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Abstract
In the 1970s, an unknown virus was suspected for documented cases of transfusion-associated hepatitis, a phenomenon called non-A, non-B hepatitis. In 1989, the infectious transmissible agent was identified and named hepatitis C virus (HCV) and, soon enough, the first diagnostic HCV antibody test was developed, which led to a dramatic decrease in new infections. Today, HCV infection remains a global health burden and a major cause of liver cirrhosis, hepatocellular carcinoma and liver transplantation. However, tremendous advances have been made over the decades, and HCV became the first curable, chronic viral infection. The introduction of direct antiviral agents revolutionized antiviral treatment, leading to viral eradication in more than 98% of all patients infected with HCV. This Perspective discusses the history of HCV research, which reads like a role model for successful translational research: starting from a clinical observation, specific therapeutic agents were developed, which finally were implemented in national and global elimination programmes.
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Affiliation(s)
- Michael P. Manns
- grid.10423.340000 0000 9529 9877Hannover Medical School, Hannover, Germany
| | - Benjamin Maasoumy
- grid.10423.340000 0000 9529 9877Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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Langness JA, Nguyen M, Wieland A, Everson GT, Kiser JJ. Optimizing hepatitis C virus treatment through pharmacist interventions: Identification and management of drug-drug interactions. World J Gastroenterol 2017; 23:1618-1626. [PMID: 28321163 PMCID: PMC5340814 DOI: 10.3748/wjg.v23.i9.1618] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Revised: 01/12/2017] [Accepted: 02/08/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To quantify drug-drug-interactions (DDIs) encountered in patients prescribed hepatitis C virus (HCV) treatment, the interventions made, and the time spent in this process.
METHODS As standard of care, a clinical pharmacist screened for DDIs in patients prescribed direct acting antiviral (DAA) HCV treatment between November 2013 and July 2015 at the University of Colorado Hepatology Clinic. HCV regimens prescribed included ledipasvir/sofosbuvir (LDV/SOF), paritaprevir/ritonavir/ombitasvir/dasabuvir (OBV/PTV/r + DSV), simeprevir/sofosbuvir (SIM/SOF), and sofosbuvir/ribavirin (SOF/RBV). This retrospective analysis reviewed the work completed by the clinical pharmacist in order to measure the aims identified for the study. The number and type of DDIs identified were summarized with descriptive statistics.
RESULTS Six hundred and sixty four patients (83.4% Caucasian, 57% male, average 56.7 years old) were identified; 369 for LDV/SOF, 48 for OBV/PTV/r + DSV, 114 for SIM/SOF, and 133 for SOF/RBV. Fifty-one point five per cent of patients were cirrhotic. Overall, 5217 medications were reviewed (7.86 medications per patient) and 781 interactions identified (1.18 interactions per patient). The number of interactions were fewest for SOF/RBV (0.17 interactions per patient) and highest for OBV/PTV/r + DSV (2.48 interactions per patient). LDV/SOF and SIM/SOF had similar number of interactions (1.28 and 1.48 interactions per patient, respectively). Gastric acid modifiers and vitamin/herbal supplements commonly caused interactions with LDV/SOF. Hypertensive agents, analgesics, and psychiatric medications frequently caused interactions with OBV/PTV/r + DSV and SIM/SOF. To manage these interactions, the pharmacists most often recommended discontinuing the medication (28.9%), increasing monitoring for toxicities (24.1%), or separating administration times (18.2%). The pharmacist chart review for each patient usually took approximately 30 min, with additional time for more complex patients.
CONCLUSION DDIs are common with HCV medications and management can require medication adjustments and increased monitoring. An interdisciplinary team including a clinical pharmacist can optimize patient care.
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Ganesh S, Almazroo OA, Tevar A, Humar A, Venkataramanan R. Drug Metabolism, Drug Interactions, and Drug-Induced Liver Injury in Living Donor Liver Transplant Patients. Clin Liver Dis 2017; 21:181-196. [PMID: 27842771 DOI: 10.1016/j.cld.2016.08.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Living donor liver transplant (LDLT) fills a critically needed gap in the number of livers available for transplant. However, little is known about the functional recovery of the liver in the donor and in the recipient after surgery. Given that both donor and recipients are treated with several drugs, it is important to characterize the time course of recovery of hepatic synthetic, metabolic, and excretory function in these patients. In the absence of data from LDLT, information on the effect of liver disease on the pharmacokinetics of medications can be used as guidance for drug dosing in LDLT patients.
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Affiliation(s)
- Swaytha Ganesh
- Thomas Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.
| | - Omar Abdulhameed Almazroo
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, 731 Salk Hall, 3501 Terrace Street, Pittsburgh, PA 15261, USA
| | - Amit Tevar
- Thomas Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Abhinav Humar
- Thomas Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.
| | - Raman Venkataramanan
- Thomas Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, 718 Salk Hall, 3501 Terrace Street, Pittsburgh, PA 15261, USA; Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
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McCarty TR, Lim JK. Developing therapies to treat hepatitis C infection in post-liver transplant recipients. Expert Opin Pharmacother 2017; 18:165-174. [PMID: 28024124 DOI: 10.1080/14656566.2016.1276564] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Currently, hepatitis C virus (HCV) infection remains the most common indication for liver transplant in the United States (US) with almost universal HCV recurrence in the post-liver transplant setting. Previous interferon (IFN)-related efficacy and tolerability concerns about worsening liver function have limited treatment options for many patients with HCV-associated decompensated liver disease and post-liver transplant recipients. However, the last decade has seen a seen a radical shift in the management of HCV with multiple direct-acting antiviral (DAA) treatments that provide more effective, all-oral, IFN-free alternatives. Areas covered: This review will serve to highlight the various pharmacotherapies available to clinicians for patients with HCV recurrence post-liver transplant. A brief history of prior regimens is provided with evidence for newer treatments presented. Also detailed are updated guidelines from societal organizations. Finally, timing of HCV treatment is discussed as the decision to treat patients in a pre or post-liver transplant setting remains challenging. Expert opinion: While there are many potential available therapies for HCV recurrence in the post-liver transplant setting, daclatasvir/sofosbuvir and ledipasvir/sofosbuvir have been the most extensively studied. Newer, pangenotypic generation drugs require more evidence before routine utilization in post-liver transplant recipients.
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Affiliation(s)
- Thomas R McCarty
- a Department of Internal Medicine , Yale University School of Medicine , New Haven , CT , USA
| | - Joseph K Lim
- b Section of Digestive Diseases , Yale University School of Medicine , New Haven , CT , USA
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Shiba H, Hashimoto K, Kelly D, Fujiki M, Quintini C, Aucejo F, Uso TD, Yerian L, Yanaga K, Matsushima M, Eghtesad B, Fung J, Miller C. Risk stratification of allograft failure secondary to hepatitis C recurrence after liver transplantation. Hepatol Res 2016; 46:1099-1106. [PMID: 26833562 DOI: 10.1111/hepr.12661] [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: 08/21/2015] [Revised: 01/06/2016] [Accepted: 01/22/2016] [Indexed: 12/24/2022]
Abstract
AIM Hepatitis C virus (HCV) recurrence after liver transplantation decreases survival rates. Improved understanding of the multiple factors influencing HCV recurrence could aid decision-making for donor-recipient pairing and maximize transplant outcomes. The aim of this study was to create a model based on pretransplant variables to stratify patients at risk of HCV-related allograft failure. METHODS This retrospective study enrolled 154 liver transplant recipients with HCV at Cleveland Clinic. RESULTS Among the study population, 54 recipients (35.1%) experienced HCV recurrence, histologically defined as moderate to severe hepatitis and/or bridging fibrosis to cirrhosis. The multivariate analysis found donor age (≥60 years, P < 0.002), donor body mass index (≥30 kg/m2 , P < 0.05), African American recipient (P < 0.01) and genotype 1 (P < 0.02) as risk factors for HCV-related allograft failure. When these four factors were scored as a combined index (no factor [n = 15], one factor [n = 76], two factors [n = 43] and three or more factors [n = 20]), the HCV recurrence-free survival showed good stratification according to the scores: 93.3% with no factor, 79.3% with one factor, 52.0% with two factors and 24.4% with three or more factors at 3 years after transplant (P < 0.0001). Moreover, this risk index also identified the patient group at high risk of HCV recurrence after acute rejection. CONCLUSION While the introduction of direct-acting antiviral agents has been changing the paradigm of HCV treatment, the natural history of recipients with HCV as shown in this study would help estimate the risk of HCV-related allograft failure in those who do not tolerate such new treatment.
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Affiliation(s)
- Hiroaki Shiba
- Department of General Surgery, Digestive Disease Institute.,Department of Hepatobiliary Surgery
| | - Koji Hashimoto
- Department of General Surgery, Digestive Disease Institute.
| | - Dympna Kelly
- Department of General Surgery, Digestive Disease Institute
| | - Masato Fujiki
- Department of General Surgery, Digestive Disease Institute
| | | | | | | | - Lisa Yerian
- Department of Anatomic Pathology, Cleveland Clinic, Cleveland, Ohio, USA
| | | | - Masato Matsushima
- Division of Clinical Research and Development, Jikei University School of Medicine, Tokyo, Japan
| | - Bijan Eghtesad
- Department of General Surgery, Digestive Disease Institute
| | - John Fung
- Department of General Surgery, Digestive Disease Institute
| | - Charles Miller
- Department of General Surgery, Digestive Disease Institute
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Management of post liver transplantation recurrent hepatitis C infection with directly acting antiviral drugs: a review. Hepatol Int 2016; 10:749-61. [PMID: 27337961 DOI: 10.1007/s12072-016-9744-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 05/17/2016] [Indexed: 12/20/2022]
Abstract
Recurrent HCV infection (rHCV) of the liver allograft following transplantation is universal and is associated with poor graft and patient survival in comparison with other indications. Treatment of rHCV infection in the previous era with pegylated interferon and ribavirin was associated with low sustained virological response (SVR) due to poor tolerability, adverse events and graft rejection. Recently, directly acting antiviral drugs (DAA) have been approved for the treatment of hepatitis C infection and a number of clinical trials have been conducted across various centers in the management of rHCV infection of the graft. In this review we discuss about recent studies that have emerged on the use of NS5b polymerase inhibitor, sofosbuvir in combination with second generation protease inhibitor, simeprevir, fixed dose ledipasvir or daclatasvir with or without ribavirin in the treatment of post transplant rHCV infection.
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Two-Year Follow-Up Analysis of Telaprevir-Based Antiviral Triple Therapy for HCV Recurrence in Genotype 1 Infected Liver Graft Recipients as a First Step towards Modern HCV Therapy. HEPATITIS RESEARCH AND TREATMENT 2016; 2016:8325467. [PMID: 27195149 PMCID: PMC4852367 DOI: 10.1155/2016/8325467] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 03/08/2016] [Indexed: 12/15/2022]
Abstract
Objective. The introduction of protease inhibitors telaprevir and boceprevir in 2011 had extended the antiviral treatment options especially in genotype 1 infected hepatitis C relapsers and nonresponders to interferon/ribavirin therapy. The aim of this study was to analyze the long-term treatment efficiency of telaprevir-based triple therapy for patients with hepatitis C reinfection after orthotopic liver transplantation. Patients and Methods. We included 12 patients with histologically confirmed graft fibrosis due to hepatitis C reinfection. The treatment duration was scheduled as 12 weeks of telaprevir-based antiviral triple therapy followed by 36 weeks of dual therapy with pegylated interferon/ribavirin. The patients were followed up for two years after the end of triple therapy. Results. Of the 12 patients, 6 (50%) completed the full 48 weeks of antiviral treatment. An end of treatment response and a sustained virological response 52 weeks after the end of the antiviral treatment course were achieved in 8/12 (67%) and 7/12 (58%) patients, respectively. Conclusion. Telaprevir-based triple therapy was shown to be a long-term effective but complex treatment option for individual patients with hepatitis C graft. With the recent improvements in hepatitis C therapy options telaprevir may not be recommended as a standard therapy for this indication anymore.
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Kawaoka T, Imamura M, Kan H, Fujino H, Fukuhara T, Kobayashi T, Honda Y, Naeshiro N, Hiramatsu A, Tsuge M, Hayes CN, Kawakami Y, Aikata H, Ochi H, Ishiyama K, Tashiro H, Ohdan H, Chayama K. Two patients treated with simeprevir plus pegylated-interferon and ribavirin triple therapy for recurrent hepatitis C after living donor liver transplantation: case report. Transplant Proc 2016; 47:809-14. [PMID: 25891736 DOI: 10.1016/j.transproceed.2014.10.052] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Revised: 10/15/2014] [Accepted: 10/28/2014] [Indexed: 12/22/2022]
Abstract
We previously reported our data on telaprevir (TVR) used in combination with pegylated-interferon and ribavirin (PEG-IFN/RBV) for the treatment of recurrent hepatitis C virus (HCV) genotype 1 infection after liver transplantation (LT). TVR substantially increases the blood levels of immunosuppressive agents such as cyclosporine and tacrolimus for drug-drug interactions. On the other hand, the effect of simeprevir (SMV) on the blood levels of these immunosuppressive agents is unclear. We report 2 patients who achieved viral responses with little effect on the blood levels of cyclosporine and tacrolimus using SMV plus PEG-IFN/RBV treatment. The first was a 71-year-old woman with HCV-related liver cirrhosis and hepatocellular carcinoma who failed to respond to PEG-IFN/RBV after living donor LT. She was treated with 40 mg/d of cyclosporine, and received SMV plus PEG-IFN/RBV treatment. The second was a 65-year-old man with HCV-related liver cirrhosis who failed to respond to PEG-IFN/RBV after living donor LT. He was treated with 3 mg/d of tacrolimus, and received SMV plus PEG-IFN/RBV treatment. Serum HCV RNA became undetectable using TaqMan polymerase chain reaction (PCR) test after 4 weeks of treatment in both patients, and no remarkable fluctuation in blood concentration was observed either in cyclosporine or tacrolimus during the 12 weeks of SMV treatment. Completion of 12-week SMV triple therapy was followed by PEG-IFNα2b plus RBV, and both patients achieved sustained virological response 12 weeks after the end of treatment. SMV plus PEG-IFNRBV treatment showed a remarkable viral response with little effect on blood levels of immunosuppressive agents for recurrent HCV genotype 1 infection after LT.
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Affiliation(s)
- T Kawaoka
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima, Japan
| | - M Imamura
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima, Japan
| | - H Kan
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima, Japan
| | - H Fujino
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima, Japan
| | - T Fukuhara
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima, Japan
| | - T Kobayashi
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima, Japan
| | - Y Honda
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima, Japan
| | - N Naeshiro
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima, Japan
| | - A Hiramatsu
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima, Japan
| | - M Tsuge
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima, Japan
| | - C N Hayes
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima, Japan
| | - Y Kawakami
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima, Japan
| | - H Aikata
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima, Japan
| | - H Ochi
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima, Japan
| | - K Ishiyama
- Division of Frontier Medical Science, Department of Surgery, Programs for Biomedical Research, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, Japan
| | - H Tashiro
- Division of Frontier Medical Science, Department of Surgery, Programs for Biomedical Research, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, Japan
| | - H Ohdan
- Division of Frontier Medical Science, Department of Surgery, Programs for Biomedical Research, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, Japan
| | - K Chayama
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima, Japan.
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Höner Zu Siederdissen C, Maasoumy B, Marra F, Deterding K, Port K, Manns MP, Cornberg M, Back D, Wedemeyer H. Drug-Drug Interactions With Novel All Oral Interferon-Free Antiviral Agents in a Large Real-World Cohort. Clin Infect Dis 2015; 62:561-7. [PMID: 26611779 DOI: 10.1093/cid/civ973] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2015] [Accepted: 11/18/2015] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND With the approval of direct-acting antivirals (DAAs), the management of drug-drug interactions (DDIs) has become an important challenge while treating individuals with hepatitis C. To date, the potential of causing DDIs for the recently approved DAAs has not been systematically investigated. We aimed to assess the clinical significance of DDI between the regular outpatient medications and DAA therapies in a large real-world cohort. METHODS Overall, 261 hepatitis C virus monoinfected patients who were selected for DAA therapy at 2 intervals between 2011 and 2014 were asked about their regular outpatient medications. The potential for DDIs between all these drugs and sofosbuvir/ribavirin, ledipasvir/sofosbuvir, sofosbuvir/daclatasvir, sofosbuvir/simeprevir, ombitasvir/paritaprevir/ritonavir ± dasabuvir as well as boceprevir and telaprevir triple therapy was assessed using www.hep-druginteractions.org and the relevant prescribing information. RESULTS The 261 patients took a median number of 2 drugs (range 0-15); 20% of patients did not take any medication. Sofosbuvir/ribavirin had the lowest risk to cause a potentially significant DDI (9.6%). In contrast, for ombitasvir/paritaprevir/ritonavir ± dasabuvir potentially significant DDIs could be expected in 66.3% of the patients. Significant DDIs for sofosbuvir/simeprevir would be expected in 31.4%, for sofosbuvir/daclatasvir in 36.8%, and for sofosbuvir/ledipasvir in 40.2%. Proton pump inhibitors, thyroid hormones, and dihydropyridine derivatives were frequently used and presented a risk of interacting with the antiviral regimen. CONCLUSIONS A significant number of patients are at risk for DDIs if treated with the recently approved DAA regimens. A careful evaluation of potential DDI is essential to prevent adverse effects or unnecessary risk of treatment failure.
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Affiliation(s)
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany
| | - Fiona Marra
- Department of Molecular and Clinical Pharmacology, University of Liverpool Pharmacy Department, Gartnavel General Hospital, Glasgow, Scotland, United Kingdom
| | - Katja Deterding
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany
| | - Kerstin Port
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany
| | - David Back
- Department of Molecular and Clinical Pharmacology, University of Liverpool
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany
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Fung J. Era of direct acting antivirals in chronic hepatitis C: Who will benefit? World J Hepatol 2015; 7:2543-2550. [PMID: 26523206 PMCID: PMC4621468 DOI: 10.4254/wjh.v7.i24.2543] [Citation(s) in RCA: 8] [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: 05/04/2015] [Revised: 09/07/2015] [Accepted: 10/13/2015] [Indexed: 02/06/2023] Open
Abstract
In the era of highly effective direct acting antiviral (DAA) drugs for the treatment of chronic hepatitis C (CHC) infection, where eradication is almost ensured with minimal side effects, all hepatitis C carriers should benefit theoretically. In the real world setting however, only a small proportion will benefit at this time point due to the multiple barriers to accessing therapy. Given that universal treatment is unlikely, treatment with DAAs will likely be restricted to those with the highest health benefits, and for those who can afford the high expense of a treatment course. Those with the highest unmet needs include those who have failed previous interferon-based therapy or who are interferon-ineligible with evidence of active disease, those with advance liver disease, and those with recurrence of hepatitis C after liver transplantation. In the future, the focus should be on increasing access to treatment for those infected with CHC.
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Kaneko J, Sugawara Y, Yamaguchi T, Harada N, Akamatsu N, Ishizawa T, Aoki T, Sakamoto Y, Hasegawa K, Tamura S, Tanaka T, Kokudo N. Telaprevir-based triple therapy for hepatitis C null responders among living donor liver transplant recipients. Biosci Trends 2015; 8:339-45. [PMID: 25641181 DOI: 10.5582/bst.2014.01101] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Telaprevir (TVR), a direct -acting protease inhibitor, was recently reported to improve treatment efficacy when used in combination with peg-interferon (PEG-IFN) and ribavirin (RBV) as triple therapy for HCV in non-transplant patients. The aim of the present study was to investigate the feasibility of TVR-based triple therapy among Japanese living donor liver transplant (LDLT) recipients who had been resistant to dual treatment with PEG-IFN and RBV. Among 133 HCV-positive LDLT recipients, 8 null responders during or after dual treatment with PEG-IFN and RBV were finally indicated for TVR-based triple therapy after treatment. All 8 patients had been resistant to dual treatment with PEG-IFN and RBV. While the cyclosporine trough level was well controlled with an 80% dose reduction during TVR administration, the end - of - treatment response rate was only 25% (2/8), with 63% (5/8) of patients developing anemia that required a blood transfusion and 50% (4/8) of patients developing leukopenia that required filgrastim. Dose reduction or treatment discontinuation was required in all cases. Based on the poor efficacy and the unacceptable high rate of cytopenic events, TVR-based triple therapy is not indicated for those resistant to dual treatment with PEG-IFN and RBV.
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Affiliation(s)
- Junichi Kaneko
- Division of Artificial Organ and Transplantation, Department of Surgery, The University of Tokyo
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12
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Aguilera V. Hepatitis C virus recurrence after liver transplantation: how to treat and when. Transplant Proc 2015; 46:3100-3. [PMID: 25420834 DOI: 10.1016/j.transproceed.2014.09.177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Chronic hepatitis C (CHC) is an important cause of cirrhosis and hepatocellular carcinoma and a common indication of liver transplantation (LT). Recurrence of hepatitis C occurs universally after LT with an accelerated course of the natural history of CHC in the graft. Treatment of hepatitis C before transplantation is the most effective strategy because it prevents graft reinfection, but applicability is low with pegylated interferon regimens. Treatment after LT is the strategy more frequently used. A sustained viral response (SVR) is achieved by one-third of those treated with dual therapy and is associated with better outcomes after LT. Triple therapy with protease inhibitors after LT has efficacy to 60%-70% of SVR but is associated with higher rates of secondary effects and drug-drug interactions that require an intensified and frequent monitoring of calcineurin inhibitors during treatment. In the near future, interferon-free regimens with new oral antiviral drugs will likely prevent viral reinfection before or after LT, and shorter treatment regimens and less toxicity are expected.
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Affiliation(s)
- V Aguilera
- Hospital Universitari i Politècnic la Fe, Valenza, Valencia, Spain Valencia, Spain.
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New hepatitis C virus therapies: drug classes and metabolism, drug interactions relevant in the transplant settings, drug options in decompensated cirrhosis, and drug options in end-stage renal disease. Curr Opin Organ Transplant 2015; 20:235-41. [PMID: 25944238 DOI: 10.1097/mot.0000000000000198] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
PURPOSE OF REVIEW This article will review the new direct acting antiviral agent (DAA) drug classes for the treatment of hepatitis C, how they are combined and the relevant drug-drug interactions in the postliver transplant setting. Treatment options for chronic hepatitis C in patients with decompensated cirrhosis and end-stage renal disease will also be discussed. RECENT FINDINGS The availability of new drug classes has increased the treatment options in patients with hepatitis C in the post-transplant settings. Clinical trials have concluded that sofosbuvir (SOF) with ledipasvir (LDV) may be safely administered with calcineurin inhibitors (tacrolimus, cyclosporine) and rapamycin inhibitors (sirolimus, everolimus). Similarly, paritaprevir/ritonavir, ombitasvir, and dasabuvir may be administered with tacrolimus and cyclosporine though appropriate dose adjustments must be made to the calcineurin inhibitors. In those with decompensated Childs B/C cirrhosis, SOF, SOF and LDV, as well as daclatasvir may be given without dose adjustment. In renal impairment, all DAAs may be used safely down to a glomerular filteration rate (GFR) of 30 ml/min. Simeprevir, paritaprevir, ombitasvir, and dasabuvir may be given for those down to GFR of 15 ml/min. Finally, daclatasvir may be given without dose administration change. SUMMARY In summary, DAAs have better tolerability and greater efficacy than interferon-based therapy post-transplant. Drug-drug interactions must be carefully assessed when these newer agents are used for therapy in the postliver transplant settings. Thus far, dose adjustments for DAAs have not been required in chronic kidney disease though data are incomplete in those with severe chronic kidney disease (CKD) or on dialysis. Hepatitis C treatment in those with decompensated cirrhosis results in impaired hepatic metabolism that may affect DAA levels, and clinicians should carefully choose treatment options for Childs B and C cirrhotic patients.
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Pipili C, Cholongitas E. Treatment of chronic hepatitis C in liver transplant candidates and recipients: Where do we stand? World J Hepatol 2015; 7:1606-16. [PMID: 26140081 PMCID: PMC4483543 DOI: 10.4254/wjh.v7.i12.1606] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2014] [Revised: 05/18/2015] [Accepted: 06/01/2015] [Indexed: 02/06/2023] Open
Abstract
The first generation direct antiviral agents (DAAs) highlighted substantial prognosis improvement among liver transplant (LT) candidates and recipients with recurrent hepatitis C virus (HCV) infection. During 2014, second generation DAAs are associated with high sustained virological response rates (> 95%), shortened duration courses and relatively few toxicities. In keeping with the currently available data, patients with decompensated cirrhosis awaiting LT is preferable to be treated with interferon-free, new generation DAAs, with or without ribavirin combinations. Although data about the safety of new DAAs combinations in this patient population are limited, sofosbuvir and daclatasvir pharmacokinetics do not appear to change significantly in moderate or severe liver impairment, while other new DAAs (simeprevir, asunaprevir) seem to be contraindicated in patients with severe liver impairment (Child-Pugh class C). On the other hand, sofosbuvir should not be given in patients with glomerular filtration rate ≤ 30 mL/min, but ongoing trials will clarify better this issue. With the objective that newer antiviral combinations will yield safer and more efficient manipulation of HCV recurrence post-transplant, the European Association for the Study of the Liver has recently updated its recommendations towards this direction. Nevertheless the new antivirals' high cost may be the biggest challenge to their implementation worldwide.
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Affiliation(s)
- Chrysoula Pipili
- Chrysoula Pipili, Division of Nephrology, Royal Infirmary of Edinburgh, Scotland EH16 4SA, United Kingdom
| | - Evangelos Cholongitas
- Chrysoula Pipili, Division of Nephrology, Royal Infirmary of Edinburgh, Scotland EH16 4SA, United Kingdom
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Mitchell O, Gurakar A. Management of Hepatitis C Post-liver Transplantation: a Comprehensive Review. J Clin Transl Hepatol 2015; 3:140-8. [PMID: 26357641 PMCID: PMC4548349 DOI: 10.14218/jcth.2015.00005] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Revised: 03/19/2015] [Accepted: 03/22/2015] [Indexed: 02/07/2023] Open
Abstract
Infection with hepatitis C virus (HCV) is a common cause of chronic liver disease, and HCV-related cirrhosis and hepatocellular carcinoma are the leading causes for liver transplantation in the Western world. Recurrent infection of the transplanted liver allograft is universal in patients with detectable HCV viremia at the time of transplant and can cause a spectrum of disease, ranging from asymptomatic chronic infection to an aggressive fibrosing cholestatic hepatitis. Recurrent HCV is more aggressive in the post-transplant population and is a leading cause of allograft loss, morbidity, and mortality. Historically, treatment of recurrent HCV has been limited by low rates of treatment success and high side effect profiles. Over the past few years, promising new therapies have emerged for the treatment of HCV that have high rates of sustained virological response without the need for interferon based regimens. In addition to being highly effective, these treatments have higher rates of adherence and a lower side effect profile. The purpose of this review is to summarize current therapies in recurrent HCV infection, to review the recent advances in therapy, and to highlight areas of ongoing research.
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Affiliation(s)
- Oscar Mitchell
- Department of Transplant Hepatology, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ahmet Gurakar
- Department of Transplant Hepatology, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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16
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Herzer K, Papadopoulos-Köhn A, Achterfeld A, Canbay A, Piras-Straub K, Paul A, Walker A, Timm J, Gerken G. Management of telaprevir-based triple therapy for hepatitis C virus recurrence post liver transplant. World J Hepatol 2015; 7:1287-1296. [PMID: 26019745 PMCID: PMC4438504 DOI: 10.4254/wjh.v7.i9.1287] [Citation(s) in RCA: 8] [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: 09/15/2014] [Revised: 02/27/2015] [Accepted: 04/02/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To characterize management of telaprevir (TVR)-based triple therapy of hepatitis C virus (HCV) reinfection after liver transplantation (LT).
METHODS: We retrospectively analyzed safety and efficacy of telaprevir - based triple therapy in a single center cohort of 19 patients with HCV genotype (GT) 1 recurrence after LT, with respect to factors possibly predicting sustained viral response (SVR) or non-SVR. All patients were treated with TVR, pegylated (PEG) and ribavirine (RBV) for 12 wk followed by a dual phase with PEG/RBV for 12 wk in 7 patients and for 36 wk in 5 patients.
RESULTS: In total 11/19 (58%) of patients achieved a sustained response. All (11/11) SVR patients showed a rapid viral response at treatment weeks 4 and 11/14 rapid virological response (RVR) patients achieved SVR. Notably, all (7/7) patients who completed 48 wk of therapy and 80% (4/5) patients who completed 24 wk of therapy achieved SVR24. Treatment failure was significantly (P > 0.049) more frequent in GT1a infection (5/7) compared to GT1b (3/12) infection and was associated with emergence of resistance-associated mutations in the NS3 protease domain. Bilirubin level at baseline is also related to SVR (P > 0.030). None of the patients had to discontinue treatment due to side effects.
CONCLUSION: RVR, GT and bilirubin are clearly related to achievement of SVR. Providing a thorough patient selection and monitoring, a full course of TVR-based triple therapy in LT patients is feasible and achieves high SVR rates.
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Fagiuoli S, Ravasio R, Lucà MG, Baldan A, Pecere S, Vitale A, Pasulo L. Management of hepatitis C infection before and after liver transplantation. World J Gastroenterol 2015; 21:4447-56. [PMID: 25914454 PMCID: PMC4402292 DOI: 10.3748/wjg.v21.i15.4447] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Revised: 02/11/2015] [Accepted: 03/12/2015] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C (CHC) is the most common indication for liver transplantation (LT). Aggressive treatment of hepatitis C virus (HCV) infection before cirrhosis development or decompensation may reduce LT need and risk of HCV recurrence post-LT. Factors associated with increased HCV risk or severity of recurrence include older age, immunosuppression, HCV genotype 1 and high viral load at LT. HCV recurrence post-LT leads to accelerated liver disease and cirrhosis development with reduced graft and patient survival. Currently, interferon (IFN)-based regimens can be used in dual-agent regimens with ribavirin, in triple-agent antiviral strategies with direct-acting antivirals (e.g., protease inhibitors telaprevir or boceprevir), or before transplant in compensated patients to reduce HCV viral load to prevent or reduce the risk of post-LT recurrence and complications; they cannot be used in patients with decompensated cirrhosis. IFN-based regimens are used in less than half of HCV-infected patients waiting for LT due to extremely low efficacy and poor tolerability. However, antiviral therapy is indicated after LT in patients with histologically confirmed CHC despite tolerability issues. Improvements in side effect management have increased survival in patients achieving therapeutic targets. HCV treatment pre- and post-LT results in significant health care costs especially when lack of efficacy leads to disease worsening, although studies have shown sofosbuvir treatment before LT vs conventional post-LT dual antiviral is cost effective. The suboptimal efficacy and tolerability of IFN-based therapies, plus the significant economic burden, means the need for effective and well tolerated IFN-free anti-HCV therapy for pre- and post-LT remains high.
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Reduced-dose telaprevir-based triple antiviral therapy for recurrent hepatitis C after living donor liver transplantation. Transplantation 2015; 98:994-9. [PMID: 25099704 DOI: 10.1097/tp.0000000000000166] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
INTRODUCTION The feasibility of telaprevir-based triple therapy for recurrent hepatitis C after liver transplantation (LT) has not been evaluated in Asian patients. METHODS Eleven Japanese patients received reduced-dose telaprevir (1500 mg) and adjusted-dose cyclosporine after LT. Six patients were nonresponders and three were transient responders to dual therapy. RESULTS Rapid viral response, early viral response, end of treatment response, and sustained viral response were achieved in 27.3%, 90.9%, 90.9%, and 81.8% of patients, respectively. One patient had viral breakthrough at week 8 with a T54A mutation in NS3. Deep sequence analysis showed that the T54A mutation reverted to wild-type after stopping telaprevir administration. Seven patients developed severe anemia, and six received blood transfusions (4-20 U). Their hemoglobin and estimated glomerular filtration rate remained significantly lower than pretreatment values at 36 weeks after treatment. Four patients developed plasma cell hepatitis after completing telaprevir treatment, and it was treated by increasing the immunosuppressants. Although the cyclosporine level/dose ratio was 2.7 times higher at week 4 than before treatment, it was 0.7 times lower at week 36. CONCLUSIONS Reduced-dosed telaprevir-based triple antiviral therapy achieved a high viral clearance rate in Japanese patients after LT. Major adverse events included severe anemia, renal dysfunction, and plasma cell hepatitis.
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Lemaitre F, Jezequel C, Verdier MC, Dermu M, Boglione-Kerrien C, Boudjema K, Bellissant E. Lack of drug interaction between cyclosporine and telaprevir in a liver transplant recipient. Transpl Infect Dis 2015; 17:106-10. [PMID: 25573697 DOI: 10.1111/tid.12335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2014] [Revised: 09/05/2014] [Accepted: 10/07/2014] [Indexed: 11/27/2022]
Abstract
Telaprevir is a novel NS3A/4A protease inhibitor approved in combination with ribavirin and peg-interferon alfa for the treatment of genotype-1 chronic hepatitis C. This drug is also known to be a potent cytochrome P450 3A and drug efflux protein ATP-binding cassette B1 (also called P-glycoprotein) inhibitor, and could therefore interact with immunosuppressive drugs. For this reason, a decrease in cyclosporine (CsA) dosage has been proposed when combining this drug with telaprevir. We report herein the case of an unpredictable lack of interaction between CsA and telaprevir in a liver transplant recipient. The decrease in CsA dosage, conducted as recommended in the literature, did not result in stable CsA concentrations but decreased them. However, the decrease in CsA exposure could have been unseen without the measurement of CsA concentrations 2 h after the administration (C2 ) of the drug, because it mainly resulted from the decrease in CsA peak. The mechanism leading to this lack of drug interaction in this patient has not been fully elucidated yet, but is likely to affect the absorption phase. Therapeutic drug monitoring using only CsA trough concentrations could be falsely reassuring, and the addition of the measurement of the C2 may add useful information to adapt CsA dosage in patients co-treated with telaprevir.
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Affiliation(s)
- F Lemaitre
- Department of Clinical and Biological Pharmacology and Pharmacovigilance, Pharmacoepidemiology and Drug Information Center, Rennes University Hospital, Rennes, France; Laboratory of Experimental and Clinical Pharmacology, Faculty of Medicine, Rennes 1 University, Rennes, France; CIC-P 1414 Clinical Investigation Center, Inserm, Rennes, France; Faculty of Pharmacy, EA4123 Barrières physiologiques et réponses thérapeutiques, Paris XI University, Châtenay-Malabry, France
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Castells L, Rimola A, Manzardo C, Valdivieso A, Montero JL, Barcena R, Abradelo M, Xiol X, Aguilera V, Salcedo M, Rodriguez M, Bernal C, Suarez F, Antela A, Olivares S, Del Campo S, Laguno M, Fernandez JR, de la Rosa G, Agüero F, Perez I, González-García J, Esteban-Mur JI, Miro JM. Pegylated interferon plus ribavirin in HIV-infected patients with recurrent hepatitis C after liver transplantation: a prospective cohort study. J Hepatol 2015; 62:92-100. [PMID: 25127748 DOI: 10.1016/j.jhep.2014.07.034] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2014] [Revised: 07/22/2014] [Accepted: 07/28/2014] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS The aim of this study was to evaluate the results of treatment with pegylated interferon and ribavirin for the recurrence of hepatitis C after liver transplantation in HCV/HIV-coinfected patients. METHODS This was a prospective, multicentre cohort study, including 78 HCV/HIV-coinfected liver transplant patients who received treatment for recurrent hepatitis C. For comparison, we included 176 matched HCV-monoinfected patients who underwent liver transplantation during the same period of time at the same centres and were treated for recurrent hepatitis C. RESULTS Antiviral therapy was discontinued prematurely in 56% and 39% (p = 0.016), mainly because of toxicity (22% and 11%, respectively; p=0.034). Sustained virological response (SVR) was achieved in 21% of the coinfected patients and in 36% of monoinfected patients (p = 0.013). For genotype 1, SVR rates were 10% and 33% (p = 0.002), respectively; no significant differences were observed for the other genotypes. A multivariate analysis based on the whole series identified HIV-coinfection as an independent predictor of lack of SVR (OR, 0.17; 95% CI, 0.06-0.42). Other predictors of SVR were donor age, pretreatment HCV viral load, HCV genotype, and early virological response. SVR was associated with a significant improvement in survival: 5-year survival after antiviral treatment was 79% for HCV/HIV-coinfected patients with SVR vs. 43% for those without (p = 0.02) and 92% vs. 60% in HCV-monoinfected patients (p < 0.001), respectively. CONCLUSIONS The response to pegylated interferon and ribavirin was poorer in HCV/HIV-coinfected liver recipients, particularly those with genotype 1. However, when SVR was achieved, survival of coinfected patients increased significantly.
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Affiliation(s)
- Lluis Castells
- Hospital Vall d'Hebrón, Universitat Autónoma de Barcelona, Barcelona, Spain; CIBEREHD, Barcelona, Spain
| | - Antoni Rimola
- CIBEREHD, Barcelona, Spain; Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, Spain
| | | | | | | | - Rafael Barcena
- Hospital Universitario Ramón y Cajal-IRYCIS, Madrid, Spain
| | | | - Xavier Xiol
- Hospital de Bellvitge-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | | | | | | | - Carmen Bernal
- Hospital Universitario Virgen del Rocío, Sevilla, Spain
| | | | - Antonio Antela
- Hospital Universitario de Santiago de Compostela, La Coruña, Spain
| | | | | | | | - José R Fernandez
- Hospital de Cruces, University of the Basque Country, Bilbao, Spain
| | | | - Fernando Agüero
- Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Iñaki Perez
- Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, Spain
| | | | - Juan I Esteban-Mur
- Hospital Vall d'Hebrón, Universitat Autónoma de Barcelona, Barcelona, Spain; CIBEREHD, Barcelona, Spain
| | - Jose M Miro
- Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, Spain.
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Saab S, Manne V, Bau S, Reynolds JA, Allen R, Goldstein L, Durazo F, El-Kabany M, Han S, Busuttil RW. Boceprevir in liver transplant recipients. Liver Int 2015; 35:192-7. [PMID: 24673728 DOI: 10.1111/liv.12548] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Accepted: 03/18/2014] [Indexed: 02/13/2023]
Abstract
BACKGROUND There has been increasing interest in using protease inhibitors with pegylated interferon and ribavirin to treat recurrent hepatitis C (HCV) disease in liver transplant recipients. METHODS We retrospectively evaluated the safety and efficacy in liver transplant recipients treated for recurrent hepatitis C genotype 1 with the combination of peginterferon, ribavirin and boceprevir. RESULTS Twenty liver transplant recipients were treated for recurrent hepatitis C. Baseline alanine aminotransferase, total bilirubin and HCV RNA values (± SD) were 67.5 (±50.9) mg/dl, 1.78 (±1.99) U/L, and 16 955 510 (±21 620 675) IU/ml. Anaemia was a common adverse event requiring epoetin in 16 of 20 recipients and ribavirin dose reductions in 17 of 20 recipients. One-third of recipients required a blood transfusion. Filgrastim was used in 11 of 20 patients (55%) and eltrombopag in two of 20 recipients (10%) over the course of treatment. Serum creatinine level increased significantly from a baseline value of 1.33 mg/dl to 1.59 mg/dl at week 20 of boceprevir (P < 0.005). The overall sustained viral response (SVR) was 50%. Of the 14 patients who had a viral load less than 1000 IU/ml at week 4 of boceprevir, the SVR was 71%. The SVR was 83% of the 11 patients who had undetectable viral levels at week 4 of boceprevir. CONCLUSIONS Antiviral therapy utilizing boceprevir in liver transplant recipients requires close monitoring. Anaemia and neutropenia were common requiring growth factors in most recipients. On-treatment viral responses appear promising but long-term data are needed.
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Affiliation(s)
- Sammy Saab
- Departments of Medicine, The University of California, Los Angeles, CA, USA; Departments of Surgery, The University of California, Los Angeles, CA, USA
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22
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Delaborde L, Logerot S, Fonrose X. [Drug-drug interaction with telaprevir or boceprevir in liver transplant patients: about four cases]. Therapie 2014; 69:491-7. [PMID: 25320939 DOI: 10.2515/therapie/2014201] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Accepted: 07/28/2014] [Indexed: 01/12/2023]
Abstract
Boceprevir and telaprevir are both direct-acting antivirals indicated, as part of combination therapy for the management of chronic hepatitis C virus (HCV) genotype 1 infection. Transplanted patients treated with anticalcineurines (tacrolimus and cyclosporine) are confronted with major risks of interactions. Indeed, these antiviral are strong inhibitors of the enzyme cytochrome 3A4/A5, responsible for the metabolisme of ciclosprine and tacrolimus. The literature gives evidence of the dangerousness of this drug-drug interaction. We report four clinical cases illustrating the dosage adaptations at liver transplant patients and treated by telaprevir or boceprevir. To protect the immunosuppressive efficiency, a multidisciplinary care and narrow monitoring of the interaction between immunosuppressing agents and protease inhibitors were necessary.
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Affiliation(s)
- Lucie Delaborde
- Département de pharmacie, Centre hospitalier universitaire de Grenoble, La Tronche, France
| | - Sophie Logerot
- Centre régional de pharmacovigilance, Centre hospitalier universitaire de Grenoble, La Tronche, France
| | - Xavier Fonrose
- Laboratoire de pharmacologie-toxicologie, Centre hospitalier universitaire de Grenoble, La Tronche France
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Campos-Varela I, Esteban JI, Bes M, Caralt M, Allende H, Rodríguez-Frías F, Salcedo MT, Sauleda S, Charco R, Guardia J, Esteban R, Castells L. Early predictors of antiviral treatment response in liver transplant recipients with recurrent hepatitis C genotype 1. J Viral Hepat 2014; 21:e118-28. [PMID: 24620835 DOI: 10.1111/jvh.12246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2013] [Accepted: 01/14/2014] [Indexed: 12/09/2022]
Abstract
The success of current antiviral treatment for hepatitis C virus (HCV) recurrence in liver transplant (LT) recipients remains limited. We aimed at evaluating the value of IL28B genotype and early viral kinetics to predict response to standard treatment in the transplant setting. We retrospectively evaluated 104 LT recipients treated for HCV genotype 1 recurrence between 2001 and 2010. Baseline variables, including IL28B genotype, and early viral kinetics were compared among patients who did or did not achieve a sustained virological response (SVR). Logistic regression analyses of candidate variables were conducted to generate a reliable predictive model based on the minimum set of variables. Twenty-nine (28%) achieved an SVR. On multivariate analysis, the magnitude of HCV RNA decline at 4 weeks (OR: 3.74, 95% CI: 1.64-9.39; P = 0.003) and treatment compliance (OR: 35.27, 95% CI: 3.35-365.54; P = 0.003) were the only independent predictors of SVR. Favourable recipient IL28B genotype significantly correlates with virological response at week 4 (OR 3.23; 95% CI, 1.12-9.15; P = 0.03). By logistic regression analysis, a model including donor age, recipient rs12979860 genotype and viral load at 4 weeks showed the best predictive value for SVR with an area under the receiver operating curve of 0.861. Favourable recipient IL28B genotype strongly correlates with the viral response at week 4 which is the strongest predictor of response. The combination of recipient IL28B genotype and donor age with the week 4 response reliably estimates the probability of SVR early on-treatment and may facilitate therapeutic strategies incorporating new antiviral agents.
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Affiliation(s)
- I Campos-Varela
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
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25
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Faisal N, Yoshida EM, Bilodeau M, Wong P, Ma M, Burak KW, Al-Judaibi B, Renner EL, Lilly LB. Protease inhibitor-based triple therapy is highly effective for hepatitis C recurrence after liver transplant: a multicenter experience. Ann Hepatol 2014. [DOI: 10.1016/s1665-2681(19)31252-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/15/2023]
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Roos K, Gotthardt D, Giese T, Schnitzler P, Stremmel W, Czock D, Eisenbach C. Pharmacodynamic monitoring of immunosuppressive effects indicates reduced cyclosporine activity during telaprevir therapy. Liver Transpl 2014; 20:1106-17. [PMID: 24890314 DOI: 10.1002/lt.23925] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Accepted: 05/29/2014] [Indexed: 01/11/2023]
Abstract
Drug interactions with immunosuppressive drugs are a major problem associated with protease inhibitor-based antiviral triple therapy for hepatitis C virus (HCV) reinfection after liver transplantation. In this retrospective cohort study, we analyzed biomarkers of the immunosuppressive effects of cyclosporine A (CSA) by quantifying nuclear factor of activated T cells (NFAT)-regulated gene expression during telaprevir (TVR) therapy in 5 liver transplant patients. Furthermore, dose adjustments and blood concentrations of CSA as well as the clinical course were analyzed. We observed a clear impact of TVR not only on doses and blood concentrations but also on the immunosuppressive effects of CSA. Despite apparently adequate CSA trough concentrations, the CSA peak concentration decreased to 68% (range = 44%-90%). This was associated with a 1.9-fold (1.6- to 4.1-fold) increase in the residual gene activity of NFAT-regulated genes, which indicated reduced immunosuppressive activity of CSA with TVR co-medication. The median dose of CSA was reduced to 25% (range = 16%-48%) and 31% (range = 22%-64%) after 1 and 2 weeks, respectively. The CSA drug clearance was reduced to 38.7% (range = 31.0%-49.4%). We report excellent antiviral efficacy. At the end of the observation period, all patients were HCV RNA-negative (1 patient at 18 weeks, 1 patient at 12 weeks, and 3 patients at 4 weeks after the end of therapy). Safety was acceptable, with mild acute rejection and reactivation of cytomegalovirus being the most serious adverse events. One patient with histologically proven recurrent cholestatic hepatitis before therapy underwent retransplantation during the course of antiviral therapy. In conclusion, the immunomonitoring of NFAT-regulated gene expression indicated reduced immunosuppressive activity of CSA during antiviral therapy with TVR in our cohort of liver transplant patients. Thus, the immunosuppressive effects of CSA may be overestimated if one is looking only at trough concentrations during co-medication with protease inhibitors or other strong cytochrome P450 3A inhibitors. Immunomonitoring of NFAT-regulated gene expression could, therefore, help to prevent overimmunosuppression or underimmunosuppression.
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Affiliation(s)
- Katja Roos
- Departments of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany
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Dumortier J, Boillot O, Scoazec JY. Natural history, treatment and prevention of hepatitis C recurrence after liver transplantation: Past, present and future. World J Gastroenterol 2014; 20:11069-11079. [PMID: 25170196 PMCID: PMC4145750 DOI: 10.3748/wjg.v20.i32.11069] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 03/07/2014] [Accepted: 06/23/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV)-related liver disease, including cirrhosis and hepatocellular carcinoma is the main indication for liver transplantation (LT) worldwide. Post-transplant HCV re-infection is almost universal and results in accelerated progression from acute hepatitis to chronic hepatitis, and liver cirrhosis. Comprehension and treatment of recurrent HCV infection after LT have been major issues for all transplant hepatologists and transplant surgeons for the last decades. The aim of this paper is to review the evolution of our knowledge on the natural history of HCV recurrence after LT, including risk factors for disease progression, and antiviral therapy. We will focus our attention on possible ways (present and future) to improve the final long-term results of LT for HCV-related liver disease.
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Dall’Agata M, Gramenzi A, Biselli M, Bernardi M. Hepatitis C virus reinfection after liver transplantation: Is there a role for direct antiviral agents? World J Gastroenterol 2014; 20:9253-9260. [PMID: 25071318 PMCID: PMC4110555 DOI: 10.3748/wjg.v20.i28.9253] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Revised: 03/27/2014] [Accepted: 06/05/2014] [Indexed: 02/06/2023] Open
Abstract
Recurrence of hepatitis C virus (HCV) infection following liver transplantation (LT) is almost universal and can accelerate graft cirrhosis in up to 30% of patients. The development of effective strategies to treat or prevent HCV recurrence after LT remains a major challenge, considering the shortage of donor organs and the accelerated progression of HCV in LT recipients. Standard antiviral therapy with pegylated-interferon plus ribavirin is the current treatment of choice for HCV LT recipients, even though the combination is not as effective as it is in immunocompetent patients. A sustained virological response in the setting of LT improves patient and graft survival, but this is only achieved in 30%-45% of patients and the treatment is poorly tolerated. To improve the efficacy of pre- and post-transplant antiviral therapy, a new class of potent direct-acting antiviral agents (DAAs) has been developed. The aim of this review is to summarize the use of DAAs in LT HCV patients. PubMed, Cochrane Library, MEDLINE, EMBASE, Web of Science and clinical trial databases were searched for this purpose. To date, only three clinical studies on the topic have been published and most of the available data are in abstract form. Although a moderately successful early virological response has been reported, DAA treatment regimens were associated with severe toxicity mitigating their potential usefulness. Moreover, the ongoing nature of data, the lack of randomized studies, the small number of enrolled patients and the heterogeneity of these studies make the results largely anecdotal and questionable. In conclusion, large well-designed clinical studies on DAAs in HCV LT patients are required before these drugs can be recommended after transplantation.
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Moore C, Levitsky J. The Current State and Future Prospects of Chronic Hepatitis C Virus Infection Treatment. Curr Infect Dis Rep 2014; 16:413. [DOI: 10.1007/s11908-014-0413-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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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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Konishi H, Motomura T, Matsumoto Y, Harimoto N, Ikegami T, Yoshizumi T, Soejima Y, Shirabe K, Fukuhara T, Maehara Y. Interferon-lambda4 genetic polymorphism is associated with the therapy response for hepatitis C virus recurrence after a living donor liver transplant. J Viral Hepat 2014; 21:397-404. [PMID: 24750545 DOI: 10.1111/jvh.12154] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The standard therapy against hepatitis C virus (HCV) recurrence postliver transplantation includes interferon (IFN)α and ribavirin. IFNL4 ss469415590 polymorphism has been reported as a novel predictor of the response to IFN therapy for chronic HCV infection. We examined the impact of IFNL4 polymorphism on the responsiveness to IFN therapy after liver transplantation. Tissue specimens were collected from 80 HCV-infected recipients and 78 liver donors, and their IFNL4 ss469415590 genotype, hepatic IFNL4 and interferon-stimulated genes' mRNA expression levels were examined. The association of the polymorphism and expression levels in terms of the IFN therapy response to HCV recurrence was analysed. Most individuals who had rs8099917 risk alleles also had ss469415590 risk alleles (R(2) = 0.9). Sustained virological response (SVR) rates were higher in both liver graft recipients and transplants with ss469415590 TT/TT alleles than in those with the risk ΔG allele (P = 0.003 and P = 0.005, respectively). In recipients with ss469415590 TT/TT, IFNL4 TT mRNA levels showed no significant differences between livers of patients who responded to therapy and those who did not (P = 0.4). In recipients with the risk ΔG allele, IFNL4 ΔG mRNA expression levels were significantly lower in SVR patients than in non-SVR patients (P = 0.02). Hepatic interferon stimulable genes and IFNL4 mRNA expression were correlated. Our findings suggest that analysing the ss469415590 genotype and IFNL4 ΔG expression provides a novel prediction strategy for the possible response to IFN therapy after liver transplantation.
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Affiliation(s)
- H Konishi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., Gotemba city, Japan
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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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Kwo PY, Ghabril M, Lacerda MA, Joseph Tector A, Fridell JA, Vianna R. Telaprevir with peginterferon/ribavirin for retreatment of null responders with advanced fibrosis post-orthotopic liver transplant. Clin Transplant 2014; 28:722-7. [DOI: 10.1111/ctr.12372] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/24/2014] [Indexed: 11/29/2022]
Affiliation(s)
- Paul Y. Kwo
- Division of Gastroenterology and Hepatology; Indiana University School of Medicine; Indiana University Health; Indianapolis IN USA
| | - Marwan Ghabril
- Division of Gastroenterology and Hepatology; Indiana University School of Medicine; Indiana University Health; Indianapolis IN USA
| | - Marco A. Lacerda
- Division of Gastroenterology and Hepatology; Indiana University School of Medicine; Indiana University Health; Indianapolis IN USA
| | - Alfred Joseph Tector
- Division of Transplantation Surgery; Indiana University School of Medicine; Indiana University Health; Indianapolis IN USA
| | - Jonathan A. Fridell
- Division of Transplantation Surgery; Indiana University School of Medicine; Indiana University Health; Indianapolis IN USA
| | - Rodrigo Vianna
- Division of Transplantation Surgery; Indiana University School of Medicine; Indiana University Health; Indianapolis IN USA
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Rendina M, D'Amato M, Castellaneta A, Castellaneta NM, Brambilla N, Giacovelli G, Rovati L, Rizzi SF, Zappimbulso M, Bringiotti RS, Di Leo A. Antiviral activity and safety profile of silibinin in HCV patients with advanced fibrosis after liver transplantation: a randomized clinical trial. Transpl Int 2014; 27:696-704. [PMID: 24673819 DOI: 10.1111/tri.12324] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Revised: 02/17/2014] [Accepted: 03/24/2014] [Indexed: 12/30/2022]
Abstract
Response to interferon-based therapies in HCV recurrence after liver transplantation (LT) is unsatisfactory, and major safety issues aroused in preliminary experience with boceprevir and telaprevir. As transplant community identified HCV viral clearance as a critical matter, efficacious and safe anti-HCV therapies are awaited. The aim of this study was to assess efficacy and safety of intravenous silibinin monotherapy in patients with established HCV recurrence after LT, nonresponders to pegylated interferon and ribavirin. This is a single center, prospective, randomized, parallel-group, double-blind, placebo-controlled, phase 2 trial including 20 patients randomly assigned (3:1) to receive daily 20 mg/kg of intravenous silibinin or saline as placebo, for 14 consecutive days. On day 14 of treatment, viral load decreased by 2.30 ± 1.32 in silibinin group versus no change in the placebo group (P = 0.0002). Sixteen days after the end of the treatment, viral load mean values were similar to baseline. Treatment resulted well tolerated apart from a transient and reversible increase in bilirubin. Neither changes in immunosuppressant through levels nor dosage adjustments were necessary. Silibinin monotherapy has a significant antiviral activity in patients with established HCV recurrence on the graft not responding to standard therapy and confirms safety and tolerability without interaction with immunosuppressive drugs (ClinicalTrials.gov number: NCT01518933).
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Affiliation(s)
- Maria Rendina
- Department of Emergency and Organ Transplantation, Section of Gastroenterology, University Hospital, Bari, Italy
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Dhanasekaran R, Firpi RJ. Challenges of recurrent hepatitis C in the liver transplant patient. World J Gastroenterol 2014; 20:3391-3400. [PMID: 24707122 PMCID: PMC3974506 DOI: 10.3748/wjg.v20.i13.3391] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2013] [Revised: 11/22/2013] [Accepted: 03/10/2014] [Indexed: 02/06/2023] Open
Abstract
Cirrhosis secondary to hepatitis C virus (HCV) is a very common indication for liver transplant. Unfortunately recurrence of HCV is almost universal in patients who are viremic at the time of transplant. The progression of fibrosis has been shown to be more rapid in the post-transplant patients than in the transplant naïve, hence treatment of recurrent HCV needs to be considered for all patients with documented recurrent HCV. Management of recurrent HCV is a challenging situation both for patients and physicians due to multiple reasons as discussed in this review. The standard HCV treatment with pegylated interferon and Ribavarin can be considered in these patients but it leads to a lower rate of sustained virologic clearance than in the non-transplanted population. Some of the main challenges associated with treating recurrent HCV in post-transplant patients include the presence of cytopenias; need to monitor drug-drug interactions and the increased incidence of renal compromise. In spite of these obstacles all patients with recurrent HCV should be considered for treatment since it is associated with improvement in survival and a delay in fibrosis progression. With the arrival of direct acting antiviral drugs there is renewed hope for better outcomes in the treatment of post-transplant HCV recurrence. This review evaluates current literature on this topic and identifies challenges associated with the management of post-transplant HCV recurrence.
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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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Outcome of early vs. deferred antiviral treatment for recurrent hepatitis C in liver transplant recipients. Ann Hepatol 2014. [PMID: 24552864 DOI: 10.1016/s1665-2681(19)30885-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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Coilly A, Roche B, Duclos-Vallée JC, Samuel D. Management of HCV transplant patients with triple therapy. Liver Int 2014; 34 Suppl 1:46-52. [PMID: 24373078 DOI: 10.1111/liv.12406] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
Hepatitis C virus (HCV) infection is one of the leading causes of end-stage liver disease and the main indication for liver transplantation (LT) in most countries. All patients who undergo LT with detectable serum HCV RNA experience graft reinfection. Between 20 and 30% of patients have developed cirrhosis at 5 years post-LT. The outcome of transplant patients with cirrhosis on the graft is severe, with a rate of decompensation at 1 year of approximately 40%. To date, retransplantation is the only option in patients with decompensated liver disease. Until 2011, standard antiviral therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV), was the only effective therapy. Obtaining a sustained virological response (SVR) in patients with LT greatly improves overall and graft survival but this only occurs in 30% of transplanted patients. Direct acting antivirals (DAAs) such as protease inhibitors (PI), polymerase or other non-structural proteins inhibitors represent a new era in HCV associated liver disease. Although their use in the field of LT will certainly be essential there are some limitations because of safety and tolerance. One limitation is the potential interaction with calcineurin inhibitors. We describe the results of triple therapy with boceprevir (BOC) or telaprevir (TVR) for efficacy and safety and comment on future therapeutic strategies in liver transplant recipients.
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Affiliation(s)
- Audrey Coilly
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France; Univ Paris-Sud, UMR-S 785, Villejuif, France; Inserm, Unité 785, Villejuif, France; Hepatinov, Villejuif, France
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The Successful Use of Telaprevir to Treat Hepatitis C Recurrence After Liver Transplantation in an HIV Co-Infected Patient. Transplantation 2014; 97:e14-5. [DOI: 10.1097/01.tp.0000438633.06344.3a] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Ramsay ID, Lestner JM, O’Sullivan CP, Cruz AL, Li HK, Barker CI. Antiviral Drugs. SIDE EFFECTS OF DRUGS ANNUAL 2014:401-443. [DOI: 10.1016/b978-0-444-63407-8.00029-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Safety and efficacy of protease inhibitors to treat hepatitis C after liver transplantation: a multicenter experience. J Hepatol 2014; 60:78-86. [PMID: 23994384 DOI: 10.1016/j.jhep.2013.08.018] [Citation(s) in RCA: 166] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2013] [Revised: 07/16/2013] [Accepted: 08/15/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Protease inhibitors (PI) with peginterferon/ribavirin have significantly improved SVR rates in HCV G1 patients. Their use to treat HCV recurrence after liver transplantation (LT) is a challenge. METHODS This cohort study included 37 liver transplant recipients (male, 92%, age 57 ± 11 years), treated with boceprevir (n=18) or telaprevir (n=19). The indication for therapy was HCV recurrence (fibrosis stage ≥F2 (n=31, 83%) or fibrosing cholestatic hepatitis (n=6, 16%). RESULTS Eighteen patients were treatment-naive, five were relapsers and fourteen were non-responders to dual therapy after LT. Twenty-two patients received cyclosporine and fifteen tacrolimus. After 12 weeks of PI therapy, a complete virological response was obtained in 89% of patients treated with boceprevir, and 58% with telaprevir (p=0.06). The end of treatment virological response rate was 72% (13/18) in the boceprevir group and 40% (4/10) in the telaprevir group (p=0.125). A sustained virological response 12 weeks after treatment discontinuation was observed in 20% (1/5) and 71% (5/7) of patients in the telaprevir and boceprevir groups, respectively (p=0.24). Treatment was discontinued in sixteen patients (treatment failures (n=11), adverse events (n=5)). Infections occurred in ten patients (27%), with three fatal outcomes (8%). The most common adverse effect was anemia (n=34, 92%), treated with erythropoietin and/or a ribavirin dose reduction; thirteen patients (35%) received red blood cell transfusions. The cyclosporine dose was reduced by 1.8 ± 1.1-fold and 3.4 ± 1.0-fold with boceprevir and telaprevir, respectively. The tacrolimus dose was reduced by 5.2 ± 1.5-fold with boceprevir and 23.8±18.2-fold with telaprevir. CONCLUSIONS Our results suggest that triple therapy is effective in LT recipients, particularly those experiencing a severe recurrence. The occurrence of anemia and drug-drug interactions, and the risk of infections require close monitoring.
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Maasoumy B, Port K, Calle Serrano B, Markova AA, Sollik L, Manns MP, Cornberg M, Wedemeyer H. The clinical significance of drug-drug interactions in the era of direct-acting anti-viral agents against chronic hepatitis C. Aliment Pharmacol Ther 2013; 38:1365-72. [PMID: 24127648 DOI: 10.1111/apt.12523] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2013] [Revised: 08/19/2013] [Accepted: 09/17/2013] [Indexed: 12/25/2022]
Abstract
BACKGROUND Drug-drug interactions (DDIs) in the treatment of chronic hepatitis C infection became a potential challenge with the introduction of direct-acting anti-virals (DAAs). Both currently approved DAAs, the protease inhibitors (PIs) telaprevir (TVR) and boceprevir (BOC), are substrates and inhibitors of P-glycoprotein and the cytochrome P450 3A4, which are regularly involved in DDIs. AIM To analyse the risk for DDIs in patients with chronic HCV genotype 1 infection considered for PI treatment at a tertiary referral centre. METHODS The first 115 consecutive patients selected for a PI therapy at Hannover Medical School were included. All changes to co-medication before and during PI treatment were documented. Drugs were checked for DDIs with TVR and BOC using DDI websites and the respective prescribing information. RESULTS Out-patient medication contained 116 different drugs. Median number of drugs/patient was 2 (range 0-11). The risk for DDIs was substantial for 38% of the drugs affecting 49% of patients. Only 4% of the drugs were strictly contraindicated. DDIs between a PI and drugs newly prescribed during anti-viral therapy were considerable in 42% of the patients. Suspected DDIs were managed by dose adjustments and discontinuation of co-medication in 7% and 21% of the patients respectively. CONCLUSIONS Many patients with chronic HCV genotype 1 infection are affected by potential DDIs if treated with a protease inhibitor, but only in a minority of cases co-medication is strictly incompatible. Overall, the challenge of DDIs is time-consuming, but well manageable by a careful review of the patient's drug chart and monitoring during treatment.
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Affiliation(s)
- B Maasoumy
- Department for Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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Feasibility of telaprevir-based triple therapy in liver transplant patients with hepatitis C virus: SVR 24 results. PLoS One 2013; 8:e80528. [PMID: 24265827 PMCID: PMC3827217 DOI: 10.1371/journal.pone.0080528] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Accepted: 10/14/2013] [Indexed: 12/18/2022] Open
Abstract
Management of recurrent Hepatitis C virus (HCV) infection following liver transplantation remains a major challenge. In non-transplanted HCV genotype 1 patients, the introduction of protease inhibitor-based regimens has significantly increased the rate of sustained virological response. In this follow-up study, on the first published cohort of post-liver transplant patients treated with telaprevir-based triple therapy, we investigated both efficacy and safety data in follow-up to 24 weeks (SVR 24) after end of treatment (EOT). SVR 24 efficacy and safety data from 9 liver transplant HCV patients being treated with telaprevir, pegylated interferon, and ribavirin, showed 5 of the transplanted patients accomplished the full duration of the 48 week triple therapy. Notable were the 4 patients found to be HCV RNA-negative at week 4, and 8 patients at week 12. Upon EOT, at week 48, 6 patients were HCV RNA-negative. Importantly, at follow-up (24 weeks after EOT), a favorable sustained virological response rate was observed in 5 of these patients with HCV RNA remaining negative, including in one patient who discontinued treatment prematurely. Due to side effects, 2 patients discontinued, 2 suffered from virological breakthrough after the telaprevir treatment phase, and 1 patient had a relapse after EOT. Two thirds of patients exhibited hematological side effects requiring ribavirin dose reductions, administration of erythropoetin, or even blood transfusions. This retrospective analysis provides evidence that - with respect to SVR 24 - liver transplant patients suffering from HCV genotype 1 recurrence may benefit from a telaprevir-based triple therapy as this new regimen showed acceptable antiviral efficacy in this small cohort of mostly pre-treated patients. Management of drug-drug interactions is challenging, but feasible. In part severe side effects are frequent during treatment and require therapeutic interventions.
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Abstract
In this article the medications that have been shown to increase rates of drug-induced liver injury in patients with cirrhosis and the important drug-drug interactions in recipients of liver transplantation are reviewed. In general, the risk of drug-induced liver injury in patients with cirrhosis does not seem to be higher when compared with the noncirrhotic population. There are, however, 2 classes of agents that have been implicated-medications used to treat tuberculosis and medications used to treat human immunodeficiency virus infection. However, with careful monitoring, even significant interactions can be effectively managed.
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Vinaixa C, Aguilera V, Berenguer M. Avances en el tratamiento de la hepatitis C. Med Clin (Barc) 2013; 141:447-52. [DOI: 10.1016/j.medcli.2013.01.041] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2012] [Revised: 01/30/2013] [Accepted: 01/31/2013] [Indexed: 12/15/2022]
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Successful anti-hepatitis C virus therapy with telaprevir in an HIV/hepatitis C virus co-infected patient with a severe recurrence of hepatitis C virus infection on the liver graft. AIDS 2013; 27:2655-7. [PMID: 23939241 DOI: 10.1097/01.aids.0000432539.77711.f4] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
We report, for the first time, the outcome of anti-hepatitis C virus (HCV) triple therapy with telaprevir in an HIV/HCV co-infected transplanted patient. After liver transplantation, the patient experienced a severe HCV recurrence with fibrosing cholestatic hepatitis, and anti-HCV therapy with pegylated interferon alpha 2a, ribavirin and telaprevir was initiated. A sustained virological response was achieved after 48 weeks of anti-HCV therapy. Drug-drug interactions between antiretroviral therapy, immunosuppressive agents and anti-HCV therapy could be managed.
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Kiser JJ, Burton JR, Everson GT. Drug-drug interactions during antiviral therapy for chronic hepatitis C. Nat Rev Gastroenterol Hepatol 2013; 10:596-606. [PMID: 23817323 PMCID: PMC4634866 DOI: 10.1038/nrgastro.2013.106] [Citation(s) in RCA: 105] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The emergence of direct-acting antiviral agents (DAAs) for HCV infection represents a major advance in treatment. The NS3 protease inhibitors, boceprevir and telaprevir, were the first DAAs to receive regulatory approval. When combined with PEG-IFN and ribavirin, these agents increase rates of sustained virologic response in HCV genotype 1 to ∼70%. However, this treatment regimen is associated with several toxicities. In addition, both boceprevir and telaprevir are substrates for and inhibitors of the drug transporter P-glycoprotein and the cytochrome P450 enzyme 3A4 and are, therefore, prone to clinically relevant drug interactions. Several new DAAs for HCV are in late stages of clinical development and are likely to be approved in the near future. These include the protease inhibitors, simeprevir and faldaprevir, the NS5A inhibitor, daclatasvir, and the nucleotide polymerase inhibitor, sofosbuvir. Herein, we review the clinical pharmacology and drug interactions of boceprevir, telaprevir and these investigational DAAs. Although boceprevir and telaprevir are involved in many interactions, these interactions are manageable if health-care providers proactively identify and adjust treatments. Emerging DAAs seem to have a reduced potential for drug interactions, which will facilitate their use in the treatment of HCV.
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Affiliation(s)
- Jennifer J Kiser
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, 12850 East Montview Boulevard, V20-C238, Aurora, CO 80045, USA
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Abstract
With the licensing of the direct acting antivirals telaprevir and boceprevir the topic of drug-drug interactions has come to the forefront. These first generation hepatitis C virus protease inhibitors are metabolized by and inhibit the key drug metabolizing enzyme CYP3A4, which means that knowledge of drug-drug interactions has become an essential component of the evaluation of a patient starting triple therapy. The number of potential co-medications means that many drugs will be used in hepatitis C virus patients where there are no pharmacokinetic study data. Here we have to use the data that are available and seek to extrapolate to unstudied drugs using key principles of clinical pharmacology (disposition characteristics, concentration-effect relationships, therapeutic window) in order to give some guidance for management of patients. This is a rapidly moving area in hepatitis C therapy, both in terms of understanding the drug interaction profile of telaprevir and boceprevir, interaction mechanisms that sometimes appear counterintuitive and that may involve enzymes other than CYP3A4 or transporters, but then seeking to understand the interaction potential of the next wave of drugs that will soon be with us.
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Berenguer Berenguer J, González-García J. [Pharmacokinetic interactions of telaprevir with other drugs]. Enferm Infecc Microbiol Clin 2013; 31 Suppl 3:37-48. [PMID: 24063902 DOI: 10.1016/s0213-005x(13)70123-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Telaprevir is a new direct-acting antiviral drug for the treatment of hepatitis C virus (HCV) infection and is both a substrate and an inhibitor of cytochrome P450 (CYP450) isoenzymes. With the introduction of this new drug, assessment of drug-drug interactions has become a key factor in the evaluation of patients under treatment for HCV infection. During the treatment of this infection, many patients require other drugs to mitigate the adverse effects of anti-HCV drugs and to control other comorbidities. Moreover, most patients coinfected with HIV and HCV require antiretroviral therapy during treatment for HCV. Physicians should therefore be familiar with the pharmacokinetic properties of direct-acting antivirals for HCV treatment and their potential drug-drug interactions. The present article reviews the available information to date on the interactions of telaprevir with other drugs and provides recommendations for daily clinical practice.
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Affiliation(s)
- Juan Berenguer Berenguer
- Unidad de Enfermedades Infecciosas/VIH, Hospital General Universitario Gregorio Marañón, IiSGM, Madrid, España.
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