepted: 04/28/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate differences in tolerability and response to treatment in compensated cirrhotic patients affected by hepatitis C virus (HCV) infection before and after liver transplantation.
METHODS: Forty-three HCV non-liver transplanted (LT) cirrhotics (mean age 55 ± 8 years, 65.1% male, Child-Pugh-A, genotype 1-4: 65.1%, 2-3: 34.9%) and 17 LT recipients with recurrent HCV-related cirrhosis (mean age 57 ± 9 years, 88.2% male, Child-Pugh-A, genotype 1-4: 76.5%, 2-3: 23.5%) were included in the analysis from retrospective series. All patients received recombinant or pegylated interferon plus ribavirin at a standard dose and duration. Adverse events were recorded and classified according to the Common Terminology Criteria for Adverse Events. The mean duration of follow-up was of 4.3 ± 1.8 years after the end of the treatment.
RESULTS: An early virological response (EVR) was achieved in 30/43 (69.8%) non-LT and in 8/17 (47.1%) LT cirrhotics, a sustained virological response (SVR) in 18/43 (41.9%) and 5/17 (29.4 %), respectively. No statistical difference was observed in EVR and SVR rates between the two groups. Among HCV non-LT cirrhotics, 6/43 (13.9%) discontinued the treatment prematurely, 11.6% of them receiving ≤ 80% of treatment; 8/17 (47%) LT cirrhotics withdrew the treatment, 35.2% of them receiving ≤ 80% of treatment. If compared with LT-ones (P = 0.015), an higher risk of treatment discontinuation could affect LT cirrhotics, who undergo more frequently ≤ 80% of treatment (P = 0.05). None of the non-LT cirrhotics died after the end of the treatment. With no regards to the achievement of SVR, LT cirrhotic patients showed a reduced survival in respect to non-LT ones (87% at 1 year, 76% at 3 and 5 years after the end of treatment).
CONCLUSION: HCV antiviral treatment is equally effective in compensated cirrhotics both before and after LT, which patients show a higher risk of premature treatment withdrawal and a reduced survival, independently of the achievement of SVR.
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20
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Berenguer M, Schuppan D. Progression of liver fibrosis in post-transplant hepatitis C: mechanisms, assessment and treatment. J Hepatol 2013; 58:1028-41. [PMID: 23262248 DOI: 10.1016/j.jhep.2012.12.014] [Citation(s) in RCA: 117] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2012] [Revised: 12/10/2012] [Accepted: 12/10/2012] [Indexed: 12/12/2022]
Abstract
Liver fibrosis results from an excessive wound healing response in most chronic liver diseases, such as hepatitis C. Despite great advances in antiviral therapy in recent years, progressive liver fibrosis remains a major problem for patients with recurrent hepatitis C after liver transplantation. Liver biopsy remains a central tool in the management of HCV-positive liver transplant recipients, but reliable non-invasive methods for the assessment of liver fibrosis, such as ultrasound elastography, are increasingly being incorporated in the management of post-transplant patients, helping predict prognosis, guide treatment decisions, and stratify patients for emerging antifibrotic therapies. In this manuscript, we will review the natural history as well as tools to monitor fibrosis progression in the HCV-positive liver transplant recipient, the mechanisms underlying rapid fibrosis progression in up to 30% of these patients, the effect of antiviral therapies and highlight promising antifibrotic approaches.
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Affiliation(s)
- Marina Berenguer
- University Valencia, Dept. of Medicine, Hepatology & Liver Transplantation Unit, La Fe Hospital and CIBEREHD, National Network Center for Hepatology and Gastroenterology Research, Instituto de Salud Carlos III, Spain.
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21
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Joshi D, Carey I, Agarwal K. Review article: the treatment of genotype 1 chronic hepatitis C virus infection in liver transplant candidates and recipients. Aliment Pharmacol Ther 2013; 37:659-71. [PMID: 23432320 DOI: 10.1111/apt.12260] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Revised: 12/20/2012] [Accepted: 02/03/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND Recently, the therapeutic landscape with regard to anti-HCV therapy has changed dramatically. The new directly acting anti-virals (DAAs) have demonstrated improved sustained virological response (SVR) compared with pegylated-interferon and ribavirin. AIM To examine and present the latest data with regard to anti-viral therapy in genotype 1 HCV-positive transplant candidates and recipients. METHODS An electronic search using Medline was performed. Search terms included 'HCV, DAA and protease inhibitor' in combination with 'treatment pre-transplantation' and 'treatment post-transplantation'. RESULTS Patients with advanced fibrosis and cirrhosis have inferior SVR rates compared with patients with minimal fibrosis. A low accelerating dose regimen (LADR) of pegylated interferon and ribavirin (PR) appears to be a safe therapeutic option. Side effects also appear to be more pronounced in patients with advanced disease. Data from the large registration studies with triple therapy (boceprevir or telaprevir plus PR) demonstrated improved SVR rates even in patients with advanced disease, although virological relapse rates were highest amongst these patients. In transplant recipients, initial data are being reported on the use of triple therapy, and although no SVR data are available, promising results are accruing. The drug-drug interactions appear to be manageable. Side effects in particular anaemia appear to be markedly increased in the posttransplant setting. CONCLUSIONS The use of the new DAAs in patients with advanced fibrosis/cirrhosis pretransplant and posttransplant appears possible, with manageable side effects and drug-drug interactions, and improved early virological response rates. We recommend that these patients are managed in centres with the appropriate expertise.
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Affiliation(s)
- D Joshi
- Institute of Liver Studies, King's College Hospital, London, UK.
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22
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Lee SW, Bae SH. Management of Hepatitis C Viral Infection Pre- and Post-liver Transplantation. KOREAN JOURNAL OF TRANSPLANTATION 2013. [DOI: 10.4285/jkstn.2013.27.1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Affiliation(s)
- Sung Won Lee
- Department of Internal Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Si Hyun Bae
- Department of Internal Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
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23
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Logge C, Vettorazzi E, Fischer L, Nashan B, Sterneck M. Cost-effectiveness analysis of antiviral treatment in liver transplant recipients with HCV infection. Transpl Int 2013; 26:527-34. [PMID: 23517333 DOI: 10.1111/tri.12085] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2012] [Revised: 07/11/2012] [Accepted: 02/11/2013] [Indexed: 01/21/2023]
Abstract
Within 5-10 years, 20-40% of hepatitis C virus (HCV)-infected liver transplant recipients can be expected to develop cirrhosis. Here, cost-effectiveness of antiviral therapy was assessed. A Markov model was developed to simulate disease progression and calculate outcome and costs of treatment. In the baseline analysis, Peg-IFN/RBV treatment prevented organ loss/death, gained quality-adjusted life-years (QALYs) and undercut the limit of cost-effectiveness of €50 000/QALY with an incremental cost-effectiveness ratio of approximately €40 400/QALY and €21 000/QALY for HCV genotype 1 and 2/3 patients, respectively. Furthermore, sensitivity analysis testing modified model parameters according to extreme data described in the literature confirmed cost-effectiveness for a lower or higher rate of fibrosis progression, increased non-HCV-related mortality, lower limits of utilities, a time horizon of 30 years, and additional costs in the year of death. On the other hand, cost-effectiveness was lost for patients with genotype 1 in case of doubled antiviral or life-time costs or an increased discount rate of 7%. New treatment strategies for HCV genotype 1 infected patients remained on the same level cost-effective, if additional costs did not exceed €10 774 per 10% sustained virologic response gain. We conclude that Peg-IFN/RBV treatment is cost-effective post transplant. This may support treatment decision in individual cases.
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Affiliation(s)
- Christoph Logge
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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24
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Levitsky J, Doucette K. Viral hepatitis in solid organ transplantation. Am J Transplant 2013; 13 Suppl 4:147-68. [PMID: 23465008 DOI: 10.1111/ajt.12108] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Affiliation(s)
- J Levitsky
- Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
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25
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Duvoux C, Firpi R, Grazi GL, Levy G, Renner E, Villamil F. Recurrent hepatitis C virus infection post liver transplantation: impact of choice of calcineurin inhibitor. Transpl Int 2013; 26:358-72. [PMID: 23413991 DOI: 10.1111/tri.12065] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2012] [Revised: 03/23/2012] [Accepted: 12/23/2012] [Indexed: 02/06/2023]
Abstract
Recurrence of hepatitis C virus infection following liver transplantation (LT) for hepatitis C is universal. After LT, hepatitis C is associated with accelerated fibrosis progression and reduced graft and patient survival. Furthermore, responses to antiviral therapy in patients with recurrent hepatitis C virus post-transplant are consistently sub-optimal. Calcineurin inhibitors (CNIs) like cyclosporine A (CsA) and tacrolimus continue to dominate immunosuppressive regimens in this population; however, there is still uncertainty as to whether either offers an advantage in terms of patient outcomes. Although tacrolimus demonstrates improved efficacy in the general LT population, differences have begun to emerge between these agents regarding diabetogenic potential, antiviral activity, and fibrosis progression in patients with hepatitis C. This review critically evaluates the existing literature, providing an overview of the reported differences, concluding that despite conflicting evidence, a potential benefit of CsA in patients with hepatitis C is supported by the data and warrants further investigation. Future studies examining the role of CNIs in hepatitis C virus-positive LT recipients are required to accurately examine the effects of CNIs on outcomes such as fibrosis progression, survival, and effects on response to antiviral therapy, to provide robust information that allows clinicians to make an informed choice concerning which CNI is best for their patients.
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26
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Hassan Q, Roche B, Buffet C, Bessede T, Samuel D, Charpentier B, Durrbach A. Liver-kidney recipients with chronic viral hepatitis C treated with interferon-alpha. Transpl Int 2013; 25:941-7. [PMID: 22882335 DOI: 10.1111/j.1432-2277.2012.01520.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Antiviral therapy with interferon-alpha (IFN-alpha) and pegylated IFN-alpha (PEG-IFN-alpha) for chronic hepatitis C (HCV)-infected kidney recipients remains controversial. IFN-alpha is not recommended in most cases because it induces severe acute graft rejection. However, IFN-alpha, as PEG-IFN-alpha, is associated with a more pronounced immune response, and is well tolerated in HCV-infected liver recipients without causing graft rejection. In combined liver-kidney transplant (LKT) recipients, IFN-alpha has been occasionally used and appears to be well tolerated. All LKT recipients with a functioning kidney and liver having a HCV replication and who needed IFN-alpha therapy have been included in the study. The occurrence of liver and/or renal acute rejection as well as the HCV replication has been collected. A total of 12 LKT patients treated with PEG-IFN-alpha plus ribavirin have been studied. No acute rejection was observed. Renal function remained stable during and after discontinuing treatment, without any graft dysfunction. Two patients had a partial viral response and four had a sustained viral response. All patients, whatever their viral response, had decreased liver-enzyme levels. Response to PEG-IFN-alpha therapy was correlated with steroid dose and transaminase level when PEG-IFN-alpha was started. These data suggest that the combination therapy of PEG-IFN-alpha plus ribavirin did not have a higher risk of acute kidney-graft rejection after liver-kidney transplantation.
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Affiliation(s)
- Qussai Hassan
- IFRNT, Nephrology and Transplantation Unit, Bicêtre Hospital, Le Kremlin Bicêtre, France
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27
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Ponziani FR, Milani A, Gasbarrini A, Zaccaria R, Viganò R, Iemmolo RM, Donato MF, Rendina M, Toniutto P, Pasulo L, Cescon M, Burra P, Miglioresi L, Merli M, Paolo DD, Fagiuoli S, Pompili M. Treatment of genotype-1 hepatitis C recurrence after liver transplant improves survival in both sustained responders and relapsers. Transpl Int 2012; 26:281-9. [PMID: 23230956 DOI: 10.1111/tri.12027] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2012] [Revised: 07/17/2012] [Accepted: 11/01/2012] [Indexed: 12/16/2022]
Abstract
The aim of this study was to evaluate the factors affecting the response to treatment and how it could affect survival in a large series of genotype-1 HCV-transplanted patients. Three-hundred and twenty six genotype-1 HCV patients were enrolled. One hundred and ninety-six patients (60.1%) were nonresponders and 130 (39.9%) showed negative HCV-RNA at the end of treatment. Eighty-four of them (25.8%) achieved sustained virological response, while 46 (14.1%) showed viral relapse. Five-year cumulative survival was significantly worse in nonresponders (76.4%) compared with sustained viral response (93.2) or relapsers (94.9%). Sustained responders and relapsers were therefore considered as a single 'response group' in further analysis. Pretreatment variables significantly associated with virological response at multivariate regression analysis were the absence of ineffective pretransplant antiviral therapy, the recurrence of HCV-hepatitis more than 1 year after transplant, an histological grading ≥4 at pretreatment liver biopsy, a pretreatment HCV-RNA level <1.2 × 10(6 ) IU/ml, and the absence of diabetes. As expected, also on-treatment variables (rapid and early virological response) were significantly associated to the response to antiviral treatment. In conclusion, this study shows that postliver transplant antiviral treatment results in beneficial effect on survival not only in sustained responders but also in relapsers.
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28
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Werner CR, Egetemeyr DP, Lauer UM, Nadalin S, Königsrainer A, Malek NP, Berg CP. Telaprevir-based triple therapy in liver transplant patients with hepatitis C virus: a 12-week pilot study providing safety and efficacy data. Liver Transpl 2012; 18:1464-70. [PMID: 22941516 DOI: 10.1002/lt.23542] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2012] [Accepted: 08/25/2012] [Indexed: 02/06/2023]
Abstract
After liver transplantation (LT), the management of recurrent hepatitis C virus (HCV) infections still remains a major challenge. In HCV genotype 1 patients not undergoing transplantation, the introduction of protease inhibitor (PI)-based regimens has increased the sustained virological response rate significantly. This pilot study investigated both the safety and efficacy of telaprevir (TVR)-based triple therapy in HCV-infected LT patients with a special emphasis on drug-drug interactions between immunosuppressants and PIs. Safety and efficacy data were gathered for 12 weeks for 9 HCV-infected LT patients who were treated with a combination of TVR, pegylated interferon, and ribavirin (RBV) in parallel with immunosuppressive drugs such as tacrolimus (TAC; n = 4), cyclosporine A (CSA; n = 4), and sirolimus (SIR; n = 1). Seven of the transplant patients completed the 12 weeks of triple therapy. At week 4, 4 of the patients were found to be HCV RNA-negative, and importantly, 8 were found to be negative at week 12. During the 12-week course of triple therapy, short-term measurements of immunosuppressant trough levels required individual dose reductions in all patients (CSA, 2.5-fold; SIR, 7-fold; and TAC, 22-fold). Furthermore, two-thirds of the patients exhibited hematological side effects requiring RBV dose reductions, the administration of erythropoietin, or even blood transfusions. In conclusion, this pilot study provides evidence showing that TVR-based triple therapy is effective within the first 4 to 12 weeks in LT patients suffering from HCV genotype 1 recurrence, and it also provides evidence showing that drug-drug interactions between TVR and immunosuppressants can be handled appropriately through the close monitoring of trough levels and adequate dosage adjustments.
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Affiliation(s)
- Christoph R Werner
- Department of Gastroenterology, Hepatology, and Infectiology, Medical Clinic, Tübingen, Germany
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Treatment of recurrent HCV infection following liver transplantation: results of a multicenter, randomized, versus placebo, trial of ribavirin alone as maintenance therapy after one year of PegIFNα-2a plus ribavirin. J Hepatol 2012; 57:564-71. [PMID: 22613001 DOI: 10.1016/j.jhep.2012.04.022] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2011] [Revised: 04/11/2012] [Accepted: 04/22/2012] [Indexed: 01/22/2023]
Abstract
BACKGROUND & AIMS We aimed at determining the effect of maintenance therapy with ribavirin alone, after a year of combined peginterferon-alfa 2a (PegIFNα-2a) and ribavirin therapy, on viral response and liver histology after liver transplantation (LT). METHODS Hundred and one patients with recurrent HCV and a minimum of stage 1 fibrosis (METAVIR scoring), 1-5years after LT, were enrolled. PegIFNα-2a and ribavirin were initiated at 90 μg/wk and 600 mg/d, respectively, then increased or adjusted as a function of tolerance. At 12 months, combination therapy was discontinued and patients were randomized to ribavirin or placebo for a further 12 months. Growth factor use was permitted. RESULTS At 18 months, a sustained virological response (SVR) was obtained in 47.9% of patients in Per Protocol (PP) analysis, and was higher in patients with genotype 2 or 3 than in patients with genotype 1 or 4, in patients with genotypes 1+4 receiving ciclosporine than in those receiving tacrolimus, in patients with worse renal function, in those having received EPO, in patients with lower weight, and in those with lower viral load at 3 months. Using logistic regression, only the early viral response, recipient weight and renal function were independently associated with better SVR. SVR, viral load, activity, and fibrosis scores were similar, at M18 and M30, in patients randomized to ribavirin, or to placebo. CONCLUSIONS A PP SVR was achieved in 47.9% of patients with established recurrent hepatitis C after LT. Maintenance therapy with ribavirin alone does not improve the virological response or the histological parameters.
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Novelli G, Rossi M, Morabito V, Ferretti G, Pretagostini R, Ruberto F, Pugliese F, Guglielmo N, Berloco P. Management of Hepatitis C Virus Infection in Liver Transplantation with Adacolumn Apheresis. Transplant Proc 2012; 44:1946-52. [DOI: 10.1016/j.transproceed.2012.06.040] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Carbone M, Lenci I, Baiocchi L. Prevention of hepatitis C recurrence after liver transplantation: An update. World J Gastrointest Pharmacol Ther 2012; 3:36-48. [PMID: 22966482 PMCID: PMC3437445 DOI: 10.4292/wjgpt.v3.i4.36] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2011] [Revised: 06/20/2012] [Accepted: 06/28/2012] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C related liver failure and hepatocarcinoma are the most common indications for liver transplantation in Western countries. Recurrent hepatitis C infection of the allograft is universal and immediate following liver transplantation, being associated with accelerated progression to cirrhosis, graft loss and death. Graft and patient survival is reduced in liver transplant recipients with recurrent Hepatitis C virus (HCV) infection compared to HCV-negative recipients. Many variables may impact on recurrent HCV liver disease. Overall, excess immunosuppression is believed to be a key factor; however, no immunosuppressive regimen has been identified to be more beneficial or less harmful. Donor age limitations, exclusion of moderately to severely steatotic livers and minimization of ischemic times could be a potential strategy to minimize the severity of HCV disease in transplanted subjects. After transplantation, antiviral therapy based on pegylated IFN alpha with or without ribavirin is associated with far less results than that reported for immunocompetent HCV-infected patients. New findings in the field of immunotherapy and genomic medicine applied to this context are promising.
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Affiliation(s)
- Marco Carbone
- Marco Carbone, Liver Unit, Queen Elizabeth Hospital, Birmingham, B15 2TH, United Kingdom
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Akamatsu N, Sugawara Y. Liver transplantation and hepatitis C. Int J Hepatol 2012; 2012:686135. [PMID: 22900194 PMCID: PMC3412106 DOI: 10.1155/2012/686135] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2012] [Accepted: 05/21/2012] [Indexed: 02/07/2023] Open
Abstract
Hepatitis-C-virus- (HCV-) related end-stage cirrhosis is the primary indication for liver transplantation in many countries. Unfortunately, however, HCV is not eliminated by transplantation and graft reinfection is universal, resulting in fibrosis, cirrhosis, and finally graft decompensation. The use of poor quality organs, particularly from older donors, has a highly negative impact on the severity of recurrence and patient/graft survival. Although immunosuppressive regimens have a considerable impact on the outcome, the optimal regimen after liver transplantation for HCV-infected patients remains unclear. Disease progression monitoring with protocol biopsy and new noninvasive methods is essential for predicting patient/graft outcome and starting antiviral treatment with the appropriate timing. Antiviral treatment with pegylated interferon and ribavirin is currently considered the most promising regimen with a sustained viral response rate of around 30% to 35%, although the survival benefit of this regimen remains to be investigated. Living-donor liver transplantation is now widely accepted as an established treatment for HCV cirrhosis and the results are equivalent to those of deceased donor liver transplantation.
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Affiliation(s)
- Nobuhisa Akamatsu
- Department of Hepato-Biliary-Pancreatic Surgery, Saitama Medical Center, Saitama Medical University, 1981 Tsujido-cho, Kamoda, Kawagoe, Saitama 350-8550, Japan
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Yasuhiko Sugawara
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
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Berenguer M, Charco R, Manuel Pascasio J, Ignacio Herrero J. Spanish society of liver transplantation (SETH) consensus recommendations on hepatitis C virus and liver transplantation. Liver Int 2012; 32:712-31. [PMID: 22221843 DOI: 10.1111/j.1478-3231.2011.02731.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2011] [Accepted: 11/23/2011] [Indexed: 02/06/2023]
Abstract
In November 2010, the Spanish Society of Liver Transplantation (Sociedad Española de Trasplante Hepático, SETH) held a consensus conference. One of the topics of debate was liver transplantation in patients with hepatitis C. This document reviews (i) the natural history of post-transplant hepatitis C, (ii) factors associated with post-transplant prognosis in patients with hepatitis C, (iii) the role of immunosuppression in the evolution of recurrent hepatitis C and response to antiviral therapy, (iv) antiviral therapy, both before and after transplantation, (v) follow-up of patients with recurrent hepatitis C and (vi) the role of retransplantation.
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Affiliation(s)
- Marina Berenguer
- Spanish Society of Liver Transplantation (Sociedad Española de Trasplante Hepático, SETH)
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34
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Perrakis A, Yedibela S, Schuhmann S, Croner R, Schellerer V, Demir R, Hohenberger W, Müller V. The effect and safety of the treatment of recurrent hepatitis C infection after orthotopic liver transplantation with pegylated interferon α2b and ribavirin. Transplant Proc 2012; 43:3824-8. [PMID: 22172854 DOI: 10.1016/j.transproceed.2011.08.103] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2011] [Revised: 08/01/2011] [Accepted: 08/31/2011] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Recurrent hepatitis C infection in the posttransplant setting is a serious problem. The aim of this study was to evaluate the efficacy, safety, indications, optimal time of administration and adequate duration of antiviral therapy with pegylated interferon alpha 2 b (PEG-IFN) and ribavirin (RIB). PATIENTS AND METHODS Between 2003 and 2009, 16 patients received antiviral therapy (PEG-IFN: 0.8-1.6 μg/kg/wk, RIB 800-1200 mg/d) for at least 6 months. Patients with a biochemical without a virologicalresponse after 12 months of therapy received antiviral treatment for a further 6 months. Hepatitis C virus load was determined at 1, 3, 6, and 12 months after start of therapy. Liver biopsy was performed in all patients before the beginning and after the end of treatment. RESULTS The mean period of antiviral therapy was 14 months. The four patients who received the full-length treatment (12 months, 33%) showed sustained virological responses (SVR) and 8 showed virological and biochemical responses (VR, BR). Patients with SVR showed significant improvement in the grading and staging of HAI (histological activity index; P=.03). Nine patients had several side effects under antiviral treatment. Acute rejection episodes were not observed. CONCLUSION The antiviral treatment combination using PEG-IFN and RIB for recurrent hepatitis C is effective procedure. The SVR of 33% after 12 months of treatment with significant improvement in HAI grading and staging and stable HAI in all treated patients favor early initiation and 12-month administration of antiviral treatment. Furthermore, all patients with BR without VR, who underwent antiviral treatment for a further 6 months, achieved a VR. However, the optimal duration of treatment needs to be investigated in large prospective studies.
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Affiliation(s)
- A Perrakis
- Department of Surgery, University of Erlangen-Nuremberg, Erlangen, Germany.
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35
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Wadhawan M, Taneja S, Shandil R, Goyal N, Gupta S, Kumar A. Management of chronic hepatitis C before and after liver transplant. APOLLO MEDICINE 2012. [DOI: 10.1016/s0976-0016(12)60116-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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Kohli V, Singhal A, Elliott L, Jalil S. Antiviral therapy for recurrent hepatitis C reduces recurrence of hepatocellular carcinoma following liver transplantation. Transpl Int 2011; 25:192-200. [PMID: 22151471 DOI: 10.1111/j.1432-2277.2011.01396.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Recurrence of hepatocellular carcinoma (HCC) is one of the major concerns following liver transplantation (LT). With the potential antitumor properties of interferon (IFN), their role in prevention of HCC recurrence is to be defined. We retrospectively reviewed 46 patients who underwent LT for hepatitis C virus (HCV)-related HCC between January 2004 and December 2008. Twenty-four (52.2%) patients with biopsy-proven HCV recurrence received antiviral therapy (IFN group); their outcomes were compared with 22 patients (control group). There was no significant difference for tumor size, number, and type of neo-adjuvant therapy between the two groups. The 1- and 3-year overall patient survival (100% vs. 90.9% and 87.3% vs. 71.8%; P = 0.150) and tumor-free survival (100% vs. 72.7% and 83.1% vs. 67.5%; P = 0.214) between IFN and control group were comparable. HCC recurrence was the most common cause of death (n = 6 of 12, 50%), all in the control group. During follow-up, seven (15.2%) patients developed HCC recurrence: one (4.1%) in the IFN group and six (27.3%) in the control group (P < 0.05). In conclusions, HCC recurrence rate and related deaths were significantly lower in patients that received post-transplant antiviral therapy for recurrent HCV.
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Affiliation(s)
- Vivek Kohli
- Nazih Zuhdi Transplant Institute, INTEGRIS Baptist Medical Center, Oklahoma City, OK 73112, USA.
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Berenguer M. Hot topic in hepatitis C virus research: the type of immunosuppression does not matter. Liver Transpl 2011; 17 Suppl 3:S24-8. [PMID: 21634004 DOI: 10.1002/lt.22347] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
1. The natural history of recurrent hepatitis C virus (HCV) is highly variable. Old donor age is a factor that has consistently been shown to affect disease progression. 2. Overall, immunosuppression determines the progression of HCV-related disease; however, the type of immunosuppressive agent used for induction or maintenance is not a key factor. 3. Steroid boluses should be avoided; they are associated with increased viremia, fibrosis progression, and reduced survival. 4. Antiviral therapy, particularly if it is successful, is associated with improved outcomes for liver transplant recipients with HCV. 5. There are no convincing data for modifying the type of immunosuppression before antiviral therapy is started.
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Limaye AR, Firpi RJ. Management of recurrent hepatitis C infection after liver transplantation. Clin Liver Dis 2011; 15:845-58. [PMID: 22032532 DOI: 10.1016/j.cld.2011.08.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Recurrence of hepatitis C virus remains a near-universal phenomenon after liver transplantation (LT) and is responsible for the high morbidity and low survival seen in these patients. The severity of recurrent disease varies depending on multiple factors, only some of which are modifiable. Antiviral therapy is associated with improved outcomes, but viral clearance is only attainable in a small percentage of this patient population. This patient population is in need of new therapeutic options, and it remains to be seen whether direct-acting antiviral agents will be the answer to this ongoing therapeutic question.
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Affiliation(s)
- Alpna R Limaye
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Florida College of Medicine, Gainesville, USA
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De Martin E, Rodriguez-Castro KI, Vitale A, Zanus G, Senzolo M, Russo FP, Burra P. Antiviral Treatment for HCV Recurrence after Liver Transplantation: When, how Much and for How Long? Future Virol 2011; 6:1179-1186. [DOI: 10.2217/fvl.11.89] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Eleonora De Martin
- Multivisceral Transplant Unit, Department of Surgical & Gastroenterological Sciences, Padua University Hospital. Via Giustiniani 2, 35128 Padua, Padua, Italy
| | - Kryssia I Rodriguez-Castro
- Multivisceral Transplant Unit, Department of Surgical & Gastroenterological Sciences, Padua University Hospital. Via Giustiniani 2, 35128 Padua, Padua, Italy
| | - Alessandro Vitale
- Department of General Surgery & Organ Transplantation, Hepatobiliary Surgery & Liver Transplant Unit, Padua University Hospital, Via Giustiniani 2, 35128Padua, Italy
| | - Giacomo Zanus
- Department of General Surgery & Organ Transplantation, Hepatobiliary Surgery & Liver Transplant Unit, Padua University Hospital, Via Giustiniani 2, 35128Padua, Italy
| | - Marco Senzolo
- Multivisceral Transplant Unit, Department of Surgical & Gastroenterological Sciences, Padua University Hospital. Via Giustiniani 2, 35128 Padua, Padua, Italy
| | - Francesco Paolo Russo
- Multivisceral Transplant Unit, Department of Surgical & Gastroenterological Sciences, Padua University Hospital. Via Giustiniani 2, 35128 Padua, Padua, Italy
| | - Patrizia Burra
- Multivisceral Transplant Unit, Department of Surgical & Gastroenterological Sciences, Padua University Hospital. Via Giustiniani 2, 35128 Padua, Padua, Italy
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Takeishi K, Shirabe K, Toshima T, Ikegami T, Morita K, Fukuhara T, Motomura T, Mano Y, Uchiyama H, Soejima Y, Taketomi A, Maehara Y. De novo autoimmune hepatitis subsequent to switching from type 2b to type 2a alpha-pegylated interferon treatment for recurrent hepatitis C after liver transplantation: report of a case. Surg Today 2011; 41:1016-9. [PMID: 21748625 DOI: 10.1007/s00595-010-4392-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2009] [Accepted: 03/24/2010] [Indexed: 02/05/2023]
Abstract
Interferon (IFN), which is the only possible agent for recurrent hepatitis C after liver transplantation, may cause serious immune-related disorders. We report a case of de novo autoimmune hepatitis (AIH), which developed subsequent to switching from 2b pegylated interferon-α (peg-IFN) to 2a peg-IFN after living donor liver transplantation (LDLT). A 51-year-old man with hepatitis C-associated liver cirrhosis underwent LDLT. About 13 months after the initiation of antiviral therapy, in the form of type 2b peg-IFN with ribavirin, a negative serum hepatitis C virus (HCV)-RNA titer was confirmed. Thereafter, the 2b peg-IFN was switched to 2a peg-IFN, 3 months after which severe liver dysfunction developed, despite a constantly negative HCV-RNA. Liver biopsy showed portal and periportal inflammatory infiltrates including numerous plasma cells, indicating AIH. He was treated with steroid pulse treatment, followed by high-level immunosuppression maintenance, but eventually died of Pneumocystis pneumonitis 4 months after the diagnosis of de novo AIH.
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Affiliation(s)
- Kazuki Takeishi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
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41
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Selzner N, Guindi M, Renner EL, Berenguer M. Immune-mediated complications of the graft in interferon-treated hepatitis C positive liver transplant recipients. J Hepatol 2011; 55:207-17. [PMID: 21145865 DOI: 10.1016/j.jhep.2010.11.012] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2010] [Revised: 11/23/2010] [Accepted: 11/23/2010] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) re-infection of the graft is universal and interferon based antiviral therapy remains at present the treatment of choice in HCV liver transplant recipients. Apart from the antiviral effects, interferon and ribavirin have both potent immunomodulatory properties resulting in a broad range of immune-related disorders including acute cellular rejection and chronic ductopenic rejection as well as de novo autoimmune hepatitis. Further complicating the picture, HCV infection per se is associated with a variety of autoimmune phenomena. We discuss here the immune-mediated complications and their relationship to chronic HCV and interferon based antiviral therapy.
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Affiliation(s)
- Nazia Selzner
- University Health Network, University of Toronto, Toronto, Canada.
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42
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Ponziani FR, Gasbarrini A, Pompili M, Burra P, Fagiuoli S. Management of hepatitis C virus infection recurrence after liver transplantation: an overview. Transplant Proc 2011; 43:291-5. [PMID: 21335208 DOI: 10.1016/j.transproceed.2010.09.102] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Hepatitis C virus (HCV) infection is the major indication for liver transplantation worldwide. Its recurrence is virtually universal. Once reinfection is established, progression to cirrhosis occurs in 25%-30% of recipients within 5 years. Several studies have attempted to identify the ideal antiviral treatment for liver transplant recipients. At present, the management of recurrent HCV infection in liver transplant recipients is based on widely accepted indications, which represent a reliable guide to identify the "ideal" candidate for therapy, when therapy should be started, and what is to be expected in terms of side effects and response to treatment.
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Affiliation(s)
- F R Ponziani
- Department of Internal Medicine, Catholic University, Rome, Italy.
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Vezali E, Aghemo A, Colombo M. A review of the treatment of chronic hepatitis C virus infection in cirrhosis. Clin Ther 2011; 32:2117-38. [PMID: 21316532 DOI: 10.1016/s0149-2918(11)00022-1] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/26/2010] [Indexed: 02/06/2023]
Abstract
BACKGROUND Cirrhosis developing during chronic infection with the hepatitis C virus (HCV) poses a risk of anticipated liver-related death, therefore representing a dominant indication to anti-HCV therapy. OBJECTIVE This review highlights the efficacy and safety of treatment of HCV infection in cirrhotic patients with respect to the clinical stage of the disease. METHODS The PubMed, MEDLINE, EMBASE, and Cochrane databases, as well as the conference proceedings from the annual meetings of the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver, and the Asian Pacific Association for the Study of the Liver, were searched for articles published in English from January 1990 through May 2010, fulfilling the following criteria: (1) randomized, prospective observational, retrospective, or meta-analysis; (2) involving adult patients with chronic HCV infection; and (3) data (fibrosis stage, treatment regimen, efficacy, safety) available for cirrhotics. Reviews were excluded. Search terms included chronic hepatitis C, fibrosis, cirrhosis, interferon alfa, ribavirin, hepatocellular carcinoma, and liver decompensation. RESULTS Forty-five studies were identified. The rates of sustained virologic response to pegylated interferon in combination with ribavirin ranged from 10% to 44% for HCV genotypes 1/4 to 33% to 72% for genotypes 2/3 in compensated cirrhosis, while falling to 0% to 16% and 44% to 57%, respectively, in the decompensated stage, compared with 29% to 55% for genotypes 1/4 and 70% to 80% for genotypes 2/3 in noncirrhotic patients (compensated cirrhosis vs no cirrhosis: P < 0.001 for genotypes 1/4 and P = 0.002 for genotypes 2/3; decompensated cirrhosis vs no cirrhosis: P < 0.001 for all genotypes). HCV clearance was associated with a reduced risk of liver decompensation, hepatocellular carcinoma development, liver-related mortality, and hepatitis recurrence after liver transplantation. Treatment during compensated cirrhosis proved to be most cost-effective versus treatment after decompensation or a no-treatment strategy. Headache (54%), irritability (38%), fatigue (34%), and nausea (30%) were the most common adverse events in compensated patients, while anorexia (100%), fatigue (59%), neutropenia (53%), and thrombocytopenia (50%) were most common in decompensated patients. CONCLUSIONS Anti-HCV treatment in cirrhotic patients was less effective than in noncirrhotic patients. Viral eradication reduced the risk of liver complications and improved survival in noncirrhotics. Based on effectiveness and tolerability data, therapy has a significant effect in patients with compensated cirrhosis, while decompensated patients need to weigh the risks versus benefits of treatment.
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Affiliation(s)
- Elena Vezali
- Centro A.M. e A. Migliavacca, Unità Operativa di Gastroenterologia 1, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
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Bzowej N, Nelson DR, Terrault NA, Everson GT, Teng LL, Prabhakar A, Charlton MR. PHOENIX: A randomized controlled trial of peginterferon alfa-2a plus ribavirin as a prophylactic treatment after liver transplantation for hepatitis C virus. Liver Transpl 2011; 17:528-38. [PMID: 21506241 PMCID: PMC3736350 DOI: 10.1002/lt.22271] [Citation(s) in RCA: 91] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The efficacy, tolerability, and safety of the prophylactic treatment of hepatitis C virus (HCV) after liver transplantation (LT) with peginterferon alfa-2a and ribavirin are not known. LT recipients with HCV were randomized to peginterferon alfa-2a/ribavirin treatment or observation 10 to 26 weeks post-LT. Prophylaxis patients received peginterferon alfa-2a (135 μg/week for 4 weeks and then 180 μg/week for 44 weeks) plus ribavirin (the initial dose of 400 mg/day was escalated to 1200 mg/day). Observation patients received the same regimen only upon significant HCV recurrence (histological activity index ≥ 3 and/or fibrosis score ≥ 2). The primary endpoint was the proportion of patients with histological evidence of significant HCV recurrence 120 weeks after randomization. In all, 115 patients were randomized (prophylaxis arm, n = 55; observation arm, n = 60). Sustained virological response was achieved by 12 of 54 prophylaxis patients (22.2%) and by 3 of 14 observation patients who switched to treatment (21.4%). On an intent-to-treat basis, significant HCV recurrence at 120 weeks was similar in the prophylaxis (61.8%) and observation arms (65.0%, P = 0.725). The patient and graft survival rates and the rates of biopsy-proven acute cellular rejection were similar in the 2 study arms. Approximately 70% of the treated patients in both arms had at least one dose reduction for safety reasons. The most common adverse event leading to treatment withdrawal was anemia. Because of the safety profile of peginterferon alfa-2a/ribavirin and the lack of a clear benefit in terms of HCV recurrence and patient or graft survival, this study does not support the routine use of prophylactic antiviral therapy.
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Affiliation(s)
| | - David R. Nelson
- Section of Hepatobiliary Diseases, University of Florida, Gainesville, FL
| | | | | | | | | | - Michael R. Charlton
- Department of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN
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Bitetto D, Fabris C, Fornasiere E, Pipan C, Fumolo E, Cussigh A, Bignulin S, Cmet S, Fontanini E, Falleti E, Martinella R, Pirisi M, Toniutto P. Vitamin D supplementation improves response to antiviral treatment for recurrent hepatitis C. Transpl Int 2011; 24:43-50. [PMID: 20649944 DOI: 10.1111/j.1432-2277.2010.01141.x] [Citation(s) in RCA: 115] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
In immune-competent patients, higher vitamin D levels predicted sustained viral response (SVR) following interferon (INF) and ribavirin therapy for chronic hepatitis C. This study aimed to verify the influence of vitamin D serum levels and/or vitamin D supplementation in predicting SVR rates for recurrent hepatitis C (RHC). Forty-two consecutive patients were treated for RHC with combination therapy with INF-α and ribavirin for 48 weeks. Vitamin D serum levels were measured in all patients before antiviral therapy. In 15 patients oral vitamin D3 supplementation was administered to avoid further bone loss. SVR was observed in 13 patients; it was achieved in 1/10 severely vitamin D deficient (≤ 10 ng/ml) patients, in 6/20 deficient (>10 and ≤ 20 ng/ml) and in 6/12 with near normal (> 20 ng/ml) 25-OH vitamin D serum levels (P < 0.05). Cholecalciferol supplementation, in the presence of a normal or near normal baseline vitamin D concentration, (improvement of chi-square P < 0.05, odds ratio 2.22) and possessing a genotype other than 1 (improvement of chi-square P < 0.05, odds ratio 3.383) were the only variables independently associated to SVR. In conclusion, vitamin D deficiency predicts an unfavourable response to antiviral treatment of RHC. Vitamin D supplementation improves the probability of achieving a SVR following antiviral treatment.
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Affiliation(s)
- Davide Bitetto
- Medical Liver Transplantation Unit, Internal Medicine, University of Udine, Udine, Italy
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Guillouche P, Féray C. Systematic review: anti-viral therapy of recurrent hepatitis C after liver transplantation. Aliment Pharmacol Ther 2011; 33:163-74. [PMID: 21083593 DOI: 10.1111/j.1365-2036.2010.04505.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Hepatitis C virus (HCV) infection is the first cause of liver transplantation worldwide. Recurrence of infection is constant, and compromises patient and graft survival. AIM To provide an updated review of the main treatments of recurrent HCV. METHODS MEDLINE (1990 to August 2010) and national meeting abstract search. Search terms included hepatitis C, liver transplantation, treatment, sustained virological response. An emphasis was placed on randomised trials. RESULTS Anti-viral therapy based on pegylated interferon and ribavirin must be considered before liver transplantation, but is poorly tolerated and has poor results in patients with cirrhosis and end-stage liver disease or hepatocellular carcinoma. Anti-viral therapy can be administrated systematically early after liver transplantation, or in patients with established recurrent chronic hepatitis. Combination of pegylated interferon alpha plus ribavirin results in a sustained virological response of up to 30% in patients with histological HCV recurrence. The results of a small trial of polyclonal anti-HCV to prevent recurrence were disappointing. CONCLUSIONS Currently available anti-viral therapy is effective only in a minority of transplanted patients infected with HCV. Specifically targeted anti-viral therapies combining interferon alpha and ribavirin, or a combination of antiprotease and antipolymerase components, associated with a genetic prediction of anti-viral response and blocking HCV cell entry should improve the long-term prognosis of recurrent hepatitis C in the near future.
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Affiliation(s)
- P Guillouche
- Institut des Maladies de l'Appareil Digestif, Hôtel-Dieu, Nantes, France
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Pillai A, Lee V, Wang E, Rinella M, Levitsky J. Factors Associated With Sustained Virological Response in Liver Transplant Recipients With Recurrent Hepatitis C. Transplant Proc 2010; 42:3647-51. [DOI: 10.1016/j.transproceed.2010.06.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2010] [Accepted: 06/18/2010] [Indexed: 02/08/2023]
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Sugawara Y, Tamura S, Kokudo N. Antiviral treatment for hepatitis C virus infection after liver transplantation. HEPATITIS RESEARCH AND TREATMENT 2010; 2010:475746. [PMID: 21151523 PMCID: PMC2989693 DOI: 10.1155/2010/475746] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/21/2010] [Revised: 08/13/2010] [Accepted: 10/06/2010] [Indexed: 12/16/2022]
Abstract
A significant proportion of patients with chronic hepatitis C virus (HCV) infection develop liver cirrhosis and complications of end-stage liver disease over two to three decades and require liver transplantation, however, reinfection is common and leads to further adverse events under immunosuppression. Pretransplant antiviral or preemptive therapy is limited to mildly decompensated patients due to poor tolerance. The mainstay of management represents directed antiviral therapy after evidence of recurrence of chronic hepatitis C. Combined pegylated interferon and ribavirin therapy is the current standard treatment with sustained viral response rates of 25% to 45%. The rate is lower than that in the immunocompetent population, partly due to the high prevalence of intolerability. To date, there is no general consensus regarding the antiviral treatment modality, timing, or dosing for HCV in patients with advanced liver disease and after liver transplantation. New anti-HCV drugs to delay disease progression or to enhance viral clearance are necessary.
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Affiliation(s)
- Yasuhiko Sugawara
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Sumihito Tamura
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Norihiro Kokudo
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
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Aytaman A, Kaufman M, Terrault NA. Management of posttransplant hepatitis C infection. Curr Opin Organ Transplant 2010; 15:301-9. [PMID: 20445452 DOI: 10.1097/mot.0b013e3283398237] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE OF REVIEW Chronic hepatitis C virus (HCV) infection is the leading cause of liver transplantation. Outcome of HCV-associated liver transplantation has been worse than transplantation from other causes. This is mostly related to universal recurrence of HCV in the allograft leading to graft and patient loss or retransplantation. Current antiviral therapies (AVTs) are inadequate and ineffective in the vast majority of the patients with intolerable side effects in most. However, a sustained virologic response (SVR) is associated with improved graft and patient survival. New specifically targeted AVTs for HCV (STAT-C) agents in development will significantly improve the success of AVT. This review focuses on recent data in peritransplant management of HCV with special emphasis on predictors of outcome, diagnosis, prevention and control of reinfection with newer treatments on the horizon. RECENT FINDINGS In the immediate pretransplant setting, AVT should be considered in select patients to eradicate the virus. Careful donor selection, immunosuppression (IMS) modulation with steroid and calcineurin inhibitor (CNI) minimization, avoidance of T-cell-depleting treatments and acute rejection episodes, and control of metabolic syndrome can improve allograft outcomes and improve the response to AVT. AVT prior to significant damage to the allograft is strongly recommended. SUMMARY With modified novel IMS protocols, careful donor selection, and AVT prior to significant damage to the allograft we can improve the outcome of posttransplant hepatitis C infection. Albeit there are no available data on new antiviral agents, STAT-Cs will have a significant impact in this setting in the near future.
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Affiliation(s)
- Ayse Aytaman
- VA New York Harbor HCS Brooklyn, Brooklyn, New York 11209, USA.
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Schmidt SC, Bahra M, Bayraktar S, Berg T, Schmeding M, Pratschke J, Neuhaus P, Neumann U. Antiviral treatment of patients with recurrent hepatitis C after liver transplantation with pegylated interferon. Dig Dis Sci 2010; 55:2063-9. [PMID: 19798575 DOI: 10.1007/s10620-009-0982-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2009] [Accepted: 09/09/2009] [Indexed: 12/14/2022]
Abstract
BACKGROUND The recurrence of hepatitis C virus (HCV) after liver transplantation (OLT) leads to recurrent cirrhosis in up to 40% of patients. AIMS To identify patients who profit the most from antiviral therapy and to delineate whether early treatment after OLT is effective to reach sustained virological response (SVR), we analyzed factors associated to SVR during pegylated interferon/ribavirin (PegIFN/RBV) therapy. METHODS A retrospective analysis of efficiency and viral decline kinetics in 83 HCV-infected liver transplant recipients who received therapy with PegIFN/RBV was carried out. RESULTS Forty-one of 83 (49.4%) patients became HCV RNA-negative. SVR was achieved in 26/83 (31.3%) patients. Viral decline of at least 2 log 10 (n = 47) at week 12 was significantly associated with an end-of-treatment (EOT) response. Eleven early viral response patients were not able to clear HCV RNA, whereas five patients without a 2 log decline achieved SVR. The highest predictive value for SVR was an undetectable viremia at week 24 (92%). CONCLUSIONS The outcome of antiviral combination therapy for HCV reinfection after OLT can be best predicted by week-24 virologic response. The high SVR rates in patients with detectable HCV RNA at week 12 might suggest a prolonged treatment protocol in liver transplant recipients.
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Affiliation(s)
- Sven C Schmidt
- Klinik für Allgemein-, Viszeral-, und Transplantationschirurgie, Charité Campus Virchow-Klinikum, Universitätsmedizin Berlin, Berlin, Germany.
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