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Kim SH, Kim YK. Emergency, ABO-Incompatible Living Donor Liver Re-Transplantation for Graft Failure Complicated by Pneumonia-Associated Sepsis. J Clin Med 2023; 12:jcm12031110. [PMID: 36769757 PMCID: PMC9917672 DOI: 10.3390/jcm12031110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/25/2023] [Accepted: 01/29/2023] [Indexed: 02/05/2023] Open
Abstract
Although liver re-transplantation is the only therapeutic option for acute and chronic graft failure, few studies have addressed the use of ABO-incompatible living donors in the emergency setting. Here, based on our experience, we report a successful case of emergency, ABO-incompatible, adult-to-adult, living donor liver re-transplantation (LDLT) for late graft failure from chronic rejection complicated by pneumonia-related sepsis. A fifty-five-year-old man had undergone LDLT for hepatocellular carcinoma accompanied by hepatitis C virus (HCV)-related cirrhosis in 30 September 2013. The voluntary donor was his 56-year-old wife, who was also a carrier of HCV. The donor and recipient blood types were the same: O and Rh positive. She underwent a right hepatectomy and was discharged on postoperative day (POD) seven. The patient was also discharged without complications on POD eleven and was followed up with on an outpatient basis. Abdominal distension and jaundice were developed at 6 months after LDLT, when the serum total bilirubin level was 2.7 mg/dL. The serum total bilirubin levels increased rapidly to 22.9 mg/dL over the next 4 months. Chronic rejection was diagnosed via liver biopsy. On 3 October 2014, he developed pneumonia-related sepsis and showed the progressive deterioration of liver function. Liver re-transplantation using the right liver from his ABO-incompatible, 20-year-old nephew was performed as an emergency in 15 October 2014. The donor blood type was A and Rh positive. The resection of the failed graft and the implantation of a new graft was performed by the intragraft dissection technique to re-use previously transplanted graft vessels in order to cope with severe adhesions. The recipient went through a gradual recovery process and was finally discharged on POD 50 with normal liver function, while the donor had an uneventful recovery and was discharged on POD 7. Biloma due to bile leak was detected three months after re-transplantation and was cured by percutaneous interventional procedures. Since then, the postoperative course has been event-free at regular outpatient follow-ups. The patient has so far had normal laboratory findings and no signs of complications. It has been 98 months since the re-transplantation, and the recipient and two donors are still in good condition with normal liver function, having complete satisfaction with the results obtained from this re-transplantation. In conclusion, long-term, satisfactory outcomes can be achieved in emergency, ABO-incompatible, adult-to-adult, living donor liver re-transplantation for graft failure complicated by pneumonia-related sepsis in selected patients.
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Affiliation(s)
- Seoung Hoon Kim
- Organ Transplantation Center, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si 10408, Republic of Korea
- Correspondence: ; Tel.: +82-31-920-1647; Fax: +82-31-920-2798
| | - Young-Kyu Kim
- Department of Surgery, Jeju National University School of Medicine, Aran 13gil 15 (Ara-1Dong), Jeju-si 63241, Republic of Korea
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Snyder HS, Wiegel JJ, Khalil K, Summers BB, Tan T, Jonchhe S, Kaiser TE. A systematic review of direct acting antiviral therapies in hepatitis C virus-negative liver transplant recipients of hepatitis C-viremic donors. Pharmacotherapy 2022; 42:905-920. [PMID: 36373198 DOI: 10.1002/phar.2742] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 09/27/2022] [Accepted: 10/21/2022] [Indexed: 11/16/2022]
Abstract
The introduction of safe and highly effective direct acting antivirals (DAAs) has significantly improved hepatitis C virus (HCV) treatment outcomes after transplant. The solid organ transplant community has sought to identify strategies aimed at increasing the donor pool including the utilization of HCV-viremic organs in HCV-negative recipients. We will review the existing literature to evaluate DAA use for the treatment of HCV viremia post-liver transplant in patients who receive HCV-viremic allografts. A PubMed search was conducted and references for each study were also reviewed to identify additional articles. Randomized controlled trials, cohort studies, case series, and case reports were included if: published in English language, evaluated DAA treatment outcomes after liver only or simultaneous liver-kidney transplantation with HCV-viremic allografts in HCV-negative recipients, and had full-text article availability. Our review included 16 studies and 2 case reports. The majority of liver transplant recipients were treated with a pangenotypic DAA for 12 weeks with a heterogeneous median time to initiation (range 1.7-118 days). Sustained virologic response was assessed in 253 liver transplant patients with 99.6% achieving cure with minimal DAA-attributed adverse drug events. There were 23 reported episodes of rejection, 12 deaths, and 1 graft loss among all studies. Treatment with DAA after transplantation of HCV-viremic livers into HCV-negative recipients appears to be safe and effective; however, long-term outcomes remain unknown. Transplant pharmacists play a key role in the development of center-specific protocols to optimize post-transplant outcomes in this unique patient population.
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Affiliation(s)
- Heather S Snyder
- Department of Pharmacy, Emory University Hospital, Atlanta, Georgia, USA
| | - Joshua J Wiegel
- Department of Pharmacy, University of Wisconsin Health, Madison, Wisconsin, USA
| | - Karen Khalil
- NYU Langone Transplant Institute, NYU Langone Health, New York, New York, USA
| | - Bryant B Summers
- Department of Pharmacy, Henry Ford Health System, Detroit, Michigan, USA
| | - Teresa Tan
- Department of Pharmaceutical Services, Ronald Reagan UCLA Medical Center, Los Angeles, California, USA
| | - Srijana Jonchhe
- Department of Pharmacy, NYU Langone Health, New York, New York, USA
| | - Tiffany E Kaiser
- Department of Medicine, Division of Digestive Diseases, University of Cincinnati, Cincinnati, Ohio, USA
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Cheung CKM, Wong SH, Law AWH, Law MF. Transfusion-transmitted hepatitis E: What we know so far? World J Gastroenterol 2022; 28:47-75. [PMID: 35125819 PMCID: PMC8793017 DOI: 10.3748/wjg.v28.i1.47] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 07/16/2021] [Accepted: 12/22/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis E virus (HEV) is a major cause of viral hepatitis globally. There is growing concern about transfusion-transmitted HEV (TT-HEV) as an emerging global health problem. HEV can potentially result in chronic infection in immunocompromised patients, leading to a higher risk of liver cirrhosis and even death. Between 0.0013% and 0.281% of asymptomatic blood donors around the world have HEV viremia, and 0.27% to 60.5% have anti-HEV immunoglobulin G. HEV is infectious even at very low blood concentrations of the virus. Immunosuppressed patients who develop persistent hepatitis E infection should have their immunosuppressant regimen reduced; ribavirin may be considered as treatment. Pegylated interferon can be considered in those who are refractory or intolerant to ribavirin. Sofosbuvir, a nucleotide analog, showed modest antiviral activity in some clinical studies but sustained viral response was not achieved. Therefore, rescue treatment remains an unmet need. The need for HEV screening of all blood donations remains controversial. Universal screening has been adopted in some countries after consideration of risk and resource availability. Various pathogen reduction methods have also been proposed to reduce the risk of TT-HEV. Future studies are needed to define the incidence of transmission through transfusion, their clinical features, outcomes and prognosis.
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Affiliation(s)
| | - Sunny Hei Wong
- Institute of Digestive Disease and Department of Medicine and Therapeutics, the Chinese University of Hong Kong, Hong Kong 852, China
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 639798, Singapore
| | | | - Man Fai Law
- Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong 852, China
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Gorris M, van der Lecq BM, van Erpecum KJ, de Bruijne J. Treatment for chronic hepatitis E virus infection: A systematic review and meta-analysis. J Viral Hepat 2021; 28:454-463. [PMID: 33301609 PMCID: PMC7898834 DOI: 10.1111/jvh.13456] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 11/09/2020] [Accepted: 11/23/2020] [Indexed: 12/19/2022]
Abstract
Hepatitis E virus infection can cause chronic hepatitis in immunocompromised patients with significant chance of progressive fibrosis and possibly cirrhosis. The aim of this systematic review was to summarize the efficacy and safety of the various treatment options for chronic hepatitis E. We performed a systematic literature search. The primary outcome measure was a sustained virological response (SVR). Secondary end points were rapid virological response (RVR), relapse rates, side effects and adverse events. Forty-four articles were included with a total of 582 patients. Reduction of immunosuppressive medication induced viral clearance in 55/174 (32%) of the patients. Meta-analysis of 395 patients showed a pooled SVR rate of 78% (95-CI 72%-84%) after ribavirin treatment. Twenty-five per cent of the patients obtained a RVR, whereas a relapse occurred in 18% of the patients. Anaemia during treatment led to dose reduction, use of erythropoietin and/or blood transfusion in 37% of the patients. A second treatment attempt with ribavirin led to a SVR in 39/51 (76%) of the patients. Pegylated interferon-alpha was administered to 13 patients and SVR was obtained in 85%. Two patients (15%) suffered from acute transplant rejection during treatment with interferon. In conclusion, reduction of immunosuppressive medication and treatment with ribavirin is safe, generally well tolerated and induced viral clearance in 32% and 78% of patients, respectively. Therefore, ribavirin should be considered as first treatment step for chronic hepatitis E. Treatment with pegylated interferon-alpha increases the risk of transplant rejection and should therefore be administered with great caution.
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Affiliation(s)
- Myrte Gorris
- Department of Gastroenterology & HepatologyUniversity Medical Center UtrechtUtrechtThe Netherlands
| | - Bernice M. van der Lecq
- Department of Gastroenterology & HepatologyUniversity Medical Center UtrechtUtrechtThe Netherlands
| | - Karel J. van Erpecum
- Department of Gastroenterology & HepatologyUniversity Medical Center UtrechtUtrechtThe Netherlands
| | - Joep de Bruijne
- Department of Gastroenterology & HepatologyUniversity Medical Center UtrechtUtrechtThe Netherlands
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Choi C, Botros Y, Shah J, Xue P, Jones A, Galan M, Olivo R, Niazi M, Paterno F, Guarrera J, Pyrsopoulos NT. A Case Report of Alloimmune Hepatitis after Direct-acting Antiviral Treatment in a Liver Transplant Patient. J Clin Transl Hepatol 2020; 8:459-462. [PMID: 33447530 PMCID: PMC7782114 DOI: 10.14218/jcth.2020.00062] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 08/12/2020] [Accepted: 08/24/2020] [Indexed: 01/14/2023] Open
Abstract
Direct-acting antiviral (DAA) therapy is often well-tolerated, and adverse events from DAA therapy are uncommon. We report a case of a woman who underwent orthotopic liver transplant for chronic hepatitis C infection and later developed alloimmune hepatitis shortly after starting DAA therapy for recurrent hepatitis C infection. The patient developed acute alloimmune hepatitis approximately 2 weeks after starting treatment with sofosbuvir, velpatasvir, and voxilaprevir. This case report proposes a dysregulation of immune surveillance due to the DAA stimulation of host immunity and rapid elimination of hepatitis C viral load as a precipitating factor for the alloimmune process, leading to alloimmune hepatitis in a post-transplant patient who starts on DAA.
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Affiliation(s)
- Catherine Choi
- Department of Internal Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Youssef Botros
- Division of Gastroenterology, St. Joseph’s University Medical Center, Paterson, NJ, USA
| | - Jamil Shah
- Division of Gastroenterology & Hepatology, The Brooklyn Hospital Center, Brooklyn, NY, USA
| | - Pei Xue
- Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Anja Jones
- Department of Pathology, Immunology & Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Mark Galan
- Department of Pathology, Immunology & Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Raquel Olivo
- Division of Gastroenterology & Hepatology, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Mumtaz Niazi
- Division of Gastroenterology & Hepatology, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Flavio Paterno
- Division of Liver Transplantation & Hepatobiliary Surgery, Department of Surgery, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - James Guarrera
- Division of Liver Transplantation & Hepatobiliary Surgery, Department of Surgery, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Nikolaos T. Pyrsopoulos
- Division of Gastroenterology & Hepatology, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
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Pegylated interferon may be considered in chronic viral hepatitis E resistant to ribavirin in kidney transplant recipients. BMC Infect Dis 2020; 20:522. [PMID: 32677900 PMCID: PMC7367388 DOI: 10.1186/s12879-020-05212-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 06/29/2020] [Indexed: 01/18/2023] Open
Abstract
Background Hepatitis E virus (HEV) may be resistant to immunosuppression reduction and ribavirin treatment in kidney transplant recipients because of mutant strains and severe side effects of ribavirin which conduct to dose reduction. Sofosbuvir efficacy is controversial. Peg-interferon 2 alpha (PEG-IFN) is currently contraindicated due to a high risk of acute humoral and cellular rejection. The present study assessed, for the first time, the effect of PEG-IFN in a kidney transplant recipient infected with HEV. Case presentation The patient had chronic active HEV that was resistant to immunosuppression reduction and optimal ribavirin treatment. He developed significant liver fibrosis. PEG-IFN was administered for 10 months, and it was well tolerated and did not induce rejection. A sustained virological response was obtained. Conclusions We conclude that prolonged treatment with PEG-IFN in kidney transplant recipients infected with HEV could be considered as a salvage option.
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Mirjalili M, Shafiekhani M, Vazin A. Coronavirus Disease 2019 (COVID-19) and Transplantation: Pharmacotherapeutic Management of Immunosuppression Regimen. Ther Clin Risk Manag 2020; 16:617-629. [PMID: 32694915 PMCID: PMC7340365 DOI: 10.2147/tcrm.s256246] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 06/13/2020] [Indexed: 12/15/2022] Open
Abstract
The 2019 novel coronavirus disease (COVID-19) was first detected in Wuhan, Hubei Province, China, in late 2019. Since then, COVID-19 has spread to more than 200 countries in the world, and a global pandemic has been declared by the World Health Organization (WHO). At present, no vaccines or therapeutic regimens with proven efficacy are available for the management of COVID-19. Hydroxychloroquine/chloroquine, lopinavir/ritonavir, ribavirin, interferons, umifenovir, remdesivir, and interleukin antagonists, such as tocilizumab, have been recommended as potential treatment options in COVID-19. Transplant patients receiving immunosuppressant medications are at the highest risk of severe illness from COVID-19. At the same time, with regard to receiving polypharmacy and immunosuppressants, treatment options should be chosen with more attention in this population. Considering drug-drug interactions and adverse effects of medications used for the treatment of COVID-19, such as QT prolongation, the dose reduction of some immunosuppressants or avoidance is recommended in transplant recipients with COVID-19. Thus, this narrative review describes clinically important considerations about the treatment of COVID-19 and immunosuppressive regimens regarding modifications, side effects, and interactions in adult kidney or liver allograft recipients.
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Affiliation(s)
- Mahtabalsadat Mirjalili
- Department of Clinical Pharmacy, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mojtaba Shafiekhani
- Department of Clinical Pharmacy, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
- Shiraz Organ Transplant Center, Abu-Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Afsaneh Vazin
- Department of Clinical Pharmacy, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
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Kwon JE, Lee YG, Kang JH, Bai YF, Jeong YJ, Baek NI, Seo YJ, Kang SC. Anti-viral activity of compounds from Agrimonia pilosa and Galla rhois extract mixture. Bioorg Chem 2019; 93:103320. [DOI: 10.1016/j.bioorg.2019.103320] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 09/18/2019] [Accepted: 09/26/2019] [Indexed: 01/22/2023]
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Tanaka T, Voigt MD. Acute cellular rejection in hepatitis C recipients following liver transplantation in the era of direct-acting antivirals: chronological analysis of the United Network for Organ Sharing database. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2019; 26:393-400. [PMID: 31211912 DOI: 10.1002/jhbp.645] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Interferon (IFN) treatment for liver transplant (LT) recipients with hepatitis C virus (HCV) increases acute cellular rejection (ACR) and worsens graft and patient survival. It is unknown if direct-acting antivirals (DAAs) affect rejection rates or post-transplant survival. METHOD The United Network for Organ Sharing STAR files of December 2017 (n = 25,916) were analyzed. RESULTS Compared with non-HCV-LT, HCV-LT survival was worse in the IFN-era (2007-2008) and IFN+DAA-era (2011), but not in the DAA-era (2014-2015). ACR6m rate has been less frequent in newer eras and was lower in HCV-LT than in non-HCV-LT in both the DAA-era (6.9% vs. 9.3%, P < 0.001) and in the IFN+DAA-era (8.8% vs. 11.8%, P = 0.001), but not in the IFN-era (10.8% vs. 11.0%, P = 0.39). HCV-LT recipients who had ACR6m had worse 2-year survival than those without ACR6m, in the IFN-era (80.0% vs. 88.4%, P < 0.0001) and in the IFN+DAA-era (81.4% vs. 89.2%, P < 0.01) but not in the DAA-era (90.4% vs. 93.2%, P = 0.085). Cox proportional hazard model identified ACR6m as independent risk factor for mortality in HCV-LT in the IFN-era (HR = 1.88, P ≤ 0.001) and in the IFN+DAA-era (HR = 1.84, P = 0.005), but not in the DAA-era (P = n.s.). CONCLUSIONS Two-year survival of HCV-LT recipients were significantly better in the DAA-era; these were associated with reduced rate and impact of ACR6m.
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Affiliation(s)
- Tomohiro Tanaka
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA
| | - Michael D Voigt
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA
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10
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Te H, Doucette K. Viral hepatitis: Guidelines by the American Society of Transplantation Infectious Disease Community of Practice. Clin Transplant 2019; 33:e13514. [DOI: 10.1111/ctr.13514] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 02/12/2019] [Indexed: 12/13/2022]
Affiliation(s)
- Helen Te
- Center for Liver Diseases, Section of Gastroenterology, Hepatology and Nutrition University of Chicago Medicine Chicago Illinois
| | - Karen Doucette
- Division of Infectious Diseases University of Alberta Edmonton Alberta Canada
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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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The Changing Face of Liver Transplantation in the United States: The Effect of HCV Antiviral Eras on Transplantation Trends and Outcomes. Transplant Direct 2019; 5:e427. [PMID: 30882032 PMCID: PMC6411219 DOI: 10.1097/txd.0000000000000866] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Accepted: 01/04/2019] [Indexed: 02/07/2023] Open
Abstract
Background Hepatitis C virus (HCV) cirrhosis is the leading indication for liver transplantation in the United States, although nonalcoholic steatohepatitis (NASH) is on the rise. Increasingly effective HCV antivirals are available, but their association with diagnosis-specific liver transplantation rates and early graft survival is not known. Methods The Scientific Registry of Transplant Recipients database records were retrospectively stratified by HCV antiviral era: interferon (2003-2010), protease inhibitors (2011-2013), and direct-acting antivirals (2014 to present). Kaplan-Meier, χ2, and multivariable Cox proportional hazards regression models evaluated the effects of antiviral era and etiology of liver disease on transplantation rates and graft survival over 3 years. Results Liver transplants for HCV decreased (35.3% to 23.6%), whereas those for NASH and alcoholic liver disease increased (5.8% to 16.5% and 15.6% to 24.0%) with each advancing era (all P < 0.05). Early graft survival improved with each advancing era for HCV but not for hepatitis B virus, NASH, or alcoholic liver disease (multivariable model era by diagnosis interaction P < 0.001). Era-specific multivariable models demonstrated that the risk of early graft loss for NASH was 22% lower than for HCV in the interferon era (hazard ratio, 0.78; 95% confidence interval, 0.64-0.96; P = 0.02) but risks associated with these diagnoses did not differ significantly in the protease inhibitor (P = 0.06) or direct-acting antiviral eras (P = 0.08). Conclusions Increasing effectiveness of HCV antivirals corresponds with decreased rates of liver transplantation for HCV and improved early graft survival. As the rates of liver transplant for NASH continue to increase, focus will be needed on the prevention and effective therapies for this disease.
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White SL, Rawlinson W, Boan P, Sheppeard V, Wong G, Waller K, Opdam H, Kaldor J, Fink M, Verran D, Webster A, Wyburn K, Grayson L, Glanville A, Cross N, Irish A, Coates T, Griffin A, Snell G, Alexander SI, Campbell S, Chadban S, Macdonald P, Manley P, Mehakovic E, Ramachandran V, Mitchell A, Ison M. Infectious Disease Transmission in Solid Organ Transplantation: Donor Evaluation, Recipient Risk, and Outcomes of Transmission. Transplant Direct 2019; 5:e416. [PMID: 30656214 PMCID: PMC6324914 DOI: 10.1097/txd.0000000000000852] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 08/15/2018] [Indexed: 12/11/2022] Open
Abstract
In 2016, the Transplantation Society of Australia and New Zealand, with the support of the Australian Government Organ and Tissue authority, commissioned a literature review on the topic of infectious disease transmission from deceased donors to recipients of solid organ transplants. The purpose of this review was to synthesize evidence on transmission risks, diagnostic test characteristics, and recipient management to inform best-practice clinical guidelines. The final review, presented as a special supplement in Transplantation Direct, collates case reports of transmission events and other peer-reviewed literature, and summarizes current (as of June 2017) international guidelines on donor screening and recipient management. Of particular interest at the time of writing was how to maximize utilization of donors at increased risk for transmission of human immunodeficiency virus, hepatitis C virus, and hepatitis B virus, given the recent developments, including the availability of direct-acting antivirals for hepatitis C virus and improvements in donor screening technologies. The review also covers emerging risks associated with recent epidemics (eg, Zika virus) and the risk of transmission of nonendemic pathogens related to donor travel history or country of origin. Lastly, the implications for recipient consent of expanded utilization of donors at increased risk of blood-borne viral disease transmission are considered.
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Affiliation(s)
- Sarah L White
- Central Clinical School, Sydney Medical School, The University of Sydney, Sydney, Australia
| | - William Rawlinson
- Serology and Virology Division, NSW Health Pathology Prince of Wales Hospital, Sydney, Australia
- Women's and Children's Health and Biotechnology and Biomolecular Sciences, University of New South Wales Schools of Medicine, Sydney, Australia
| | - Peter Boan
- Departments of Infectious Diseases and Microbiology, Fiona Stanley Hospital, Perth, Australia
- PathWest Laboratory Medicine, Perth, Australia
| | - Vicky Sheppeard
- Communicable Diseases Network Australia, New South Wales Health, Sydney, Australia
| | - Germaine Wong
- Centre for Transplant and Renal Research, Westmead Hospital, Sydney, Australia
- Centre for Kidney Research, The Children's Hospital at Westmead, Sydney, Australia
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
| | - Karen Waller
- Central Clinical School, Sydney Medical School, The University of Sydney, Sydney, Australia
| | - Helen Opdam
- Austin Health, Melbourne, Australia
- The Organ and Tissue Authority, Australian Government, Canberra, Australia
| | - John Kaldor
- Kirby Institute, University of New South Wales, Sydney, Australia
| | - Michael Fink
- Austin Health, Melbourne, Australia
- Department of Surgery, Melbourne Medical School, The University of Melbourne, Melbourne, Australia
| | - Deborah Verran
- Transplantation Services, Royal Prince Alfred Hospital, Sydney, Australia
| | - Angela Webster
- Centre for Transplant and Renal Research, Westmead Hospital, Sydney, Australia
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
| | - Kate Wyburn
- Central Clinical School, Sydney Medical School, The University of Sydney, Sydney, Australia
- Renal Medicine, Royal Prince Alfred Hospital, Sydney, Australia
| | - Lindsay Grayson
- Austin Health, Melbourne, Australia
- Department of Surgery, Melbourne Medical School, The University of Melbourne, Melbourne, Australia
| | - Allan Glanville
- Department of Thoracic Medicine and Lung Transplantation, St Vincent's Hospital, Sydney, Australia
| | - Nick Cross
- Department of Nephrology, Canterbury District Health Board, Christchurch Hospital, Christchurch, New Zealand
| | - Ashley Irish
- Department of Nephrology, Fiona Stanley Hospital, Perth, Australia
- Faculty of Health and Medical Sciences, UWA Medical School, The University of Western Australia, Crawley, Australia
| | - Toby Coates
- Renal and Transplantation, Royal Adelaide Hospital, Adelaide, Australia
- Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia
| | - Anthony Griffin
- Renal Transplantation, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia
| | - Greg Snell
- Lung Transplant, Alfred Health, Melbourne, Victoria, Australia
| | - Stephen I Alexander
- Centre for Kidney Research, The Children's Hospital at Westmead, Sydney, Australia
| | - Scott Campbell
- Department of Renal Medicine, University of Queensland at Princess Alexandra Hospital, Woolloongabba, Queensland, Australia
| | - Steven Chadban
- Central Clinical School, Sydney Medical School, The University of Sydney, Sydney, Australia
- Renal Medicine, Royal Prince Alfred Hospital, Sydney, Australia
| | - Peter Macdonald
- Department of Cardiology, St Vincent's Hospital, Sydney, Australia
- St Vincent's Hospital Victor Chang Cardiac Research Institute, University of New South Wales, Sydney, Australia
| | - Paul Manley
- Kidney Disorders, Auckland District Health Board, Auckland City Hospital, Auckland, New Zealand
| | - Eva Mehakovic
- The Organ and Tissue Authority, Australian Government, Canberra, Australia
| | - Vidya Ramachandran
- Serology and Virology Division, NSW Health Pathology Prince of Wales Hospital, Sydney, Australia
| | - Alicia Mitchell
- Department of Thoracic Medicine and Lung Transplantation, St Vincent's Hospital, Sydney, Australia
- Woolcock Institute of Medical Research, Sydney, Australia
- School of Medical and Molecular Biosciences, University of Technology, Sydney, Australia
| | - Michael Ison
- Divisions of Infectious Diseases and Organ Transplantation, Northwestern University Feinberg School of Medicine, Chicago, IL
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14
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De Novo Autoimmune Hepatitis Following Liver Transplantation. Transplant Proc 2018; 50:1451-1456. [DOI: 10.1016/j.transproceed.2018.02.066] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2017] [Revised: 02/01/2018] [Accepted: 02/17/2018] [Indexed: 02/07/2023]
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15
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Mauro E, Crespo G, Montironi C, Londoño MC, Hernández-Gea V, Ruiz P, Sastre L, Lombardo J, Mariño Z, Díaz A, Colmenero J, Rimola A, Garcia-Pagán JC, Brunet M, Forns X, Navasa M. Portal pressure and liver stiffness measurements in the prediction of fibrosis regression after sustained virological response in recurrent hepatitis C. Hepatology 2018; 67:1683-1694. [PMID: 28960366 DOI: 10.1002/hep.29557] [Citation(s) in RCA: 117] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Revised: 08/21/2017] [Accepted: 09/25/2017] [Indexed: 12/11/2022]
Abstract
UNLABELLED Sustained virological response (SVR) improves survival in post-liver transplant (LT) recurrent hepatitis C. However, the impact of SVR on fibrosis regression is not well defined. In addition, the performance of noninvasive methods to evaluate the presence of fibrosis and portal hypertension (PH) post-SVR has been scarcely evaluated. We aimed to investigate the degree of fibrosis regression (decrease ≥1 METAVIR stage) after-SVR and its associated factors in recurrent hepatitis C, as well as the diagnostic capacity of noninvasive methods in the assessment of liver fibrosis and PH after viral clearance. We evaluated 112 hepatitis C virus-infected LT recipients who achieved SVR between 2001 and 2015. A liver biopsy was performed before treatment and 12 months post-SVR. Hepatic venous pressure gradient (HVPG), liver stiffness measurement (LSM), and Enhanced Liver Fibrosis (ELF) score were also determined at the same time points. Sixty-seven percent of the cohort presented fibrosis regression: 43% in recipients with cirrhosis and 72%-85% in the remaining stages (P = 0.002). HVPG, LSM, and ELF significantly decreased post-SVR. Liver function significantly improved, and survival was significantly better in patients achieving fibrosis regression. Baseline HVPG and LSM as well as decompensations before therapy were independent predictors of fibrosis regression. One year post-SVR, LSM had a high diagnostic accuracy to discard the presence of advanced fibrosis (AF) and clinically significant PH (AUROC, 0.902 and 0.888). CONCLUSION In conclusion, SVR post-LT induces fibrosis regression in most patients, leading to significant clinical benefits. Pretreatment HVPG and LSM are significant determinants of the likelihood of fibrosis regression. Finally, LSM accurately predicts the presence of AF and PH 1 year after SVR and thus can be used to determine monitoring strategies. (Hepatology 2018;67:1683-1694).
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Affiliation(s)
- Ezequiel Mauro
- Liver Transplant Unit, Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain.,Liver Unit, Hospital Italiano, Buenos Aires, Argentina
| | - Gonzalo Crespo
- Liver Transplant Unit, Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
| | | | | | - Virginia Hernández-Gea
- Barcelona Hemodynamics Laboratory, Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
| | - Pablo Ruiz
- Liver Transplant Unit, Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
| | - Lydia Sastre
- Liver Transplant Unit, Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
| | - Julissa Lombardo
- Liver Transplant Unit, Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
| | - Zoe Mariño
- Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
| | - Alba Díaz
- Pathology Department, Hospital Clínic, Barcelona, Spain
| | - Jordi Colmenero
- Liver Transplant Unit, Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
| | - Antoni Rimola
- Liver Transplant Unit, Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
| | - Juan Carlos Garcia-Pagán
- Barcelona Hemodynamics Laboratory, Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
| | - Mercé Brunet
- Pharmacology and Toxicology, IDIBAPS, CIBERehd, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Xavier Forns
- Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
| | - Miquel Navasa
- Liver Transplant Unit, Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
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16
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Cholankeril G, Li AA, March KL, Yoo ER, Kim D, Snyder H, Gonzalez SA, Younossi ZM, Ahmed A. Improved Outcomes in HCV Patients Following Liver Transplantation During the Era of Direct-Acting Antiviral Agents. Clin Gastroenterol Hepatol 2018; 16:452-453. [PMID: 28838786 DOI: 10.1016/j.cgh.2017.08.020] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 08/08/2017] [Accepted: 08/17/2017] [Indexed: 02/07/2023]
Affiliation(s)
- George Cholankeril
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California
| | - Andrew A Li
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California
| | - Katherine L March
- Division of Gastroenterology and Hepatology, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Eric R Yoo
- Department of Medicine, University of Illinois College of Medicine, Chicago, Illinois
| | - Donghee Kim
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California
| | - Heather Snyder
- Division of Gastroenterology and Hepatology, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Stevan A Gonzalez
- Simmons Transplant Institute, Baylor All Saints Medical Center, Fort Worth, Texas
| | - Zobair M Younossi
- Department of Medicine, Inova Fairfax Hospital, Falls Church, Virginia
| | - Aijaz Ahmed
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California.
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17
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Choudhary NS, Saraf N, Saigal S, Gautam D, Rastogi A, Goja S, Bhangui P, Srinivasan T, Yadav SK, Soin A. Revisiting chronic rejection following living donor liver transplantation in the tacrolimus era: A single center experience. Clin Transplant 2018; 32. [DOI: 10.1111/ctr.13161] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/12/2017] [Indexed: 01/02/2023]
Affiliation(s)
- Narendra Singh Choudhary
- Institute of Liver Transplantation and Regenerative Medicine; Medanta, The Medicity; Gurgaon India
| | - Neeraj Saraf
- Institute of Liver Transplantation and Regenerative Medicine; Medanta, The Medicity; Gurgaon India
| | - Sanjiv Saigal
- Institute of Liver Transplantation and Regenerative Medicine; Medanta, The Medicity; Gurgaon India
| | - Dheeraj Gautam
- Department of Histopathology; Medanta, The Medicity; Gurgaon India
| | - Amit Rastogi
- Institute of Liver Transplantation and Regenerative Medicine; Medanta, The Medicity; Gurgaon India
| | - Sanjay Goja
- Institute of Liver Transplantation and Regenerative Medicine; Medanta, The Medicity; Gurgaon India
| | - Prashant Bhangui
- Institute of Liver Transplantation and Regenerative Medicine; Medanta, The Medicity; Gurgaon India
| | - Thiagrajan Srinivasan
- Institute of Liver Transplantation and Regenerative Medicine; Medanta, The Medicity; Gurgaon India
| | - Sanjay Kumar Yadav
- Institute of Liver Transplantation and Regenerative Medicine; Medanta, The Medicity; Gurgaon India
| | - Arvinder Soin
- Institute of Liver Transplantation and Regenerative Medicine; Medanta, The Medicity; Gurgaon India
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18
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Nakano R, Ohira M, Ishiyama K, Ide K, Kobayashi T, Tahara H, Shimizu S, Arihiro K, Imamura M, Chayama K, Tanaka Y, Ohdan H. Acute Graft Rejection and Formation of De Novo Donor-Specific Antibodies Triggered by Low Cyclosporine Levels and Interferon Therapy for Recurrent Hepatitis C Infection After Liver Transplantation: A Case Report. Transplant Proc 2017; 49:1634-1638. [PMID: 28838454 DOI: 10.1016/j.transproceed.2017.05.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Accepted: 05/13/2017] [Indexed: 12/20/2022]
Abstract
BACKGROUND We report a case of acute rejection of a liver graft, together with the occurrence of de novo donor-specific antibodies (DSAs), in a 53-year-old Japanese man who had undergone deceased-donor liver transplantation. METHODS The graft rejection was triggered by low cyclosporine levels and pegylated interferon treatment for the recurrence of hepatitis C virus (HCV) infection 18 months after transplantation. Although the graft was ABO-compatible, pre-formed DSA B51 was detected; therefore, total plasma exchange was performed and intravenous rituximab (500 mg/body) was administered before transplantation. RESULTS DSA was absent 6 months after transplantation. HCV recurrence was treated with pegylated interferon-α-2a. Renal function deteriorated with this anti-HCV therapy, with serum cyclosporine levels decreasing to 50 ng/mL. A rapid virologic response was achieved, but liver function deteriorated after 3 months of anti-HCV therapy, with histologic evidence of acute cellular rejection and formation of de novo DSAs. Anti-thymocyte globulin was administered for 5 days, which led to immediate improvement in liver function. However, renal function declined, warranting hemodialysis. The patient recovered 2 months after acute rejection, although de novo DSAs persisted. CONCLUSIONS Careful immunologic monitoring may be required for patients receiving interferon therapy for HCV infection to maintain sufficient blood levels of immunosuppressive agents and to prevent acute liver graft rejection.
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Affiliation(s)
- R Nakano
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - M Ohira
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
| | - K Ishiyama
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - K Ide
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - T Kobayashi
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - H Tahara
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - S Shimizu
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - K Arihiro
- Department of Pathology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
| | - M Imamura
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan
| | - K Chayama
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan
| | - Y Tanaka
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - H Ohdan
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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19
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ELITA consensus statements on the use of DAAs in liver transplant candidates and recipients. J Hepatol 2017; 67:585-602. [PMID: 28323126 DOI: 10.1016/j.jhep.2017.03.006] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2016] [Revised: 03/01/2017] [Accepted: 03/09/2017] [Indexed: 02/07/2023]
Abstract
The advent of safe and highly effective direct-acting antiviral agents (DAAs) has had huge implications for the hepatitis C virus (HCV) transplant field, and changed our management of both patients on the waiting list and those with HCV graft re-infection after liver transplantation (LT). When treating HCV infection before LT, HCV re-infection of the graft can be prevented in nearly all patients. In addition, some candidates show a remarkable clinical improvement and may be delisted. Alternatively, HCV infection can be treated post-LT either soon after the transplant, taking advantage of the removal of the infected native liver, or at the time of disease recurrence, as was carried out in the past. In either case, some DAAs have a limited use because of their drug to drug interactions with various immunosuppressants as well as the many other drugs liver transplant recipients are often prescribed. In addition, some DAAs should be avoided in case of severe renal failure, which is not an unusual complication after LT. The present document provides a series of consensus statements on the LT issues that have not been extensively addressed previously. These statements have been developed to support physicians and other stakeholders in charge of LT candidates and recipients when deciding to treat HCV, especially in difficult situations.
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20
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Abstract
Recurrent autoimmune hepatitis (AIH) and de novo AIH are 2 important causes of late graft failure after liver transplantation (LT). Recurrent AIH occurs in patients who undergo LT for AIH. De novo AIH occurs in patients who are transplanted for etiologies other than AIH. Although typically treated with standard treatment for AIH, including corticosteroids and azathioprine, both recurrent and de novo AIH may progress to end-stage liver disease requiring retransplantation.
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Affiliation(s)
- Eliza W Beal
- Division of Transplantation, Department of Surgery, The Ohio State University Wexner Medical Center, 395 West 12th Avenue, Suite 100, Columbus, OH 43210, USA
| | - Sylvester M Black
- Division of Transplantation, Department of Surgery, The Ohio State University Wexner Medical Center, 395 West 12th Avenue, Suite 100, Columbus, OH 43210, USA
| | - Anthony Michaels
- Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, 395 West 12th Avenue, Suite 200, Columbus, OH 43210, USA.
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21
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Little EC, Berenguer M. The New Era of Hepatitis C: Therapy in Liver Transplant Recipients. Clin Liver Dis 2017; 21:421-434. [PMID: 28364822 DOI: 10.1016/j.cld.2016.12.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) is the leading cause of end-stage liver disease in both Europe and the United States and is the most common reason for liver transplant. In the absence of antiviral therapy, recurrent infection is the norm with subsequent graft hepatitis and impaired survival. Whether it may be better to postpone therapy in patients in whom higher risk of failure and toxicity is coupled with lower chance of liver function improvement likely depends on several factors, including waiting time, center allocation policy, presence of hepatocellular carcinoma and local prevalence of anti-HCV-positive donors.
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Affiliation(s)
- Ester Coelho Little
- Banner Transplant Institute, 1441 North 12th Street, Second floor, Phoenix, AZ 85006, USA; Banner University Medical Center Phoenix, Phoenix, AZ, USA
| | - Marina Berenguer
- Servicio de Medicina Digestivo (Torre F-5), La Fe University Hospital, Ciberehd*, University of Valencia, Avda Fernando Abril Martorell n 106, Valencia 46026, Spain.
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22
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Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res 2017; 142:83-122. [PMID: 28238877 PMCID: PMC7172984 DOI: 10.1016/j.antiviral.2017.02.014] [Citation(s) in RCA: 126] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Revised: 02/07/2017] [Accepted: 02/22/2017] [Indexed: 12/12/2022]
Abstract
One of the most exciting developments in antiviral research has been the discovery of the direct-acting antivirals (DAAs) that effectively cure chronic hepatitis C virus (HCV) infections. Based on more than 100 clinical trials and real-world studies, we provide a comprehensive overview of FDA-approved therapies and newly discovered anti-HCV agents with a special focus on drug efficacy, mechanisms of action, and safety. We show that HCV drug development has advanced in multiple aspects: (i) interferon-based regimens were replaced by interferon-free regimens; (ii) genotype-specific drugs evolved to drugs for all HCV genotypes; (iii) therapies based upon multiple pills per day were simplified to a single pill per day; (iv) drug potency increased from moderate (∼60%) to high (>90%) levels of sustained virologic responses; (v) treatment durations were shortened from 48 to 12 or 8 weeks; and (vi) therapies could be administered orally regardless of prior treatment history and cirrhotic status. However, despite these remarkable achievements made in HCV drug discovery, challenges remain in the management of difficult-to-treat patients.
HCV genotype-specific drugs evolve to pan-genotypic drugs. Drug potency increases from moderate (∼60%) to high (>90%) levels of sustained virologic response. Treatment durations are shortened from a 48-week to 12-week or 8-week period. HCV therapies based upon multiple pills per day are simplified to a single pill per day. HCV therapies are administered orally regardless of prior treatment history and cirrhotic status.
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23
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Ibáñez-Samaniego L, Salcedo M, Vaquero J, Bañares R. De novo autoimmune hepatitis after liver transplantation: A focus on glutathione S-transferase theta 1. Liver Transpl 2017; 23:75-85. [PMID: 27712026 DOI: 10.1002/lt.24652] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Accepted: 09/13/2016] [Indexed: 02/07/2023]
Abstract
De novo autoimmune hepatitis (DAIH) is a rare clinical condition with features that resemble those of autoimmune hepatitis (AIH) in patients undergoing liver transplantation (LT) for nonautoimmune liver disease. The diagnosis of this entity has been based on the presence of biochemical and histological patterns similar to those observed in the primary AIH, although several considerations must be taken into account. The impact of DAIH on graft survival is relevant, and early diagnosis and treatment is associated with a good longterm outcome. Although glutathione S-transferase theta 1 (GSTT1) alloimmune recognition has been shown to be involved in the pathogenesis of DAIH, further studies are necessary to fully determine its pathogenic mechanisms and risk factors. We review the pathophysiology, the most common histological patterns, the treatment strategies, and the longterm outcomes of DAIH after LT with a special focus on GSTT1. Liver Transplantation 23:75-85 2017 AASLD.
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Affiliation(s)
- Luis Ibáñez-Samaniego
- Digestive Disease Department and Liver Transplantation Unit, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria del Hospital Gregorio Marañón, Madrid, Spain
| | - Magdalena Salcedo
- Digestive Disease Department and Liver Transplantation Unit, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria del Hospital Gregorio Marañón, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - Javier Vaquero
- Digestive Disease Department and Liver Transplantation Unit, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria del Hospital Gregorio Marañón, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - Rafael Bañares
- Digestive Disease Department and Liver Transplantation Unit, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria del Hospital Gregorio Marañón, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain.,Facultad de Medicina, Universidad Complutense, Madrid, Spain
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24
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Bifano M, Adamczyk R, Hwang C, Kandoussi H, Marion A, Bertz RJ. An open-label investigation into drug-drug interactions between multiple doses of daclatasvir and single-dose cyclosporine or tacrolimus in healthy subjects. Clin Drug Investig 2016; 35:281-9. [PMID: 25896946 PMCID: PMC4544506 DOI: 10.1007/s40261-015-0279-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Background and Objective Chronic hepatitis C virus (HCV) infection is a major cause of liver transplantation. Drug–drug interactions (DDIs) with cyclosporine and tacrolimus hindered the use of first-generation protease inhibitors in transplant recipients. The current study investigated DDIs between daclatasvir—a pan-genotypic HCV NS5A inhibitor with clinical efficacy in multiple regimens (including all-oral)—and cyclosporine or tacrolimus in healthy subjects. Methods Healthy fasted subjects (aged 18–49 years; body mass index 18–32 kg/m2) received single oral doses of cyclosporine 400 mg on days 1 and 9, and daclatasvir 60 mg once daily on days 4–11 (group 1, n = 14), or a single oral dose of tacrolimus 5 mg on days 1 and 13, and daclatasvir 60 mg once daily on days 8–19 (group 2, n = 14). Blood samples for pharmacokinetic analysis [by liquid chromatography with tandem mass spectrometry (LC–MS/MS)] were collected on days 1 and 9 for cyclosporine (72 h), on days 1 and 13 for tacrolimus (168 h) and on days 8 and 9 (group 1) or on days 12 and 13 (group 2) for daclatasvir (24 h). Plasma concentrations were determined by validated LC–MS/MS methods. Results Daclatasvir did not affect the pharmacokinetic parameters of cyclosporine or tacrolimus, and tacrolimus did not affect the pharmacokinetic parameters of daclatasvir. Co-administration of cyclosporine resulted in a 40 % increase in the area under the concentration–time curve of daclatasvir but did not affect its maximum observed concentration. Conclusion On the basis of these observations in healthy subjects, no clinically relevant DDIs between daclatasvir and cyclosporine or tacrolimus are anticipated in liver transplant recipients infected with HCV; dose adjustments during co-administration are unlikely to be required.
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Affiliation(s)
- Marc Bifano
- />Bristol-Myers Squibb Research and Development, 311 Pennington Rock Hill Road, Hopewell, NJ 08534 USA
| | - Robert Adamczyk
- />Bristol-Myers Squibb Research and Development, 311 Pennington Rock Hill Road, Hopewell, NJ 08534 USA
| | - Carey Hwang
- />Bristol-Myers Squibb Research and Development, 311 Pennington Rock Hill Road, Hopewell, NJ 08534 USA
| | - Hamza Kandoussi
- />Bristol-Myers Squibb Research and Development, Lawrenceville, NJ USA
| | | | - Richard J. Bertz
- />Bristol-Myers Squibb Research and Development, 311 Pennington Rock Hill Road, Hopewell, NJ 08534 USA
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25
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Tanaka T, Akamatsu N, Kaneko J, Arita J, Tamura S, Hasegawa K, Sakamoto Y, Kokudo N. Daclatasvir and asunaprevir for recurrent hepatitis C following living donor liver transplantation with HIV co-infection. Hepatol Res 2016; 46:829-832. [PMID: 26508337 DOI: 10.1111/hepr.12614] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2015] [Revised: 10/05/2015] [Accepted: 10/19/2015] [Indexed: 02/06/2023]
Abstract
Antiviral treatment in liver transplant recipients co-infected with hepatitis C virus (HCV) and HIV remains a challenge. We herein report a case of HCV recurrence that was successfully treated using interferon-free anti-HCV therapy with daclatasvir and asunaprevir. A 48-year-old man underwent antiviral therapy with a 24-week course of daclatasvir and asunaprevir for biopsy-proven recurrent HCV 15 months after living donor liver transplantation, following non-response to pre-emptive antiviral treatment with pegylated interferon plus ribavirin. Anti-HIV and immunosuppressive regimens were modified safely. Renal function was feasibly preserved. The anti-HCV effect was remarkable with an undetectable viral load confirmed within 2 weeks, and this patient achieved a sustained virological response after 12 weeks of post-transplantation treatment. No serious adverse events were observed. This case indicates that daclatasvir and asunaprevir for recurrent HCV in a HIV co-infected recipient after liver transplantation is safe and effective.
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Affiliation(s)
- Tomohiro Tanaka
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo
| | - Nobuhisa Akamatsu
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo
| | - Junichi Kaneko
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo
| | - Junichi Arita
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo
| | - Sumihito Tamura
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo
| | - Kiyoshi Hasegawa
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo
| | - Yoshihiro Sakamoto
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo
| | - Norihiro Kokudo
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo
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Abstract
Recurrence of hepatitis C after liver transplantation is a major problem; it is characterized by high hepatitis C virus (HCV)-RNA, rapid progression, and cholestatic hepatitis. Treatment for HCV infection with peginterferon and ribavirin has been administered to prevent progression of hepatitis C after liver transplantation. However, it has low efficacy and causes many adverse events, including immune-mediated graft dysfunction. Interferon-containing regimens with direct-acting antivirals (DAAs) improve treatment efficacy but DAAs cause serious adverse events and drug-drug interactions. Recent studies have demonstrated the efficacy and safety of interferon-free therapy with DAAs before and after liver transplantation, which has ushered in a new era in the strategy for treating HCV in transplant recipients. Interferon-free therapies are safe and effective in patients before and after liver transplantation as well as in those with severe cholestatic hepatitis C. Several obstacles must be overcome before the widespread adoption of interferon-free therapy, including drug-drug interactions, DAA-resistant HCV, treatment for decompensated cirrhosis, and treatment for renal failure. These problems are expected to be solved in the near future, and the poor prognosis of HCV-positive recipients will improve.
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Fontana RJ, Brown RS, Moreno-Zamora A, Prieto M, Joshi S, Londoño MC, Herzer K, Chacko KR, Stauber RE, Knop V, Jafri SM, Castells L, Ferenci P, Torti C, Durand CM, Loiacono L, Lionetti R, Bahirwani R, Weiland O, Mubarak A, ElSharkawy AM, Stadler B, Montalbano M, Berg C, Pellicelli AM, Stenmark S, Vekeman F, Ionescu-Ittu R, Emond B, Reddy KR. Daclatasvir combined with sofosbuvir or simeprevir in liver transplant recipients with severe recurrent hepatitis C infection. Liver Transpl 2016; 22:446-458. [PMID: 26890629 DOI: 10.1002/lt.24416] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Revised: 01/12/2016] [Accepted: 01/24/2016] [Indexed: 12/11/2022]
Abstract
Daclatasvir (DCV) is a potent, pangenotypic nonstructural protein 5A inhibitor with demonstrated antiviral efficacy when combined with sofosbuvir (SOF) or simeprevir (SMV) with or without ribavirin (RBV) in patients with chronic hepatitis C virus (HCV) infection. Herein, we report efficacy and safety data for DCV-based all-oral antiviral therapy in liver transplantation (LT) recipients with severe recurrent HCV. DCV at 60 mg/day was administered for up to 24 weeks as part of a compassionate use protocol. The study included 97 LT recipients with a mean age of 59.3 ± 8.2 years; 93% had genotype 1 HCV and 31% had biopsy-proven cirrhosis between the time of LT and the initiation of DCV. The mean Model for End-Stage Liver Disease (MELD) score was 13.0 ± 6.0, and the proportion with Child-Turcotte-Pugh (CTP) A/B/C was 51%/31%/12%, respectively. Mean HCV RNA at DCV initiation was 14.3 × 6 log10 IU/mL, and 37% had severe cholestatic HCV infection. Antiviral regimens were selected by the local investigator and included DCV+SOF (n = 77), DCV+SMV (n = 18), and DCV+SMV+SOF (n = 2); 35% overall received RBV. At the end of treatment (EOT) and 12 weeks after EOT, 88 (91%) and 84 (87%) patients, respectively, were HCV RNA negative or had levels <43 IU/mL. CTP and MELD scores significantly improved between DCV-based treatment initiation and last contact. Three virological breakthroughs and 2 relapses occurred in patients treated with DCV+SMV with or without RBV. None of the 8 patient deaths (6 during and 2 after therapy) were attributed to therapy. In conclusion, DCV-based all-oral antiviral therapy was well tolerated and resulted in a high sustained virological response in LT recipients with severe recurrent HCV infection. Most treated patients experienced stabilization or improvement in their clinical status.
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Affiliation(s)
- Robert J Fontana
- Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI
| | - Robert S Brown
- College of Physicians and Surgeons, Columbia University, New York, NY
| | | | - Martin Prieto
- Hospital Universitario y Politécnico La Fe and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Valencia, Spain
| | - Shobha Joshi
- Department of Gastroenterology, Ochsner Health System, New Orleans, LA
| | | | - Kerstin Herzer
- Department for General, Viszeral and Transplantation Surgery and Department of Gastroenterology and Hepatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Kristina R Chacko
- Einstein Center for Transplantation, Montefiore Medical Center, New York, NY
| | - Rudolf E Stauber
- Department of Internal Medicine, Karl-Franzens-University, Graz, Austria
| | - Viola Knop
- Department of Internal Medicine, University Hospital-Goethe University, Frankfurt, Germany
| | - Syed-Mohammed Jafri
- Department of Gastroenterology and Hepatology, Henry Ford Hospital, Detroit, MI
| | - Lluís Castells
- Internal Medicine Department, Hospital Universitary Vall Hebron, University of Barcelona, Barcelona, Spain
| | - Peter Ferenci
- Department of Internal Medicine IV, Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Carlo Torti
- Unit of Infectious and Tropical Diseases, Magna Graecia University, Cantanzaro, Italy
| | - Christine M Durand
- Department of Medicine Infectious Diseases, Johns Hopkins Medical Institution, Baltimore, MD
| | | | - Raffaella Lionetti
- Liver Unit, IRCCS Lazzaro Spallanzani, National Institute for Infectious Diseases, Rome, Italy
| | - Ranjeeta Bahirwani
- Division of Gastroenterology, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Ola Weiland
- Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Abdullah Mubarak
- Department of Hepatology, Dallas Medical Physicians Group, Dallas, TX
| | - Ahmed M ElSharkawy
- University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Medical Centre, Birmingham, United Kingdom
| | | | - Marzia Montalbano
- Liver Unit, IRCCS Lazzaro Spallanzani, National Institute for Infectious Diseases, Rome, Italy
| | - Christoph Berg
- Department of Internal Medicine, Hepatology, Gastroenterology, Infectious Diseases, University Hospital of Tübingen, Tübingen, Germany
| | | | | | | | | | - Bruno Emond
- Analysis Group, Inc, Montreal, Quebec, Canada
| | - K Rajender Reddy
- Division of Gastroenterology, Hospital of the University of Pennsylvania, Philadelphia, PA
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Saab S, Rheem J, Jimenez M, Bau S, Choi G, Durazo F, El Kabany M, Han S, Farid A, Jamal N, Grotts J, Elashoff D, Busuttil RW. Curing Hepatitis C in Liver Transplant Recipients Is Associated with Changes in Immunosuppressant Use. J Clin Transl Hepatol 2016; 4:32-8. [PMID: 27047770 PMCID: PMC4807141 DOI: 10.14218/jcth.2016.00001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Revised: 02/19/2016] [Accepted: 02/24/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND AND AIMS All-oral interferon-free antivirals are highly effective in treating recurrent hepatitis C (HCV) infection in liver transplant (LT) recipients. The aim of the study was to assess immunosuppression needs after achieving a sustained viral response (SVR). METHODS We compared immunosuppression needs before and after achieving a SVR in adult LT recipients treated for recurrent HCV infection with all-oral direct acting agents. RESULTS We identified 52 liver LT treated recipients who achieved a SVR. The median (25th and 75th percentile interquartile range [IQR]) age was 62 years (57.75, 65). Most recipients received tacrolimus (TAC) for their immunosuppressant regimen. After achieving SVR, there was no statistically significant difference in daily dose of TAC unadjusted per weight (p > 0.05). However, there was a statistically significant decrease in daily dose of TAC adjusted per weight, serum levels of TAC, and the product of glomerular filtration rate and TAC. No statistically significant differences in cyclosporine unadjusted/adjusted per weight daily dose or serum levels were noted. CONCLUSIONS Immunosuppression needs were increased for those patients treated with TAC but not cyclosporine. LT recipients prescribed TAC require close monitoring after treatment completion to avoid potential risk of acute rejection.
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Affiliation(s)
- Sammy Saab
- Departments of Medicine at the University of California at Los Angeles, Los Angeles, California, USA
- Department of Surgery at the University of California at Los Angeles, Los Angeles, California, USA
- Correspondence to: Sammy Saab, Pfleger Liver Institute, UCLA Medical Center, 200 Medical Plaza, Suite 214, Los Angeles, CA 90095, USA. Tel: +1-310-206-6705, Fax: +1-310-206-4197, E-mail:
| | - Justin Rheem
- Department of Medicine at Harbor-University of California at Los Angeles Medical Center, Torrance, California, USA
| | - Melissa Jimenez
- Departments of Medicine at the University of California at Los Angeles, Los Angeles, California, USA
| | - Sherona Bau
- Department of Surgery at the University of California at Los Angeles, Los Angeles, California, USA
| | - Gina Choi
- Departments of Medicine at the University of California at Los Angeles, Los Angeles, California, USA
- Department of Surgery at the University of California at Los Angeles, Los Angeles, California, USA
| | - Francisco Durazo
- Departments of Medicine at the University of California at Los Angeles, Los Angeles, California, USA
- Department of Surgery at the University of California at Los Angeles, Los Angeles, California, USA
| | - Mohammed El Kabany
- Departments of Medicine at the University of California at Los Angeles, Los Angeles, California, USA
- Department of Surgery at the University of California at Los Angeles, Los Angeles, California, USA
| | - Steven Han
- Departments of Medicine at the University of California at Los Angeles, Los Angeles, California, USA
- Department of Surgery at the University of California at Los Angeles, Los Angeles, California, USA
| | - Alexander Farid
- Departments of Medicine at the University of California at Los Angeles, Los Angeles, California, USA
| | - Naadir Jamal
- Departments of Medicine at the University of California at Los Angeles, Los Angeles, California, USA
| | - Jonathan Grotts
- Departments of Medicine at the University of California at Los Angeles, Los Angeles, California, USA
| | - David Elashoff
- Departments of Medicine at the University of California at Los Angeles, Los Angeles, California, USA
- Department of Biostatistics at the University of California at Los Angeles, Los Angeles, California, USA
| | - Ronald W. Busuttil
- Department of Surgery at the University of California at Los Angeles, Los Angeles, California, USA
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Vukotic R, Vitale G, D’Errico-Grigioni A, Muratori L, Andreone P. De novo autoimmune hepatitis in liver transplant: State-of-the-art review. World J Gastroenterol 2016; 22:2906-2914. [PMID: 26973387 PMCID: PMC4779914 DOI: 10.3748/wjg.v22.i10.2906] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Revised: 11/06/2015] [Accepted: 12/30/2015] [Indexed: 02/06/2023] Open
Abstract
In the two past decades, a number of communications, case-control studies, and retrospective reports have appeared in the literature with concerns about the development of a complex set of clinical, laboratory and histological characteristics of a liver graft dysfunction that is compatible with autoimmune hepatitis. The de novo prefix was added to distinguish this entity from a pre-transplant primary autoimmune hepatitis, but the globally accepted criteria for the diagnosis of autoimmune hepatitis have been adopted in the diagnostic algorithm. Indeed, de novo autoimmune hepatitis is characterized by the typical liver necro-inflammation that is rich in plasma cells, the presence of interface hepatitis and the consequent laboratory findings of elevations in liver enzymes, increases in serum gamma globulin and the appearance of non-organ specific auto-antibodies. Still, the overall features of de novo autoimmune hepatitis appear not to be attributable to a univocal patho-physiological pathway because they can develop in the patients who have undergone liver transplantation due to different etiologies. Specifically, in subjects with hepatitis C virus recurrence, an interferon-containing antiviral treatment has been indicated as a potential inception of immune system derangement. Herein, we attempt to review the currently available knowledge about de novo liver autoimmunity and its clinical management.
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30
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Ikegami T, Yoshizumi T, Yoshida Y, Kurihara T, Harimoto N, Itoh S, Shimokawa M, Fukuhara T, Shirabe K, Maehara Y. Telaprevir versus simeprevir for the treatment of recurrent hepatitis C after living donor liver transplantation. Hepatol Res 2016; 46:E136-45. [PMID: 26096514 DOI: 10.1111/hepr.12546] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2015] [Revised: 06/16/2015] [Accepted: 06/16/2015] [Indexed: 12/17/2022]
Abstract
AIM Our aim was to evaluate the clinical outcomes of telaprevir (TVR)- or simeprevir (SMV)-based triple therapy for recurrent hepatitis C after living donor liver transplantation. METHODS Twenty-six patients received antiviral therapy, consisting of either TVR (n = 12) or SMV (n = 14) in combination with pegylated interferon and ribavirin, plus cyclosporin. RESULTS More patients had a dose reduction of the direct-acting agent (36.3% vs 0.0%, P = 0.02) or required blood transfusion for anemia (58.3% vs 7.1%, P < 0.01) in the TVR group. The cyclosporin trough/dose ratio increased significantly from week 0 to week 4 in the TVR group (1.6 ± 0.4 to 5.1 ± 2.0, P < 0.01), but not in the SMV group (1.2 ± 0.3 to 1.3 ± 0.2, P = 0.68). The 24-week cumulative viral clearance rate was 91.7% and 85.7% in the TVR and in SMV groups, respectively. The early viral response and sustained viral response rates were 91.7% and 83.3%, respectively, in the TVR group, compared with 85.7% and 64.3%, respectively, in the SMV group. Interferon-mediated graft dysfunction occurred in four and five patients in the TVR and SMV groups, respectively; two patients were treated by oral steroids, five by steroid pulse and two by thymoglobulin, resulting in viral breakthrough in one case. CONCLUSION SMV-based triple therapy was associated with fewer adverse events and drug interactions with cyclosporin, and possibly less antiviral properties to TVR. Interferon-mediated graft dysfunction is a significant clinical problem that warrants particular caution following living donor liver transplantation.
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Affiliation(s)
- Toru Ikegami
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshihro Yoshida
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeshi Kurihara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Norifumi Harimoto
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shinji Itoh
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masahiro Shimokawa
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takasuke Fukuhara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ken Shirabe
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshihiko Maehara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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31
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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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Reappraisal of the hepatitis C virus-positive donor in solid organ transplantation. Curr Opin Organ Transplant 2015; 20:267-75. [PMID: 25944236 DOI: 10.1097/mot.0000000000000191] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
PURPOSE OF REVIEW Hepatitis C virus (HCV)-positive donor allografts may be considered for HCV-positive recipients, but are underutilized. With new effective antiviral treatments, we aim to review data on the use of HCV-positive allografts in solid organ transplantation and place them in the context of the changing HCV landscape. RECENT FINDINGS Hepatitis C is the most common indication for liver transplant in the USA and Europe and a significant comorbidity in patients on the waitlist for nonliver solid organ transplantation. Patients with HCV on the waitlist for nonliver solid organ transplantation have worse outcomes compared with those without HCV. However, survival after transplantation is improved compared with those who remain on the waitlist. There has been concern that use of HCV-positive allografts would lead to worse post-transplant outcomes. However, more recent data suggest that transplant outcomes for recipients who accept HCV-positive donor allografts may be comparable with those who receive HCV-negative allografts. Emerging treatments to eradicate HCV have further improved the course of HCV-positive individuals, with improved efficacy and reduced side-effects. SUMMARY In view of the changing landscape of hepatitis C treatment and reduced wait time on the transplant waiting lists for those accepting HCV-positive donors, future use of select HCV-positive donors in solid organ transplantation should be encouraged.
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Charlton M, Gane E, Manns MP, Brown RS, Curry MP, Kwo PY, Fontana RJ, Gilroy R, Teperman L, Muir AJ, McHutchison JG, Symonds WT, Brainard D, Kirby B, Dvory-Sobol H, Denning J, Arterburn S, Samuel D, Forns X, Terrault NA. Sofosbuvir and ribavirin for treatment of compensated recurrent hepatitis C virus infection after liver transplantation. Gastroenterology 2015; 148:108-17. [PMID: 25304641 DOI: 10.1053/j.gastro.2014.10.001] [Citation(s) in RCA: 274] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 09/23/2014] [Accepted: 10/02/2014] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Interferon alfa-based regimens used to treat recurrent hepatitis C virus (HCV) infection after liver transplantation are poorly tolerated, associated with generally modest efficacy, and can interact with immunosuppressive agents. We evaluated the efficacy and safety of an interferon-free regimen of the nucleotide polymerase inhibitor sofosbuvir combined with ribavirin for 24 weeks in treating post-transplantation HCV infection. METHODS In a prospective, multicenter, open-label pilot study, we enrolled patients with compensated recurrent HCV infection of any genotype after a primary or secondary liver transplantation. All patients received 24 weeks of sofosbuvir 400 mg daily and ribavirin starting at 400 mg daily, which was adjusted according to creatinine clearance and hemoglobin values. The primary end point was sustained virologic response 12 weeks after treatment. RESULTS Of the 40 patients enrolled and treated, 78% were male, 85% were white, 83% had HCV genotype 1, 40% had cirrhosis (based on biopsy), and 88% had been previously treated with interferon. Sustained virologic response 12 weeks after treatment was achieved by 28 of 40 patients (70%; 90% confidence interval: 56%-82%). Relapse accounted for all cases of virologic failure. No patients had detectable viral resistance during or after treatment. The most common adverse events were fatigue (30%), diarrhea (28%), and headache (25%). In addition, 20% of the subjects experienced anemia. Two patients discontinued study treatment because of adverse events, which were considered unrelated to study treatment. No deaths, graft losses, or episodes of rejection occurred. No interactions with any concomitant immunosuppressive agents were reported. CONCLUSIONS Sofosbuvir and ribavirin combination therapy for 24 weeks is an effective and well-tolerated interferon-free treatment for post-transplantation HCV infection. EudraCT, Number: 2012-002417-19; ClinicalTrials.gov, Number: NCT01687270.
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Affiliation(s)
| | - Edward Gane
- Auckland City Hospital, Auckland, New Zealand
| | | | | | | | - Paul Y Kwo
- Indiana School of Medicine, Indianapolis, Indiana
| | | | | | | | - Andrew J Muir
- Duke University Medical Center, Durham, North Carolina
| | | | | | | | | | | | | | | | - Didier Samuel
- AP-HP Hôpital Paul Brousse, Centre Hépatobiliaire, and Université Paris Sud, Villejuif, France
| | - Xavier Forns
- Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, Barcelona, Spain
| | - Norah A Terrault
- University of California at San Francisco, San Francisco, California
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Kwo PY, Mantry PS, Coakley E, Te HS, Vargas HE, Brown R, Gordon F, Levitsky J, Terrault NA, Burton JR, Xie W, Setze C, Badri P, Pilot-Matias T, Vilchez RA, Forns X. An interferon-free antiviral regimen for HCV after liver transplantation. N Engl J Med 2014; 371:2375-82. [PMID: 25386767 DOI: 10.1056/nejmoa1408921] [Citation(s) in RCA: 308] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Hepatitis C virus (HCV) infection is the leading indication for liver transplantation worldwide, and interferon-containing regimens are associated with low response rates owing to treatment-limiting toxic effects in immunosuppressed liver-transplant recipients. We evaluated the interferon-free regimen of the NS5A inhibitor ombitasvir coformulated with the ritonavir-boosted protease inhibitor ABT-450 (ABT-450/r), the nonnucleoside NS5B polymerase inhibitor dasabuvir, and ribavirin in liver-transplant recipients with recurrent HCV genotype 1 infection. METHODS We enrolled 34 liver-transplant recipients with no fibrosis or mild fibrosis, who received ombitasvir-ABT-450/r (at a once-daily dose of 25 mg of ombitasvir, 150 mg of ABT-450, and 100 mg of ritonavir), dasabuvir (250 mg twice daily), and ribavirin for 24 weeks. Selection of the initial ribavirin dose and subsequent dose modifications for anemia were at the investigator's discretion. The primary efficacy end point was a sustained virologic response 12 weeks after the end of treatment. RESULTS Of the 34 study participants, 33 had a sustained virologic response at post-treatment weeks 12 and 24, for a rate of 97% (95% confidence interval, 85 to 100). The most common adverse events were fatigue, headache, and cough. Five patients (15%) required erythropoietin; no patient required blood transfusion. One patient discontinued the study drugs owing to adverse events after week 18 but had a sustained virologic response. Blood levels of calcineurin inhibitors were monitored, and dosages were modified to maintain therapeutic levels; no episode of graft rejection was observed during the study. CONCLUSIONS Treatment with the multitargeted regimen of ombitasvir-ABT-450/r and dasabuvir with ribavirin was associated with a low rate of serious adverse events and a high rate of sustained virologic response among liver-transplant recipients with recurrent HCV genotype 1 infection, a historically difficult-to-treat population. (Funded by AbbVie; CORAL-I ClinicalTrials.gov number, NCT01782495.).
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Affiliation(s)
- Paul Y Kwo
- From Indiana University, Indianapolis (P.Y.K.); the Liver Institute at Methodist Dallas, Dallas (P.S.M.); AbbVie, North Chicago, IL (E.C., W.X., C.S., P.B., T.P.-M., R.A.V.); University of Chicago Medical Center (H.S.T.) and Northwestern University Comprehensive Transplant Center (J.L.) - both in Chicago; Mayo Clinic, Phoenix, AZ (H.E.V.); Columbia University Medical Center, Center for Liver Disease and Transplantation, New York (R.B.); Lahey Hospital and Medical Center, Burlington, MA (F.G.); University of California, San Francisco, San Francisco (N.A.T.); University of Colorado Denver, Aurora (J.R.B.); and the Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, University of Barcelona, Barcelona (X.F.)
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Ueda Y, Yoshizawa A, Ogura Y, Miyagawa-Hayashino A, Haga H, Chiba T, Uemoto S. Plasma cell hepatitis induced by the termination of antiviral therapy for recurrent hepatitis C after living donor liver transplantation. Hepatol Res 2014; 44:E279-83. [PMID: 24112365 DOI: 10.1111/hepr.12243] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2013] [Revised: 09/12/2013] [Accepted: 09/13/2013] [Indexed: 02/08/2023]
Abstract
Plasma cell hepatitis (PCH) is an idiopathic disorder characterized by plasma cell infiltration in the allografts of patients who have undergone liver transplantation. Although an increasing number of cases of PCH have been reported in liver transplant recipients with hepatitis C recurrence treated with interferon, it is unclear whether PCH is induced by interferon itself. Here, we describe the cases of two patients who developed PCH just after the termination of antiviral therapy for recurrent hepatitis C after living donor liver transplantation. Liver dysfunction appeared at 1 month in one patient and 2 months in the other patient after pegylated interferon plus ribavirin therapy, and liver histology showed interface hepatitis with plasma cell-rich lymphoid aggregates. Both patients recovered after steroid therapy and achieved sustained virological response. These cases suggest that PCH could be induced by the alteration of the immune condition resulting from the termination of antiviral therapy. PCH should be considered when the transaminase levels increase after antiviral therapy, and it should be carefully distinguished from hepatitis C relapse.
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Affiliation(s)
- Yoshihide Ueda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Borentain P, Colson P, Dhiver C, Gregoire E, Hardwigsen J, Botta-Fridlund D, Garcia S, Gerolami R. Successful treatment with sofosbuvir of fibrosing cholestatic hepatitis C after liver transplantation in an HIV-HCV-coinfected patient. Antivir Ther 2014; 20:353-6. [PMID: 25105441 DOI: 10.3851/imp2841] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/20/2014] [Indexed: 12/15/2022]
Abstract
Fibrosing cholestatic hepatitis is a severe form of post-liver transplantation HCV recurrence. Fibrosing cholestatic hepatitis is characterized by its early onset and severe prognosis in HIV-infected patients. We report the case of an HIV-HCV genotype-4 coinfected patient successfully treated with a combination of sofosbuvir and ribavirin. After 4 weeks of treatment we observed a resolution of HCV recurrence related symptoms associated with a normalization of liver biochemistry and dramatic decrease of HCV viral load. This case illustrates the efficiency and tolerance of a sofosbuvir-based anti-HCV interferon-free regimen in post-liver HCV recurrence. Because of the absence of drug interactions between sofosbuvir and antiretroviral treatment or calcineurin inhibitors, its administration in HIV-HCV-coinfected liver transplanted patients is very promising.
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Affiliation(s)
- Patrick Borentain
- Service d'Hépato-Gastroentérologie, Centre Hospitalo-Universitaire Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France.
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Bunchorntavakul C, Reddy KR. Management of Hepatitis C Before and After Liver Transplantation in the Era of Rapidly Evolving Therapeutic Advances. J Clin Transl Hepatol 2014; 2:124-33. [PMID: 26357623 PMCID: PMC4521260 DOI: 10.14218/jcth.2014.00002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2014] [Revised: 02/13/2014] [Accepted: 02/20/2014] [Indexed: 12/14/2022] Open
Abstract
Management of hepatitis C (HCV) in liver transplantation (LT) population presents unique challenges. Suboptimal graft survival in HCV+ LT recipients is attributable to universal HCV recurrence following LT. Although eradication of HCV prior to LT is ideal for the prevention of HCV recurrence it is often limited by adverse events, particularly in patients with advanced cirrhosis. Antiviral therapy in LT candidates needs careful monitoring, and prophylaxis with HCV antibodies is ineffective. Early antiviral therapy after LT has been investigated, but no clear benefit has been demonstrated. Protocol liver biopsy is generally recommended in HCV+ LT recipients, and antiviral therapy can be considered in those with severe/progressive HCV recurrence. Sustained virological response (SVR) can be achieved in approximately 30% of LT recipients with pegylated interferon/ribavirin (PEG-IFN/RBV) with survival benefit, but adverse effects are common. Favorable patient characteristics for response to therapy include non-1 genotype, previously untreated, low baseline HCV-RNA, and donor IL28B genotype CC. Direct acting antiviral (DAA)-based triple therapy is associated with higher rates of SVR, but with similar or slightly higher rates of side effects, and immunosuppressive regimens need to be closely monitored and adjusted during the treatment period. Notably, the safety and efficacy of HCV treatment are very likely to improve with newer generation DAA. The benefit of immunosuppressive strategy on the natural history HCV recurrence has not been well elucidated. Based upon available evidence, cyclosporine A (CSA), mycophenolate mofetil (MMF), and sirolimus appear to have a neutral or small beneficial impact on HCV recurrence. Donor interleukin 28 B (IL28B) polymorphisms appear to impact the course and treatment outcomes in recurrent HCV. Retransplantation should be considered for patients with reasonable survival probability.
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Affiliation(s)
- Chalermrat Bunchorntavakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Rajavithi Hospital, College of Medicine, Rangsit University, Bangkok, Thailand
| | - K. Rajender Reddy
- Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA, USA
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Pipili C, Cholongitas E. Μanagement of patients with hepatitis B and C before and after liver and kidney transplantation. World J Hepatol 2014; 6:315-25. [PMID: 24868325 PMCID: PMC4033289 DOI: 10.4254/wjh.v6.i5.315] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2013] [Revised: 03/10/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
New nucleos(t)ide analogues (NAs) with high genetic barrier to hepatitis B virus (HBV) resistance (such as entecavir, tenofovir) have improved the prognosis of patients with HBV decompensated cirrhosis and have prevented HBV recurrence after liver transplantation (LT). NAs are considered the most proper approach for HBV infection in patients under renal replacement therapy but their doses should be adjusted according to the patient's creatinine clearance. In addition, physicians should be aware of the potential nephrotoxicity. However, patients with chronic hepatitis C and decompensated cirrhosis can receive only one therapeutic option before LT, as well as for Hepatitis C virus (HCV) recurrence after LT, which is the combination of subcutaneous Peg-IFN and ribavirin. Generally, therapy for HCV after renal transplantation should be avoided. Although the optimal antiviral therapy for HCV infection has not been established, attention has turned to a new, oral direct acting antiviral treatment which marks a promising strategy in prognosis and in amelioration of these diseases.
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Affiliation(s)
- Chrysoula Pipili
- Chrysoula Pipili, Department of Nephrology, Laiki Merimna, 17343 Athens, Greece
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39
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Ueda Y, Kaido T, Ito T, Ogawa K, Yoshizawa A, Fujimoto Y, Mori A, Miyagawa-Hayashino A, Haga H, Marusawa H, Chiba T, Uemoto S. Chronic rejection associated with antiviral therapy for recurrent hepatitis C after living-donor liver transplantation. Transplantation 2014; 97:344-50. [PMID: 24157473 DOI: 10.1097/01.tp.0000435702.61642.0a] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Chronic rejection (CR) has been reported to be associated with antiviral therapy for recurrent hepatitis C in liver transplant (LT) recipients. The aims of this study were to clarify the details of antiviral therapy-associated CR after living-donor liver transplantation (LDLT) and to identify the factors associated with CR. METHODS A retrospective chart review was performed on 125 recipients who had received antiviral therapy for recurrent hepatitis C after LDLT between January 2001 and September 2012. The characteristics of patients who developed CR during or within 6 months after antiviral therapy were compared with those of 76 patients who did not develop CR despite receiving antiviral therapy for more than 1 year. RESULTS Seven of 125 (6%) patients developed CR during or within 6 months after the end of antiviral therapy. CR was diagnosed after a median (range) of 9 (1-16) months of antiviral therapy. In five patients, rejection progressed rapidly and resulted in death within 3 months after diagnosis. Analysis revealed two significant factors associated with CR: reduction of the immunosuppressant dose during antiviral therapy and a low fibrosis score as the indication for antiviral therapy. CONCLUSIONS CR developed in association with antiviral therapy for recurrent hepatitis C after LDLT. This complication may be prevented by ensuring that the immunosuppressant dose is not reduced during antiviral therapy.
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Affiliation(s)
- Yoshihide Ueda
- 1 Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. 2 Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan. 3 Department of Diagnostic Pathology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. 4 Address correspondence to: Yoshihide Ueda, M.D., Ph.D., Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
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40
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Tischer S, Fontana RJ. Drug-drug interactions with oral anti-HCV agents and idiosyncratic hepatotoxicity in the liver transplant setting. J Hepatol 2014; 60:872-84. [PMID: 24280292 PMCID: PMC4784678 DOI: 10.1016/j.jhep.2013.11.013] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Revised: 11/14/2013] [Accepted: 11/17/2013] [Indexed: 02/06/2023]
Abstract
Studies of boceprevir and telaprevir based antiviral therapy in liver transplant (LT) recipients with hepatitis C genotype 1 infection have demonstrated dramatic increases in tacrolimus, cyclosporine, and mTOR inhibitor exposure. In addition to empiric dose reductions, daily monitoring of immunosuppressant blood levels is required when initiating as well as discontinuing the protease inhibitors to maximize patient safety. Although improved suppression of HCV replication is anticipated, 20 to 40% of treated subjects have required early treatment discontinuation due to various adverse events including anemia (100%), infection (30%), nephrotoxicity (20%) and rejection (5 to 10%). Simeprevir and faldaprevir will likely have improved efficacy and safety profiles but potential drug interactions with other OATP1B1 substrates and unconjugated hyperbilirubinemia are expected. In contrast, sofosbuvir and daclatasvir based antiviral therapy are not expected to lead to clinically significant drug-drug interactions in LT recipients but confirmatory studies are needed. Liver transplant recipients may also be at increased risk of developing drug induced liver injury (DILI). Establishing a diagnosis of DILI in the transplant setting is very difficult with the variable latency, laboratory features and histopathological manifestations of hepatotoxicity associated with a given drug, the need to exclude competing causes of allograft injury, and the lack of an objective and verifiable confirmatory test. Nonetheless, a heightened awareness of the possibility of DILI is warranted in light of the large number of medications used in LT recipients and the potential adverse impact that DILI may have on patient outcomes.
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Affiliation(s)
- Sarah Tischer
- Department of Pharmacy Services, University of Michigan Medical Center, Ann Arbor, MI 48109, United States
| | - Robert J Fontana
- Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109, United States.
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Ikegami T, Yoshizumi T, Shirabe K, Maehara Y. Frequent plasma cell hepatitis during telaprevir-based triple therapy for hepatitis C after liver transplantation. J Hepatol 2014; 60:894-6. [PMID: 24316026 DOI: 10.1016/j.jhep.2013.10.037] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Revised: 10/26/2013] [Accepted: 10/29/2013] [Indexed: 12/14/2022]
Affiliation(s)
- Toru Ikegami
- Department of Surgery and Science, Graduate School of Medical Science, Kyushu University, 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan.
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Science, Kyushu University, 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan
| | - Ken Shirabe
- Department of Surgery and Science, Graduate School of Medical Science, Kyushu University, 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan
| | - Yoshihiko Maehara
- Department of Surgery and Science, Graduate School of Medical Science, Kyushu University, 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan
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42
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Vasuri F, Malvi D, Gruppioni E, Grigioni WF, D’Errico-Grigioni A. Histopathological evaluation of recurrent hepatitis C after liver transplantation: A review. World J Gastroenterol 2014; 20:2810-2824. [PMID: 24659874 PMCID: PMC3961976 DOI: 10.3748/wjg.v20.i11.2810] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Revised: 11/08/2013] [Accepted: 12/13/2013] [Indexed: 02/06/2023] Open
Abstract
Although the morphological features of hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT) have been well established in the last decades, the differential diagnosis still represents a challenge for the pathologist, especially early recurrent hepatitis C vs mild acute cellular rejection. The present review focuses on the role of the pathologist and the pathology laboratory in the management of recipients with recurrent hepatitis C, the usefulness of early and late post-OLT liver biopsies, and the potential role of ancillary techniques (immunohistochemistry and reverse transcription-polymerase chain reaction, RT-PCR). The English literature on the topic is reviewed, focusing on the histopathology, the immunohistochemistry and the use of RT-PCR on HCV-positive post-OLT biopsies. The different histopathological illustrations of early and chronic recurrent hepatitis C are presented, with special focus on the main differential diagnoses and those features with prognostic relevance (cholestasis above all). The usefulness of ancillary techniques are discussed, especially HCV RNA quantitation by RT-PCR. Finally, the usefulness of long-term protocol biopsies is addressed: their usefulness for the study of allograft disease progression is clear, but their meaning in the long term is still debated. The significance of plasma cell infiltrate in HCV-positive allografts, the prognostic weight of graft steatosis, and the impact of donor age in recurrent hepatitis C also represent additional open issues.
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43
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EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol 2014; 60:392-420. [PMID: 24331294 DOI: 10.1016/j.jhep.2013.11.003] [Citation(s) in RCA: 646] [Impact Index Per Article: 58.7] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Accepted: 11/05/2013] [Indexed: 02/06/2023]
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Shetty S, Adams DH, Hubscher SG. Post-transplant liver biopsy and the immune response: lessons for the clinician. Expert Rev Clin Immunol 2014; 8:645-61. [DOI: 10.1586/eci.12.65] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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45
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Ho CM, Hu RH, Lee PH. Perspective of antiviral therapeutics for hepatitis C after liver transplantation. World J Pharmacol 2014; 3:193. [DOI: 10.5497/wjp.v3.i4.193] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Revised: 09/22/2014] [Accepted: 10/10/2014] [Indexed: 02/06/2023] Open
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46
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Carbone M, Neuberger JM. Autoimmune liver disease, autoimmunity and liver transplantation. J Hepatol 2014; 60:210-223. [PMID: 24084655 DOI: 10.1016/j.jhep.2013.09.020] [Citation(s) in RCA: 161] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2013] [Revised: 08/13/2013] [Accepted: 09/22/2013] [Indexed: 02/08/2023]
Abstract
Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) represent the three major autoimmune liver diseases (AILD). PBC, PSC, and AIH are all complex disorders in that they result from the effects of multiple genes in combination with as yet unidentified environmental factors. Recent genome-wide association studies have identified numerous risk loci for PBC and PSC that host genes involved in innate or acquired immune responses. These loci may provide a clue as to the immune-based pathogenesis of AILD. Moreover, many significant risk loci for PBC and PSC are also risk loci for other autoimmune disorders, such type I diabetes, multiple sclerosis and rheumatoid arthritis, suggesting a shared genetic basis and possibly similar molecular pathways for diverse autoimmune conditions. There is no curative treatment for all three disorders, and a significant number of patients eventually progress to end-stage liver disease requiring liver transplantation (LT). LT in this context has a favourable overall outcome with current patient and graft survival exceeding 80% at 5years. Indications are as for other chronic liver disease although recent data suggest that while lethargy improves after transplantation, the effect is modest and variable so lethargy alone is not an indication. In contrast, pruritus rapidly responds. Cholangiocarcinoma, except under rigorous selection criteria, excludes LT because of the high risk of recurrence. All three conditions may recur after transplantation and are associated with a greater risk of both acute cellular and chronic ductopenic rejection. It is possible that a crosstalk between alloimmune and autoimmune response perpetuate each other. An immunological response toward self- or allo-antigens is well recognised after LT in patients transplanted for non-autoimmune indications and sometimes termed "de novo autoimmune hepatitis". Whether this is part of the spectrum of rejection or an autoimmune process is not clear. In this manuscript, we review novel findings about disease processes and mechanisms that lead to autoimmunity in the liver and their possible involvement in the immune response vs. the graft after LT.
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Affiliation(s)
- Marco Carbone
- Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke's Hospital, Cambridge, United Kingdom; Organ Donation and Transplantation, National Health Service Blood and Transplant (NHSBT), Bristol, United Kingdom
| | - James M Neuberger
- Liver Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom; Organ Donation and Transplantation, National Health Service Blood and Transplant (NHSBT), Bristol, United Kingdom.
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47
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Ikegami T, Wang H, Yoshizumi T, Toshima T, Aishima S, Fukuhara T, Furusyo N, Kotoh K, Shimoda S, Shirabe K, Maehara Y. Strategies to treat interferon-induced graft dysfunction after living donor liver transplantation for hepatitis C. Hepatol Int 2013. [DOI: 10.1007/s12072-013-9496-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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48
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Histologic findings predictive of a diagnosis of de novo autoimmune hepatitis after liver transplantation in adults. Transplantation 2013; 96:670-8. [PMID: 23982338 DOI: 10.1097/tp.0b013e31829eda7f] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Autoimmune hepatitis (AIH) after liver transplantation has been defined histologically as a "hepatitic" pattern of injury, characterized by lymphoplasmacytic inflammation with necroinflammatory activity (NIA), comparable with findings seen in native livers. This definition, however, is difficult to apply in practice because specific histologic criteria are not clearly delineated. This study aimed to determine which histologic features correlated best with clinical and serologic features of dAIH. METHODS Index liver biopsies from patients with autoimmune-like hepatitis transplanted for non-AIH in two centers (n=35 and 20) were reviewed. Histologic features were correlated with the clinical diagnosis of AIH based on a retrospective review of clinical and serologic data, including therapeutic response. RESULTS A clinical diagnosis of AIH was retrospectively assigned to 24 of 35 (68%) and 18 of 20 (90%) patients, respectively (P=0.10). In multivariate analysis, centrilobular NIA and centrilobular plasma cell (PC) ratio of 30% to 50% were independently discriminating for a clinical diagnosis of AIH (P=0.04 and 0.05, respectively). The best level of predictability (99.6%) was mathematically achieved when severe centrilobular NIA and centrilobular PC ratio of 30% to 50% were both present. CONCLUSION A histologic pattern of centrilobular injury including increased NIA and increased PC infiltration correlates with measurements of autoimmunity in liver recipients. It could be used to segregate cases for further study and introduced into the AIH scoring systems when applied in the context of liver transplantation.
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49
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Zhao XY, Rakhda MIA, Wang TI, Jia JD. Immunoglobulin G4-associated de novo autoimmune hepatitis after liver transplantation for chronic hepatitis B- and C-related cirrhosis and hepatocellular carcinoma: a case report with literature review. Transplant Proc 2013; 45:824-7. [PMID: 23498828 DOI: 10.1016/j.transproceed.2012.02.049] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2011] [Accepted: 02/28/2012] [Indexed: 12/14/2022]
Abstract
Immunoglobulin G4 (IgG4)-associated autoimmune hepatitis (AIH) was recognized as a new disease entity; however, IgG4-associated de novo AIH after the liver transplantation had not been reported yet. Herein we have described a 56-year-old man who developed IgG4 de novo AIH as 1 year-post liver transplantation after receiving pegylated interferon alpha-2a and ribavirin therapy for hepatitis C virus recurrence. The histopathologic evidence showed an aggressive lymphoplasmacytic interface hepatitis with centrilobular necrosis (plasma cells > 30%) and IgG4-positive plasma cells (>10 per high power field). Serum IgG (9220 mg/dL) and IgG4 (3289 mg/dL) were also elevated. Improvement of liver function tests (LFTs) by prednisone and azathioprine therapy are manifested as normalized alanine aminotransferase and IgG levels. IgG4 relates to more severe histological activity; however, it is believed to be a good prognostic predictor of a response to prednisone plus azathioprine therapy especially with early diagnosis and timely management.
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Affiliation(s)
- X-y Zhao
- Liver Research Center, Beijing Friendship Hospital, Beijing, PR China; Capital Medical University, Beijing, PR China.
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50
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Adeyi OA. Common problems in liver allograft biopsy interpretation: Resolving clinical dilemmas. Clin Liver Dis (Hoboken) 2013; 2:181-187. [PMID: 30992858 PMCID: PMC6448648 DOI: 10.1002/cld.229] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Revised: 03/22/2013] [Accepted: 06/06/2013] [Indexed: 02/04/2023] Open
Affiliation(s)
- Oyedele A. Adeyi
- Laboratory Medicine Program, University Health Network and University of Toronto, Toronto, Canada
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