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1
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Coilly A, Sebagh M, Fougerou-Leurent C, Pageaux GP, Leroy V, Radenne S, Silvain C, Lebray P, Houssel-Debry P, Cagnot C, Rossignol E, Danjou H, Veislinger A, Samuel D, Duclos-Vallée JC, Dumortier J. HCV eradication does not protect from fibrosis progression in patients with fibrosing cholestatic hepatitis after liver transplantation. Clin Res Hepatol Gastroenterol 2022; 46:102024. [PMID: 36122871 DOI: 10.1016/j.clinre.2022.102024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 09/05/2022] [Accepted: 09/11/2022] [Indexed: 02/04/2023]
Abstract
INTRODUCTION Hepatitis C virus (HCV) may recur after liver transplantation (LT) in the severe form of fibrosing cholestatic hepatitis (FCH). The prognosis dramatically improved by the use of direct acting antivirals (DAAs). The aim of the present study was to describe the change in histological features of FCH after virological eradication. METHODS From the ANRS CUPILT cohort we included 17 patients who presented FCH and at least two graft biopsies, one before DAA-treatment and one after. A single expert pathologist, blinded for clinical outcome, retrospectively confirmed the diagnosis of FCH and progression of fibrosis. RESULTS Diagnosis of FCH was made after a median [IQR] 6.0 [3.1-11.8] months after LT, and the median interval between diagnosis and onset of treatment was 1.2 [0.7-6.1] months. The rate of viral eradication was 94.1%. The median delay between the pre-treatment and the treatment biopsies was 12.5 [11.1-20.0] months. Between the end of treatment and the second biopsy, the delay was 5.3 [0.6-7.4] months. Fibrosis stage worsened in 10 patients (58.8%); 6 patients had cirrhosis (35.3%). Chronic rejection appeared in 4 (23.5%) patients. CONCLUSION Our results suggest that, despite viral eradication in patients presenting FCH after LT, fibrosis progression was observed in half of patients. This should encourage monitoring fibrosis progression despite HCV cure.
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Affiliation(s)
- Audrey Coilly
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire; Université Paris-Saclay, UMR-S 1193; Inserm Unité 1193; FHU Hepatinov, Villejuif 94800, France.
| | - Mylène Sebagh
- AP-HP Hôpital Bicêtre, Service d'Anatomie Pathologique, Kremlin-Bicêtre, France
| | - Claire Fougerou-Leurent
- Rennes University Hospital, Unit of Clinical Pharmacology; INSERM Clinical Investigation Centre 1414, Rennes, France
| | - Georges-Philippe Pageaux
- CHU Saint-Eloi, Département D'hépato-Gastroentérologie et de Transplantation Hépatique, Université Montpellier 1, Montpellier, France
| | - Vincent Leroy
- CHU de Grenoble, Pôle Digidune, Clinique Universitaire d'Hépato-Gastroentérologie; Unité INSERM /Université Grenoble Alpes U823, IAPC Institut Albert Bonniot, Grenoble, France
| | - Sylvie Radenne
- Hospices Civils de Lyon, Hôpital de la Croix Rousse, Service d'Hépato-gastroentérologie, Lyon, France
| | - Christine Silvain
- Département d'Hépato-gastroentérologie, CHU de Poitiers, Pôle Biologie Santé, Poitiers EA 4331, France
| | - Pascal Lebray
- AP-HP, Departement d'hépatologie et de Gastroenterologie, Groupe Hospitalier Pitié-Salpétrière, Université Pierre et Marie Curie Paris 6, Paris, France
| | | | - Carole Cagnot
- Unit for Basic and Clinical Research on Viral Hepatitis, ANRS (France Recherche Nord&sud Sida-hiv Hépatites), Paris, France
| | - Emilie Rossignol
- Rennes University Hospital, Unit of Clinical Pharmacology; INSERM Clinical Investigation Centre 1414, Rennes, France
| | - Hélène Danjou
- Rennes University Hospital, Unit of Clinical Pharmacology; INSERM Clinical Investigation Centre 1414, Rennes, France
| | - Aurélie Veislinger
- Rennes University Hospital, Unit of Clinical Pharmacology; INSERM Clinical Investigation Centre 1414, Rennes, France
| | - Didier Samuel
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire; Université Paris-Saclay, UMR-S 1193; Inserm Unité 1193; FHU Hepatinov, Villejuif 94800, France
| | - Jean-Charles Duclos-Vallée
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire; Université Paris-Saclay, UMR-S 1193; Inserm Unité 1193; FHU Hepatinov, Villejuif 94800, France
| | - Jérôme Dumortier
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Service d'Hépato-gastroentérologie, Université Claude Bernard Lyon 1, Pavillons D et L, 69437, Lyon Cedex 03, France.
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Aly OA, Yousry WA, Teama NM, Shona EM, ElGhandour AM. Sofosbuvir and daclatasvir are safe and effective in treatment of recurrent hepatitis C virus in Egyptian patients underwent living donor liver transplantation. EGYPTIAN LIVER JOURNAL 2020. [DOI: 10.1186/s43066-020-00056-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Abstract
Background
Liver transplant population has been considered as a special population in the treatment of hepatitis C virus infection, not only because of lower sustained virological response (SVR) rates in comparison with pretransplant setting, but also for other aspects (i.e., immunosuppressive therapy, renal function, drug–drug interactions). We aimed to evaluate the efficacy and safety of the combined treatment with sofosbuvir and daclatasvir with or without ribavirin in liver transplant recipients with recurrent hepatitis C following transplantation and screening for the development of hepatocellular carcinoma during treatment, after the end of treatment, or during follow-up. This multicenteric prospective study was conducted in Egypt. This study included 40 patients who underwent living donor liver transplantation that started treatment at least 3 months following transplantation. All participants received 400 mg sofosbuvir once daily plus daclatasvir 60 mg daily ± ribavirin. Treatment lasted for up to 24 weeks, and participants were followed up as outpatients monthly for 12 and 24 weeks and 36 weeks post-treatment to determine sustained virological response (SVR12 and SVR24), considered to be a cure and detection of any changes in tumor markers or radiological imaging during follow-up.
Results
In the current study, 40 patients (100%) have good response to treatment during treatment and during follow-up (SVR 12 was 100%). No abnormal side effects to treatment were detected; also, no drug–drug interactions were noted during the treatment.
Conclusions
Treatment of HCV after living donor liver transplantation with combined sofosbuvir and daclatasvir is safe and well-tolerated and provides high rates of SVR.
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3
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Fu H, Dong J, Sun Z, Zhang X, Yu A, Chen G, Li W. Efficacy and safety of sofosbuvir-containing regimens in patients with chronic hepatitis C virus infection after liver transplantation: a meta-analysis. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:648. [PMID: 32566585 PMCID: PMC7290620 DOI: 10.21037/atm-20-3074] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Background This meta-analysis evaluated the efficacy and safety of a sofosbuvir (SOF)-containing regimen in patients with hepatitis C virus (HCV) infection after liver transplantation (LT). Methods We performed a systematic search for relevant published data on the PubMed, EMBASE, and Cochrane Library databases. Studies that evaluated any regimen in which SOF was used to treat patients with HCV infection after LT and reported the sustained virologic response 12 weeks (SVR12) after therapy were included. Results A total of 12 studies, involving 892 patients, were included in this analysis. The pooled estimate of SVR12 (sustained virologic response 12 weeks) was 88.1%. Subgroup analysis showed that patients who received SOF plus other DAAs had higher SVR12 than those treated with SOF plus ribavirin or peg-IFN. The pooled incidence of any adverse events (AEs) was 73.7%. Conclusions The results of this study showed that the treatment response of SOF-containing regimens in patients with HCV infection after LT was satisfactory. However, more attention needs to be paid to the high rate of AEs associated with such regimens.
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Affiliation(s)
- Hua Fu
- Hospital and Institute of Hepatobiliary Surgery, Chinese PLA General Hospital, Chinese PLA Medical School, Beijing, China.,Department of Hepatobiliary Surgery, Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Jiahong Dong
- Hospital and Institute of Hepatobiliary Surgery, Chinese PLA General Hospital, Chinese PLA Medical School, Beijing, China.,Center of Hepatopancreatobiliary Diseases, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Zhide Sun
- Department of Hepatobiliary Surgery, Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Xuejun Zhang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Aijun Yu
- Department of Hepatobiliary Surgery, Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Guoli Chen
- Department of Hepatobiliary Surgery, Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Wei Li
- Department of Hepatobiliary Surgery, Affiliated Hospital of Chengde Medical University, Chengde, China
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4
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Gad M, Hassan SA, Zaazaa HE, Amer SM. Multivariate Development and Optimization of Stability Indicating Method for Determination of Daclatasvir in Presence of Potential Degradation Products. Chromatographia 2019. [DOI: 10.1007/s10337-019-03793-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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5
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Therapy with Direct-Acting Antiviral Agents in Transplanted Patients with HCV Recurrence: A Retrospective Analysis. HEPATITIS MONTHLY 2019. [DOI: 10.5812/hepatmon.90624] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
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6
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Shaffer AA, Thomas AG, Bowring MG, Van Pilsum Rasmussen SE, Cash A, Kucirka LM, Alqahtani SA, Gurakar A, Sulkowski MS, Cameron AM, Segev DL, Durand CM. Changes in practice and perception of hepatitis C and liver transplantation: Results of a national survey. Transpl Infect Dis 2018; 20:e12982. [PMID: 30144258 DOI: 10.1111/tid.12982] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 06/14/2018] [Accepted: 08/12/2018] [Indexed: 12/18/2022]
Abstract
With new practice guidelines, it is important to understand how liver transplant (LT) centers have incorporated direct-acting antivirals (DAAs) into the management of hepatitis C virus-infected (HCV+) candidates and recipients. To explore how DAAs have affected LT centers' willingness to treat HCV+ candidates and recipients and to use HCV+ donors, we surveyed high volume US LT centers (11/2014-12/2015) regarding practices for HCV+ candidates, recipients, and donors, before vs after DAAs. We used the Scientific Registry of Transplant Recipients to compare centers' number of LTs, HCV+ recipients, and HCV+ donors in the years before (1/1/2012-12/31/2013) and after (1/1/2016-12/31/2017) survey administration. Of 80 centers contacted, 57 (71.3%) responded, representing 69.0% of the total volume of LTs in 2013. After DAAs, most centers increased treating candidates with low (≤15) model for end-stage liver disease (MELD) (85.2%), intermediate/high (>15) MELD (92.6%), and hepatocellular carcinoma (79.6%). There was consensus to treat low MELD candidates (90.8% "most of the time/always"), but less certainty for intermediate/high MELD candidates (48.2% "sometimes"). Universal post-LT HCV treatment increased (7.4% vs 57.4%). After DAAs, 42.6% were more willing to use HCV+ donors for HCV+ candidates, and 38.9% were willing to consider using HCV+ donors for HCV- candidates. Overall, with DAAs, centers were more willing to treat HCV+ candidates and recipients and to use HCV+ donors; recent recommendations may help to guide treatment decisions for intermediate/high MELD candidates.
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Affiliation(s)
- Ashton A Shaffer
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, Maryland
| | - Alvin G Thomas
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, North Carolina
| | - Mary Grace Bowring
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | | | - Ayla Cash
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Lauren M Kucirka
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, Maryland
| | - Saleh A Alqahtani
- Department of Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ahmet Gurakar
- Department of Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Mark S Sulkowski
- Department of Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Infectious Disease, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Andrew M Cameron
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Dorry L Segev
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, Maryland
| | - Christine M Durand
- Department of Infectious Disease, Johns Hopkins University School of Medicine, Baltimore, Maryland
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7
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Mason S, Devincenzo JP, Toovey S, Wu JZ, Whitley RJ. Comparison of antiviral resistance across acute and chronic viral infections. Antiviral Res 2018; 158:103-112. [PMID: 30086337 DOI: 10.1016/j.antiviral.2018.07.020] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 07/24/2018] [Accepted: 07/26/2018] [Indexed: 12/26/2022]
Abstract
Antiviral therapy can lead to drug resistance, but multiple factors determine the frequency of drug resistance mutations and the clinical consequences. When chronic infections caused by Human Immunodeficiency Virus (HIV), Hepatitis C Virus (HCV) and Hepatitis B Virus (HBV) are compared with acute infections such as influenza virus, respiratory syncytial virus (RSV), and other respiratory viruses, there are similarities in how and why antiviral resistance substitutions occur, but the clinical significance can be quite different. Emergence of resistant variants has implications for design of new therapeutics, treatment guidelines, clinical trial design, resistance monitoring, reporting, and interpretation. In this discussion paper, we consider the molecular factors contributing to antiviral drug resistance substitutions, and a comparison is made between chronic and acute infections. The implications of resistance are considered for clinical trial endpoints and public health, as well as the requirements for therapeutic monitoring in clinical practice with acute viral infections.
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Affiliation(s)
- Stephen Mason
- SWM Consulting, 9 Clearview Dr, Wallingford, CT 06492, USA
| | - John P Devincenzo
- Dpt of Pediatrics, College of Medicine, University of Tennessee Center for Health Sciences, Memphis, TN, USA; Dpt of Microbiology, Immunology, and Biochemistry, College of Medicine, University of Tennessee Center for Health Sciences, Memphis, TN, USA; Children's Foundation Research Institute at Le Bonheur Children's Hospital, Memphis, TN, USA
| | | | - Jim Z Wu
- Ark Biosciences Inc, Shanghai, PR China
| | - Richard J Whitley
- Department of Pediatrics, Microbiology, Medicine and Neurosurgery, The University of Alabama at Birmingham, USA
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8
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Sofosbuvir inhibits hepatitis A virus replication in vitro assessed by a cell-based fluorescent reporter system. Antiviral Res 2018; 154:51-57. [DOI: 10.1016/j.antiviral.2018.04.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 03/28/2018] [Accepted: 04/08/2018] [Indexed: 02/07/2023]
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9
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Rupp C, Hippchen T, Neuberger M, Sauer P, Pfeiffenberger J, Stremmel W, Gotthardt DN, Mehrabi A, Weiss KH. Successful combination of direct antiviral agents in liver-transplanted patients with recurrent hepatitis C virus. World J Gastroenterol 2018; 24:1353-1360. [PMID: 29599610 PMCID: PMC5871830 DOI: 10.3748/wjg.v24.i12.1353] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 03/02/2018] [Accepted: 03/18/2018] [Indexed: 02/07/2023] Open
Abstract
AIM To analyze the safety and efficiency of direct-acting antiviral (DAA) regimens in liver-transplanted patients with hepatitis C virus (HCV) reinfection.
METHODS Between January 2014 and December 2016, 39 patients with HCV reinfection after liver transplantation were treated at our tertiary referral center with sofosbuvir (SOF)-based regimens, including various combinations with interferon (IFN), daclatasvir (DAC), simeprivir (SIM) and/or ledipasvir (LDV). Thirteen patients were treated with SOF + IFN ± RBV. Ten patients were treated with SOF + DAC ± RBV. Fiveteen patients were treated with fixed-dose combination of SOF + LDV ± RBV. One patient was treated with SOF + SIM + RBV. Three patients with relapse were retreated with SOF + LDV + RBV. The treatment duration was 12-24 wk in all cases. The decision about the HCV treatment was made by specialists at our transplant center, according to current available or recommended medications.
RESULTS The majority of patients were IFN-experienced (29/39, 74.4%) and had a history of hepatocellular carcinoma (26/39, 66.7%) before liver transplantation. Sustained virological response at 12 wk (SVR12) was achieved in 10/13 (76.9%) of patients treated with SOF + IFN ± RBV. All patients with relapse were treated with fixed-dose combination of SOF + LDV + RBV. Patients treated with SOF + DAC + RBV or SOF + LDV + RBV achieved 100% SVR12. SVR rates after combination treatment with inhibitors of the HCV nonstructural protein (NS)5A and NS5B for 24 wk were significantly higher, as compared to all other therapy regimens (P = 0.007). Liver function was stable or even improved in the majority of patients during treatment. All antiviral therapies were safe and well-tolerated, without need of discontinuation of treatment or dose adjustment of immunosuppression. No serious adverse events or any harm to the liver graft became overt. No patient experienced acute cellular rejection during the study period.
CONCLUSION Our cohort of liver-transplanted patients achieved high rates of SVR12 after a 24-wk course of treatment, especially with combination of NS5A and NS5B inhibitors.
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Affiliation(s)
- Christian Rupp
- Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg 69120, Germany
- Interdisciplinary Endoscopy Unit, University Hospital of Heidelberg, Heidelberg 69120, Germany
| | - Theresa Hippchen
- Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg 69120, Germany
| | - Manuel Neuberger
- Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg 69120, Germany
| | - Peter Sauer
- Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg 69120, Germany
- Interdisciplinary Endoscopy Unit, University Hospital of Heidelberg, Heidelberg 69120, Germany
| | - Jan Pfeiffenberger
- Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg 69120, Germany
| | - Wolfgang Stremmel
- Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg 69120, Germany
| | - Daniel Nils Gotthardt
- Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg 69120, Germany
| | - Arianeb Mehrabi
- Department of General, Visceral and Transplantation Surgery, University Hospital of Heidelberg, Heidelberg 69120, Germany
| | - Karl-Heinz Weiss
- Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg 69120, Germany
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10
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Tronina O, Ślubowska K, Mikołajczyk-Korniak N, Komuda-Leszek E, Wieczorek-Godlewska R, Łągiewska B, Pacholczyk M, Lisik W, Kosieradzki M, Durlik M. Fibrosing Cholestatic Hepatitis C After Liver Transplantation: Therapeutic Options Before and After Introduction of Direct-Acting Antivirals: Our Experience and Literature Review. Transplant Proc 2018; 49:1409-1418. [PMID: 28736015 DOI: 10.1016/j.transproceed.2017.01.077] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Accepted: 01/24/2017] [Indexed: 12/26/2022]
Abstract
BACKGROUND Cirrhosis caused by hepatitis C is the most common indication for liver transplantation. The most aggressive form of hepatitis C virus (HCV) relapse after liver transplantation is fibrosing cholestatic hepatitis C, which can be observed in 2% to 15% of recipients. METHODS Double therapy with peg-interferon and ribavirin was characterized by low antiviral response, rapid fibrosis, and frequent graft failure within 1 year after surgery. RESULTS Introduction of direct-acting antivirals for HCV treatment allows for more efficient therapy with less adverse reactions, including patients with fibrosing cholestatic hepatitis C. CONCLUSIONS We present 4 (2.5%) cases of cholestatic viral hepatitis C recurrence in patients undergoing transplantation between 2006 and 2015 at the Transplantation Institute of Warsaw; during this period, 158 liver transplants were performed in patients with cirrhosis caused by HCV infection.
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Affiliation(s)
- O Tronina
- Department of Transplantation Medicine, Nephrology, and Internal Diseases, Medical University of Warsaw, Warsaw, Poland.
| | - K Ślubowska
- Department of Transplantation Medicine, Nephrology, and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - N Mikołajczyk-Korniak
- Department of Transplantation Medicine, Nephrology, and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - E Komuda-Leszek
- Department of Transplantation Medicine, Nephrology, and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - R Wieczorek-Godlewska
- Department of Transplantation Medicine, Nephrology, and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - B Łągiewska
- Department of General and Transplantation Surgery, Medical University of Warsaw, Warsaw, Poland
| | - M Pacholczyk
- Department of General and Transplantation Surgery, Medical University of Warsaw, Warsaw, Poland
| | - W Lisik
- Department of General and Transplantation Surgery, Medical University of Warsaw, Warsaw, Poland
| | - M Kosieradzki
- Department of General and Transplantation Surgery, Medical University of Warsaw, Warsaw, Poland
| | - M Durlik
- Department of Transplantation Medicine, Nephrology, and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
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11
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Lionetti R, Calvaruso V, Piccolo P, Mancusi RL, Mazzarelli C, Fagiuoli S, Montalbano M, Lenci I, Carrai P, Guaraldi G, Visco-Comandini U, Milana M, Biolato M, Loiacono L, Valente G, Craxì A, Angelico M, D'offizi G. Sofosbuvir plus daclatasvir with or without ribavirin is safe and effective for post-transplant hepatitis C recurrence and severe fibrosis and cirrhosis: A prospective study. Clin Transplant 2018; 32. [PMID: 29193356 DOI: 10.1111/ctr.13165] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/12/2017] [Indexed: 12/20/2022]
Abstract
BACKGROUND In 2012, an Italian Named Patient Program began for hepatitis C virus (HCV)-infected liver transplant (LT) recipients with advanced fibrosis, before approval of direct antiviral agents (DAA), to benefit severely ill patients. The aim of this "real-life" study was to assess treatment efficacy and safety with an extended course of daclatasvir (DCV) plus sofosbuvir (SOF) with or without ribavirin (RBV). METHODS All HCV LT recipients with severe fibrosis in 15 Italian transplant centers were treated with DCV+SOF±RBV for 24 weeks; sustained virological response was assessed at 12 weeks post-treatment (SVR12). RESULTS Eighty-seven patients were enrolled (75.9% males, mean age 58.4 ± 7.2 years, 83.9% genotype 1, 81.6% cirrhosis); 52 (59.8%) received RBV. Overall, 79 obtained SVR12 (90.8%): 100% in F3 and 88.7% in cirrhotics (91.5% in Child-Pugh A, 83.3% in Child-Pugh B and C). According to the treatment group, SVR was 80% in DCV + SOF group and 98.1% in SOF + DCV + RBV. Two virological relapses occurred during follow-up in cirrhotic patients who received DCV + SOF. Four cirrhotic patients in DCV + SOF group and 1 in DCV + SOF + RBV group died on treatment. CONCLUSION An extended course of SOF plus DCV for 24 weeks, with or without RBV, is effective and well tolerated for the treatment of post-LT HCV recurrence with severe fibrosis.
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Affiliation(s)
- Raffaella Lionetti
- Infectious and Liver Diseases, Lazzaro Spallanzani National Infectious Disease Institute, Rome, Italy
| | | | - Paola Piccolo
- Department of Internal Medicine, San Giovanni Calibita Fatebenefratelli Hospital, Rome, Italy
- Hepatology Unit, Tor Vergata University, Rome, Italy
| | | | - Chiara Mazzarelli
- Gastroenterology and Liver Unit, Niguarda Ca' Granda Hospital, Milan, Italy
| | - Stefano Fagiuoli
- Gastroenterology and Liver Unit, San Giovanni XXIII Hospital, Bergamo, Italy
| | - Marzia Montalbano
- Infectious and Liver Diseases, Lazzaro Spallanzani National Infectious Disease Institute, Rome, Italy
| | - Ilaria Lenci
- Hepatology Unit, Tor Vergata University, Rome, Italy
| | - Paola Carrai
- Liver Transplantation Unit, Pisa Hospital, Pisa, Italy
| | | | - Ubaldo Visco-Comandini
- Infectious and Liver Diseases, Lazzaro Spallanzani National Infectious Disease Institute, Rome, Italy
| | | | - Marco Biolato
- Liver Transplant Medicine, Fondazione Policlinico Gemelli Catholic University, Rome, Italy
| | - Laura Loiacono
- Infectious and Liver Diseases, Lazzaro Spallanzani National Infectious Disease Institute, Rome, Italy
| | | | - Antonio Craxì
- Gastroenterology Unit, University of Palermo, Palermo, Italy
| | | | - Gianpiero D'offizi
- Infectious and Liver Diseases, Lazzaro Spallanzani National Infectious Disease Institute, Rome, Italy
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12
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Disease Reversibility in Patients With Post-Hepatitis C Cirrhosis: Is the Point of No Return the Same Before and After Liver Transplantation? A Review. Transplantation 2017; 101:916-923. [PMID: 28060241 DOI: 10.1097/tp.0000000000001633] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Liver fibrosis can regress in patients with chronic hepatitis in whom the underlying cause of liver damage is adequately treated. Studies documenting this benefit have been mostly performed in the setting of viral hepatitis, particularly hepatitis C virus, where sustained viral response has been unequivocally shown to result in histological and clinical improvement. With the advent of the new IFN-free regimens, highly effective and safe even in those historically considered "difficult to treat and cure patients," additional benefits have been documented in patients treated at advanced stages of disease, including improvement in liver function with hepatic "recompensation," reduction of portal hypertension, and eventually avoidance of liver transplantation. Disease reversibility has been also demonstrated in the posttransplant setting and appears to be similar to what is observed in the nontransplant patient.
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13
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Maria C, Michael S, Susanne C, Catarina S, Ola W. INF-free sofosbuvir-based treatment of post-transplant hepatitis C relapse - a Swedish real life experience. Scand J Gastroenterol 2017; 52:585-588. [PMID: 28270038 DOI: 10.1080/00365521.2017.1283439] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Relapse of hepatitis C virus (HCV) infection after liver transplantation has been universal, and the fibrosis progression faster than in non-transplanted patients. Interferon (IFN)-free treatment with direct antiviral agents (DAA) has improved the treatment outcome dramatically. We here report on the outcome of IFN-free treatment for HCV relapse after liver transplantation in a real life setting in Sweden. MATERIAL In total, 93 patients with a mean age of 60 years (range 32-80) with HCV relapse after liver transplantation were given sofosbuvir-based treatment in combination with a protease inhibitor (simeprevir) or a NS5A inhibitor (daclatasvir or ledipasvir) with or without addition of ribavirin (RBV), or sofosbuvir and RBV only. Treatment was generally given during 24 weeks for advanced fibrosis or cirrhosis cases and 12 weeks for mild fibrosis with fibrosis stage 2 or less. The distribution of genotype 1, 2, 3, 4 in our patients was 58, 7.5, 26.5 and 7.5%, respectively. RESULTS All recipients reached end-of-treatment response (ETR) with HCV RNA <15 IU/mL. Sustained viral response 12 weeks after treatment cessation (SVR12) was achieved in 91/93 (97.8%) recipients. The SVR12 rates for genotype 1, 2, 3 and 4 were the SVR12 rate were 96, 100, 100 and 100%, respectively (p = .04). CONCLUSION It is concluded that IFN-free treatment with DAAs for HCV relapse after liver transplantation is highly effective also in a real life setting and offers cure for most recipients.
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Affiliation(s)
- Castedal Maria
- The Transplant Institute, Sahlgrenska University Hospital, Institution of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Segenmark Michael
- Department of Medicine, Division of Infectious Diseases, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Cederberg Susanne
- Department of Medicine, Division of Infectious Diseases, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Skoglund Catarina
- The Transplant Institute, Sahlgrenska University Hospital, Institution of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Weiland Ola
- Department of Medicine, Division of Infectious Diseases, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden
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14
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Neuberger JM, Bechstein WO, Kuypers DRJ, Burra P, Citterio F, De Geest S, Duvoux C, Jardine AG, Kamar N, Krämer BK, Metselaar HJ, Nevens F, Pirenne J, Rodríguez-Perálvarez ML, Samuel D, Schneeberger S, Serón D, Trunečka P, Tisone G, van Gelder T. Practical Recommendations for Long-term Management of Modifiable Risks in Kidney and Liver Transplant Recipients: A Guidance Report and Clinical Checklist by the Consensus on Managing Modifiable Risk in Transplantation (COMMIT) Group. Transplantation 2017; 101:S1-S56. [PMID: 28328734 DOI: 10.1097/tp.0000000000001651] [Citation(s) in RCA: 216] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Short-term patient and graft outcomes continue to improve after kidney and liver transplantation, with 1-year survival rates over 80%; however, improving longer-term outcomes remains a challenge. Improving the function of grafts and health of recipients would not only enhance quality and length of life, but would also reduce the need for retransplantation, and thus increase the number of organs available for transplant. The clinical transplant community needs to identify and manage those patient modifiable factors, to decrease the risk of graft failure, and improve longer-term outcomes.COMMIT was formed in 2015 and is composed of 20 leading kidney and liver transplant specialists from 9 countries across Europe. The group's remit is to provide expert guidance for the long-term management of kidney and liver transplant patients, with the aim of improving outcomes by minimizing modifiable risks associated with poor graft and patient survival posttransplant.The objective of this supplement is to provide specific, practical recommendations, through the discussion of current evidence and best practice, for the management of modifiable risks in those kidney and liver transplant patients who have survived the first postoperative year. In addition, the provision of a checklist increases the clinical utility and accessibility of these recommendations, by offering a systematic and efficient way to implement screening and monitoring of modifiable risks in the clinical setting.
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Affiliation(s)
- James M Neuberger
- 1 Liver Unit, Queen Elizabeth Hospital Birmingham, United Kingdom. 2 Department of General and Visceral Surgery, Frankfurt University Hospital and Clinics, Germany. 3 Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Campus Gasthuisberg, Belgium. 4 Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, Padova, Italy. 5 Renal Transplantation Unit, Department of Surgical Science, Università Cattolica Sacro Cuore, Rome, Italy. 6 Department of Public Health, Faculty of Medicine, Institute of Nursing Science, University of Basel, Switzerland. 7 Department of Public Health, Faculty of Medicine, Centre for Health Services and Nursing Research, KU Leuven, Belgium. 8 Department of Hepatology and Liver Transplant Unit, Henri Mondor Hospital (AP-HP), Paris-Est University (UPEC), France. 9 Department of Nephrology, University of Glasgow, United Kingdom. 10 Department of Nephrology and Organ Transplantation, CHU Rangueil, Université Paul Sabatier, Toulouse, France. 11 Vth Department of Medicine & Renal Transplant Program, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany. 12 Department of Gastroenterology and Hepatology, Erasmus MC, University Hospital Rotterdam, the Netherlands. 13 Department of Gastroenterology and Hepatology, University Hospitals KU Leuven, Belgium. 14 Abdominal Transplant Surgery, Microbiology and Immunology Department, University Hospitals KU Leuven, Belgium. 15 Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Spain. 16 Hepatobiliary Centre, Hospital Paul-Brousse (AP-HP), Paris-Sud University, Université Paris-Saclay, Villejuif, France. 17 Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Austria. 18 Nephrology Department, Hospital Vall d'Hebrón, Autonomous University of Barcelona, Spain. 19 Transplant Center, Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic. 20 Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Italy. 21 Department of Hospital Pharmacy and Internal Medicine, Erasmus MC, the Netherlands
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15
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Abstract
Cirrhosis due to chronic hepatitis C (HCV) is the leading indication for liver transplantation in North America and Europe. HCV re-infection post-transplant is nearly universal and if left untreated negatively affects patient and graft survival. Until recently, treatment options for HCV were limited to interferon (IFN)-based therapies which had low sustained viral response (SVR) rates and were poorly tolerated in the post-transplant setting. In the last 3 years, the promise of the directly acting antivirals (DAAs) for the treatment of HCV has been fulfilled with high sustained viral response (SVR) rates and a low side effect profile demonstrated in both registration trials and real-world studies. This innovation has allowed post-liver transplant patients with HCV recurrence access to interferon-free therapies with extraordinary efficacy, safety, tolerability, and fewer drug-drug interactions.
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16
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Smolders EJ, Pape S, de Kanter CTMM, van den Berg AP, Drenth JPH, Burger DM. Decreased tacrolimus plasma concentrations during HCV therapy: a drug-drug interaction or is there an alternative explanation? Int J Antimicrob Agents 2017; 49:379-382. [PMID: 28185946 DOI: 10.1016/j.ijantimicag.2016.12.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Revised: 11/23/2016] [Accepted: 12/03/2016] [Indexed: 12/13/2022]
Abstract
Chronic hepatitis C virus (HCV) infection can cause severe liver cirrhosis, for which liver transplantation is the only therapy. To prevent organ rejection, transplanted patients are treated with immunosuppressive agents. We describe two transplanted patients treated with tacrolimus who were simultaneously treated with direct-acting antivirals (DAAs) for their chronic HCV infection. No pharmacokinetic drug-drug interactions (DDIs) were expected between tacrolimus and the selected DAAs. However, in both patients, tacrolimus plasma concentrations decreased during HCV treatment. We hypothesise that decreased plasma concentrations were not caused by a DDI but were an indirect result of the clearance of the HCV infection. During chronic HCV infection, pro-inflammatory cytokines may inhibit cytochrome P450 (CYP) enzymes, which are primarily responsible for tacrolimus metabolism. If this is true, then with clearance of the virus the activity of these enzymes will normalise and tacrolimus metabolism will increase. These changes were clinically relevant because the tacrolimus dosage needed to be adjusted. Therefore, physicians should be aware that CYP substrates with narrow therapeutic ranges might require dose adaption during HCV therapy with DAAs.
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Affiliation(s)
- E J Smolders
- Department of Pharmacy, radboud university medical center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands.
| | - S Pape
- Department of Gastroenterology and Hepatology, radboud university medical center, Nijmegen, The Netherlands
| | - C T M M de Kanter
- Department of Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands
| | - A P van den Berg
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
| | - J P H Drenth
- Department of Gastroenterology and Hepatology, radboud university medical center, Nijmegen, The Netherlands
| | - D M Burger
- Department of Pharmacy, radboud university medical center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands
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17
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Talavera Pons S, Boyer A, Lamblin G, Chennell P, Châtenet F, Nicolas C, Sautou V, Abergel A. Managing drug-drug interactions with new direct-acting antiviral agents in chronic hepatitis C. Br J Clin Pharmacol 2017; 83:269-293. [PMID: 27530469 PMCID: PMC5237698 DOI: 10.1111/bcp.13095] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Revised: 07/21/2016] [Accepted: 07/26/2016] [Indexed: 12/16/2022] Open
Abstract
Several direct-acting antiviral agents (DAAs) have marketing authorization in Europe and in the USA and have changed the landscape of hepatitis C treatment: each DAA has its own metabolism and drug-drug interactions (DDIs), and managing them is a challenge. To compile the pharmacokinetics and DDI data of the new DAA and to provide a guide for management of DDI. An indexed MEDLINE search was conducted using the keywords: DAA, hepatitis C, simeprevir, daclatasvir, ledipasvir, sofosbuvir, 3D regimen (paritaprevir/ritonavir, ombitasvir, dasabuvir), DDI and pharmacokinetics. Data were also collected from hepatology, and infectious disease and clinical pharmacology conferences abstracts. Food can play a role in the absorption of DAAs. Most of the interactions are linked to metabolism (cytochrome P450-3 A4 [CYP3A4]) or hepatic and/or intestinal transporters (organic anion-transporting polypeptide and P-glycoprotein [P-gp]). To a lesser extent other pathways can be involved such as breast cancer resistance protein transporter or UDP-glucuronosyltransferase metabolism. DDI are more likely to occur with 3D regimen, daclatasvir, simeprevir and ledipasvir, as they are all both substrates and inhibitors of P-gp and/or CYP3A4, than with sofosbuvir. They can increase concentrations of coadministered drugs and their concentrations may be influenced by P-gp or CYP3A4 inducers or inhibitors. Overdosage or low dosage can be encountered with potent inducers or inhibitors of CYP3A4 or drugs with a narrow therapeutic range. The key to interpret DDI data is a good understanding of the pharmacokinetic profiles of the drugs involved. Their ability to inhibit CYP450-3A4 and transporters (hepatic and/or intestinal) can have significant clinical consequences.
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Affiliation(s)
| | - Anne Boyer
- Service de Pharmacie Centre Hospitalier UniversitaireClermont‐FerrandFrance
| | - Geraldine Lamblin
- Service de Médecine Digestive et Hépato‐biliaire Centre Hospitalier Universitaire EstaingClermont‐FerrandFrance
| | - Philip Chennell
- Service de Pharmacie Centre Hospitalier UniversitaireClermont‐FerrandFrance
- EA 4676 C‐BiosenssUniversité d'AuvergneClermont‐FerrandCedexFrance
| | | | - Carine Nicolas
- Service de Médecine Digestive et Hépato‐biliaire Centre Hospitalier Universitaire EstaingClermont‐FerrandFrance
| | - Valérie Sautou
- Service de Pharmacie Centre Hospitalier UniversitaireClermont‐FerrandFrance
- EA 4676 C‐BiosenssUniversité d'AuvergneClermont‐FerrandCedexFrance
| | - Armand Abergel
- Service de Médecine Digestive et Hépato‐biliaire Centre Hospitalier Universitaire EstaingClermont‐FerrandFrance
- Unité Mixte de Recherche Université d'Auvergne, CNRS 6284University of Clermont‐FerrandFrance
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18
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Bowring MG, Kucirka LM, Massie AB, Luo X, Cameron A, Sulkowski M, Rakestraw K, Gurakar A, Kuo I, Segev DL, Durand CM. Changes in Utilization and Discard of Hepatitis C-Infected Donor Livers in the Recent Era. Am J Transplant 2017; 17:519-527. [PMID: 27456927 PMCID: PMC5266634 DOI: 10.1111/ajt.13976] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Accepted: 07/12/2016] [Indexed: 01/25/2023]
Abstract
The impact of interferon (IFN)-free direct-acting antiviral (DAA) hepatitis C virus (HCV) treatments on utilization and outcomes associated with HCV-positive deceased donor liver transplantation (DDLT) is largely unknown. Using the Scientific Registry of Transplant Recipients, we identified 25 566 HCV-positive DDLT recipients from 2005 to 2015 and compared practices according to the introduction of DAA therapies using modified Poisson regression. The proportion of HCV-positive recipients who received HCV-positive livers increased from 6.9% in 2010 to 16.9% in 2015. HCV-positive recipients were 61% more likely to receive an HCV-positive liver after 2010 (early DAA/IFN era) (aRR:1.45 1.611.79 , p < 0.001) and almost three times more likely to receive one after 2013 (IFN-free DAA era) (aRR:2.58 2.853.16 , p < 0.001). Compared to HCV-negative livers, HCV-positive livers were 3 times more likely to be discarded from 2005 to 2010 (aRR:2.69 2.993.34 , p < 0.001), 2.2 times more likely after 2010 (aRR:1.80 2.162.58 , p < 0.001) and 1.7 times more likely after 2013 (aRR:1.37 1.682.04 , p < 0.001). Donor HCV status was not associated with increased risk of all-cause graft loss (p = 0.1), and this did not change over time (p = 0.8). Use of HCV-positive livers has increased dramatically, coinciding with the advent of DAAs. However, the discard rate remains nearly double that of HCV-negative livers. Further optimization of HCV-positive liver utilization is necessary to improve access for all candidates.
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Affiliation(s)
- Mary G Bowring
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Lauren M Kucirka
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD,Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore MD
| | - Allan B Massie
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD,Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore MD
| | - Xun Luo
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Andrew Cameron
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Mark Sulkowski
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Katie Rakestraw
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Ahmet Gurakar
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Irene Kuo
- Department of Epidemiology and Biostatistics, George Washington University School of Public Health, Washington, DC
| | - Dorry L Segev
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD,Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore MD,Scientific Registry of Transplant Recipients, Minneapolis, MN
| | - Christine M Durand
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD,Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
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19
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Pol S, Bourliere M, Lucier S, Hezode C, Dorival C, Larrey D, Bronowicki JP, Ledinghen VDE, Zoulim F, Tran A, Metivier S, Zarski JP, Samuel D, Guyader D, Marcellin P, Minello A, Alric L, Thabut D, Chazouilleres O, Riachi G, Bourcier V, Mathurin P, Loustaud-Ratti V, D'Alteroche L, Fouchard-Hubert I, Habersetzer F, Causse X, Geist C, Rosa I, Gournay J, Saillard E, Billaud E, Petrov-Sanchez V, Diallo A, Fontaine H, Carrat F. Safety and efficacy of daclatasvir-sofosbuvir in HCV genotype 1-mono-infected patients. J Hepatol 2017; 66:39-47. [PMID: 27622858 DOI: 10.1016/j.jhep.2016.08.021] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Revised: 08/24/2016] [Accepted: 08/26/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS We report the first real-life results of the sofosbuvir+daclatasvir combination in hepatitis C virus (HCV) genotype 1 infected patients. METHODS The France REcherche Nord&Sud Sida-hiv Hépatites (ANRS) CO22 HEPATHER "Therapeutic options for hepatitis B and C: A French cohort" is a multicentre observational cohort which aims to include 15,000 HCV- and 10,000 HBV-infected patients. We selected all participants (n=768) with a HCV genotype 1 who initiated sofosbuvir (400mg/day) and daclatasvir (60mg/day) before October 1st 2014, with or without ribavirin (1-1.2g/day) for a duration of 12weeks or 24weeks. The main endpoint criterion was sustained virological response at 12weeks (SVR12), defined by the absence of detectable HCV-RNA 12weeks after the last treatment intake. Missing SVR12 measurements were imputed using SVR24 measurements (n=45), otherwise considered as virological failure (n=18). RESULTS A SVR12 was obtained in 729/768 (95%) patients, ranging from 92% (12-week sofosbuvir+daclatasvir) to 99% (24-week sofosbuvir+daclatasvir+ribavirin). The SVR12 rates did not significantly differ between the 24-week (550/574 (96%)) and the 12-week (179/194 (92%); p=0.0688) durations or between regimens with (165/169 (98%)) or without ribavirin (564/599 (94%); p=0.0850). The SVR12 rate was greater than 97% in non-cirrhotic patients irrespective of the treatment duration or the addition of ribavirin. Among cirrhotic patients, the SVR12 rate was higher with 24 than 12-week regimen (423/444 (95%) vs. 105/119 (88%); p=0.0054). CONCLUSION The sofosbuvir+daclatasvir combination is associated with a high rate of SVR12 in patients infected by genotype 1, with an optimal duration of 12weeks in non-cirrhotic and 24weeks in cirrhotic patients. The number of patients receiving ribavirin was too low to adequately assess its impact. LAY SUMMARY The sofosbuvir+daclatasvir combination of antiviral drugs is associated with a high rate (95%) of viral eradication in patients infected by HCV genotype 1. The best duration of a ribavirin-free sofosbuvir+daclatasvir combination seems to be 12weeks in non-cirrhotic patients and 24weeks for those with cirrhosis. Clinical trial number: NCT01953458.
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Affiliation(s)
- Stanislas Pol
- Université Paris Descartes, AP-HP, Unité d'Hépatologie, Hôpital Cochin, INSERM U-1213 et USM20, Institut Pasteur, Paris, France.
| | - Marc Bourliere
- Department of Hepatology and Gastroenterology, Hôpital Saint Joseph, Marseille, France
| | - Sandy Lucier
- Sorbonne Universités, UPMC Univ Paris 06, INSERM, Institut Pierre Louis d'épidémiologie et de Santé Publique (IPLESP UMRS 1136), F75012 Paris, France
| | - Christophe Hezode
- Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, AP-HP, Université Paris-Est, INSERM U955, Créteil, France
| | - Céline Dorival
- Sorbonne Universités, UPMC Univ Paris 06, INSERM, Institut Pierre Louis d'épidémiologie et de Santé Publique (IPLESP UMRS 1136), F75012 Paris, France
| | - Dominique Larrey
- Liver unit-IRB-INSERM1040, Hôpital Saint Eloi, Montpellier, France
| | - Jean-Pierre Bronowicki
- Department of Hepatology and Gastroenterology, Centre Hospitalier Universitaire de Nancy, Université de Lorraine, INSERM U954, Vandoeuvre-lès-nancy, France
| | - Victor D E Ledinghen
- Department of Hepatology and Gastroenterology, Hôpital Haut-Lévêque, Pessac, France; INSERM, U1053, Université Bordeaux Segalen, Bordeaux, France
| | - Fabien Zoulim
- Department of Hepatology, Hospices Civils de Lyon, INSERM U1052, Université de Lyon, Lyon, France
| | - Albert Tran
- Digestive Centre, Centre Hospitalier Universitaire de Nice, INSERM U1065-8, Nice, France
| | - Sophie Metivier
- Department of Hepatology and Gastroenterology, CHU Purpan, Toulouse, France
| | - Jean-Pierre Zarski
- Department of Hepatology and Gastroenterology, Centre Hospitalo-Universitaire, INSERM U823, Grenoble, France
| | - Didier Samuel
- Centre Hépato-Biliaire, Hôpital Paul Brousse, AP-HP, UMR-S785, Université Paris-Sud, INSERM U785, Villejuif, France
| | - Dominique Guyader
- Liver Disease Unit, CHU Rennes, Université de Rennes 1, INSERM U991, Rennes, France
| | - Patrick Marcellin
- Department of Hepatology, Hôpital Beaujon, AP-HP, Université Paris-Diderot, INSERM CRB3, Clichy, France
| | - Anne Minello
- Department of Hepatology and Gastroenterology, Dijon University Hospital, Burgundy University, INSERM U866, France
| | - Laurent Alric
- Internal Medicine-Digestive Department CHU Purpan, UMR152, IRD, Toulouse 3 University, France
| | - Dominique Thabut
- Department of Hepatology and Gastroenterology, Groupe Hospitalier Pitié-Salpétrière, AP-HP, Université Pierre et Marie Curie Paris 6, INSERM UMR-S938, Paris, France
| | - Olivier Chazouilleres
- Department of Hepatology, Hôpital Saint-Antoine, AP-HP, Université Pierre et Marie Curie Paris 6, Paris, France
| | - Ghassan Riachi
- Department of Hepatology and Gastroenterology, CHU Charles Nicolle, Rouen, France
| | - Valérie Bourcier
- Department of Hepatology and Gastroenterology, Hôpital Jean Verdier, AP-HP, Université Paris 13, Bondy, France
| | - Philippe Mathurin
- Department of Hepatology and Gastroenterology, Centre Hospitalier Régional et Universitaire Claude Huriez, Lille, France
| | - Véronique Loustaud-Ratti
- Department of Hepatology and Gastroenterology, CHU Limoges, U850 INSERM, Univ. Limoges, F-87000 Limoges, France
| | - Louis D'Alteroche
- Unit of Hepatology, Hépatogastroenterologie, CHU Trousseau, 37044 Tours, France
| | | | - François Habersetzer
- Inserm CIC-1434, Inserm 1110 et Pôle Hépato-digestif des Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Xavier Causse
- Department of Hepatology and Gastroenterology, CHR La Source, Orléans, France
| | - Claire Geist
- Department of Hepatology and Gastroenterology, Centre Hospitalier Régional, Metz, France
| | - Isabelle Rosa
- Department of Hepatology and Gastroenterology, Centre Hospitalier Intercommunal, Créteil, France
| | - Jérôme Gournay
- Department of Hepatology and Gastroenterology, Hôpital Hôtel-Dieu, Nantes, France
| | - Eric Saillard
- Department of Gastroenterology, CHU de Pointe-à-Pitre, Guadeloupe, France
| | - Eric Billaud
- Division of Infectious Diseases, University Hospital of Nantes, Nantes, France
| | - Ventzislava Petrov-Sanchez
- ANRS (France REcherche Nord&sud Sida-vih Hépatites), Unit for Basic and Clinical Research on Viral Hepatitis, Paris, France
| | - Alpha Diallo
- ANRS (France REcherche Nord&sud Sida-vih Hépatites), Clinical Trial Safety and Public Health, Paris, France
| | - Hélène Fontaine
- Université Paris Descartes, AP-HP, Unité d'Hépatologie, Hôpital Cochin, INSERM U-1213 et USM20, Institut Pasteur, Paris, France
| | - Fabrice Carrat
- Sorbonne Universités, UPMC Univ Paris 06, INSERM, Institut Pierre Louis d'épidémiologie et de Santé Publique (IPLESP UMRS 1136), F75012 Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Unité de Santé Publique, F-75012 Paris, France
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20
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Ueda Y, Ikegami T, Soyama A, Akamatsu N, Shinoda M, Ishiyama K, Honda M, Marubashi S, Okajima H, Yoshizumi T, Eguchi S, Kokudo N, Kitagawa Y, Ohdan H, Inomata Y, Nagano H, Shirabe K, Uemoto S, Maehara Y. Simeprevir or telaprevir with peginterferon and ribavirin for recurrent hepatitis C after living-donor liver transplantation: A Japanese multicenter experience. Hepatol Res 2016; 46:1285-1293. [PMID: 26899352 DOI: 10.1111/hepr.12684] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2015] [Revised: 02/10/2016] [Accepted: 02/12/2016] [Indexed: 02/08/2023]
Abstract
AIM This study aimed to clarify the efficacy and safety of simeprevir, a second-generation NS3/4A inhibitor, with peginterferon and ribavirin for recurrent hepatitis C after liver transplantation. METHODS A retrospective cohort study of living-donor liver transplant recipients with recurrent hepatitis C with the hepatitis C virus genotype 1 treated with either simeprevir- or telaprevir-based triple therapy was carried out at eight Japanese liver transplant centers. RESULTS Simeprevir- and telaprevir-based triple therapies were given to 79 and 36 patients, respectively. Of the 79 patients treated with simeprevir-based triple therapy, 44 (56%) achieved sustained virological response 12 weeks (SVR12) after treatment ended, and there was no significant difference in the SVR12 between the simeprevir- and telaprevir-based triple therapy groups (69%). The rates of adverse events were not significantly different between the simeprevir- and telaprevir-based triple therapy groups, although the rate of patients who received blood cell transfusion and erythropoietin due to anemia and had renal insufficiency were significantly higher in the telaprevir group than in the simeprevir group. Three baseline factors, the presence of prior dual therapy with peginterferon and ribavirin (P = 0.001), a non-responder to the prior dual therapy (P < 0.001), and male sex (P = 0.040), were identified as significant predictive factors for non-SVR with simeprevir-based triple therapy. CONCLUSION Simeprevir-based triple therapy for recurrent hepatitis C after living-donor liver transplantation resulted in a high SVR rate and good tolerability, especially in treatment-naïve patients.
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Affiliation(s)
- Yoshihide Ueda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University
| | - Toru Ikegami
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Akihiko Soyama
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki
| | - Nobuhisa Akamatsu
- Division of Artificial Organ and Transplantation, Department of Surgery, University of Tokyo
| | - Masahiro Shinoda
- Department of Surgery, Keio University School of Medicine, Tokyo
| | - Kohei Ishiyama
- Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masaki Honda
- Department of Transplantation and Pediatric Surgery, Kumamoto University, Kumamoto
| | - Shigeru Marubashi
- Department of Surgery, Osaka University Graduate School of Medicine, Osaka
| | - Hideaki Okajima
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Susumu Eguchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki
| | - Norihiro Kokudo
- Division of Artificial Organ and Transplantation, Department of Surgery, University of Tokyo
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, Tokyo
| | - Hideki Ohdan
- Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yukihiro Inomata
- Department of Transplantation and Pediatric Surgery, Kumamoto University, Kumamoto
| | - Hiroaki Nagano
- Department of Surgery, Osaka University Graduate School of Medicine, Osaka
| | - Ken Shirabe
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Shinji Uemoto
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoshihiko Maehara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka
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Raschzok N, Schott E, Reutzel-Selke A, Damrah I, Gül-Klein S, Strücker B, Sauer IM, Pratschke J, Eurich D, Stockmann M. The impact of directly acting antivirals on the enzymatic liver function of liver transplant recipients with recurrent hepatitis C. Transpl Infect Dis 2016; 18:896-903. [PMID: 27632190 DOI: 10.1111/tid.12606] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Revised: 05/23/2016] [Accepted: 06/29/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND The new directly acting antivirals (DAAs) enable all-oral interferon-free treatment of chronic hepatitis C virus (HCV) infection. We here investigated the effect of DAAs on the enzymatic liver function of liver transplant recipients with recurrent hepatitis C. METHODS Twenty-one patients with elevated liver enzymes or advanced fibrosis/compensated cirrhosis caused by recurrent HCV were treated with sofosbuvir either in combination with simeprevir, or in combination with ribavirin or daclatasvir with or without ribavirin for 12 weeks. Biochemical parameters, tacrolimus trough levels, and the maximal liver function capacity (LiMAx) were measured monthly during the treatment and 12 weeks after the end of treatment. RESULTS All patients achieved sustained virological response 12 weeks after the end of the treatment. The transaminases and cholestasis parameters normalized until week 8 of treatment. The mean LiMAx (normal ranges >315 μg/kg/h) increased from 344±142 μg/kg/h before treatment to 458±170 μg/kg/h (P<.0001) at the 12-week follow-up. In parallel, the tacrolimus trough level to dose ratio decreased from 4.68 down to 2.72 (P=.0004). CONCLUSION Antiviral treatment with DAAs enabled sustained elimination of recurrent HCV in liver transplant recipients and was associated with a significant improvement of the enzymatic liver function.
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Affiliation(s)
- Nathanael Raschzok
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Eckart Schott
- Medical Department, Division of Hepatology and Gastroenterology, Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Anja Reutzel-Selke
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Iman Damrah
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Safak Gül-Klein
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Benjamin Strücker
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Igor Maximilian Sauer
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Johann Pratschke
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Dennis Eurich
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Martin Stockmann
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Evangelisches Krankenhaus Paul Gerhardt Stift, Lutherstadt Wittenberg, Germany
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22
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Saleem A, Akhtar MF, Mushtaq MF, Saleem M, Muhammad ST, Akhtar B, Sharif A, Peerzada S. Current trends in the treatment of hepatitis C: interventions to avoid adverse effects and increase effectiveness of anti-HCV drugs. EXCLI JOURNAL 2016; 15:578-588. [PMID: 28096788 PMCID: PMC5225681 DOI: 10.17179/excli2016-582] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/14/2016] [Accepted: 09/26/2016] [Indexed: 12/14/2022]
Abstract
Viral hepatitis, an inflammatory liver disease, is caused by various genotypes of hepatitis C viruses (HCV). Hepatitis C slowly sprouts into fibrosis, which progresses to cirrhosis. Over a prolonged period of time compensated cirrhosis can advance to decompensated cirrhosis culminating in hepatic failure and death. Conventional treatment of HCV involves the administration of interferons. However, association of interferon with the adverse drug reactions led to the development of novel anti-HCV drugs given as monotherapy or in combination with the other drugs. Advances in drug delivery systems (DDS) improved the pharmacokinetic profile and stability of drugs, ameliorated tissue damages on extravasation and increased the targeting of affected sites. Liposomes and lipid based vehicles have been employed with polyethylene glycol (PEG) so as to stabilize the formulations as PEG drug complex. Sofosbuvir, a novel anti-HCV drug, is administered as monotherapy or in combination with daclatasvir, ledipasivir, protease inhibitors, ribavirin and interferon for the treatment of HCV genotypes 1, 2 and 3. These drug combinations are highly effective in eradicating the interferon resistance, recurrent HCV infection in liver transplant, concurrent HIV infection and preventing interferon related adverse effects. Further investigations to improve drug targeting and identification of new drug targets are highly warranted due to the rapid emergence of drug resistance in HCV.
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Affiliation(s)
- Ammara Saleem
- Faculty of Pharmaceutical Sciences, GC University, Faisalabad, Pakistan
| | | | | | - Muhammad Saleem
- Faculty of Pharmaceutical Sciences, GC University, Faisalabad, Pakistan
| | | | - Bushra Akhtar
- Institute of Pharmacy, Physiology and Pharmacology, University of Agriculture, Faisalabad, Pakistan
| | - Ali Sharif
- Faculty of Pharmacy, The University of Lahore, Lahore, Pakistan
| | - Sohaib Peerzada
- Faculty of Pharmacy, The University of Lahore, Lahore, Pakistan
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23
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Coilly A, Fougerou-Leurent C, de Ledinghen V, Houssel-Debry P, Duvoux C, Di Martino V, Radenne S, Kamar N, D'Alteroche L, Leroy V, Canva V, Lebray P, Moreno C, Dumortier J, Silvain C, Besch C, Perre P, Botta-Fridlund D, Anty R, Francoz C, Abergel A, Debette-Gratien M, Conti F, Habersetzer F, Rohel A, Rossignol E, Danjou H, Roque-Afonso AM, Samuel D, Duclos-Vallée JC, Pageaux GP. Multicentre experience using daclatasvir and sofosbuvir to treat hepatitis C recurrence - The ANRS CUPILT study. J Hepatol 2016; 65:711-718. [PMID: 27262758 DOI: 10.1016/j.jhep.2016.05.039] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Revised: 05/19/2016] [Accepted: 05/23/2016] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS HCV recurrence remains a major issue in the liver transplant field, as it has a negative impact on both graft and patient survival. The purpose of this study was to investigate the efficacy and safety of treating HCV recurrence with sofosbuvir (SOF) and daclatasvir (DCV) combination therapy. METHODS From October 2013 to March 2015, 559 liver recipients were enrolled in the prospective multicentre France REcherche Nord&Sud Sida-hiv Hépatites (ANRS) Compassionate use of Protease Inhibitors in viral C Liver Transplantation cohort. We selected 137 patients with an HCV recurrence receiving SOF and DCV, whatever the genotype or fibrosis stage. The use of ribavirin and the duration of therapy were at the investigator's discretion. The primary efficacy end point was a sustained virological response (SVR) 12weeks after the end of treatment. RESULTS The SVR rate 12weeks after completing treatment was 96% under the intention-to treat analysis and 99% when excluding non-virological failures. Only two patients experienced a virological failure. The serious adverse event (SAE) rate reached 17.5%. Four patients (3%) stopped their treatment prematurely because of SAEs. Anaemia was the most common AE, with significantly more cases in the ribavirin group (56% vs. 18%; p<0.0001). A slight but significant reduction in creatinine clearance was reported. No clinically relevant drug-drug interactions were noted, but 52% of patients required a change to the dosage of immunosuppressive drugs. CONCLUSIONS Treatment with SOF plus DCV was associated with a high SVR12 and low rates of serious adverse events among liver recipients with HCV recurrence. LAY SUMMARY The recurrence of hepatitis C used to be the first cause of graft failure in infected liver transplanted recipients. Our study demonstrates the great efficacy of one combination of new all-oral direct-acting antiviral, sofosbuvir and daclatasvir, to treat the recurrence of hepatitis C on the graft. Ninety-six per cent of recipients were cured. The safety profile of this combination seemed to be good, especially no relevant drug-drug interaction with immunosuppressive drugs.
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Affiliation(s)
- Audrey Coilly
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif F-94800, France; Université Paris Sud, Université Paris Sud-Saclay, UMR-S 1193, Villejuif F-94800, France; INSERM, Unité 1193, Villejuif F-94800, France; DHU Hepatinov, Villejuif F-94800, France.
| | - Claire Fougerou-Leurent
- Hôpital Universitaire de Pontchaillou, Service de Pharmacologie, Rennes, France; INSERM, CIC 1414 Clinical Investigation Centre, Rennes, France
| | - Victor de Ledinghen
- Service d'Hépato-Gastroentérologie, Hôpital Haut-Lévêque, CHU Bordeaux, & INSERM U1053, Bordeaux, France
| | - Pauline Houssel-Debry
- Hôpital Universitaire de Pontchaillou, Service d'Hépatologie et Transplantation Hépatique, Rennes, France
| | - Christophe Duvoux
- Service d'Hépatologie, Hôpital Henri-Mondor, AP-HP, 94000 Créteil, France
| | - Vincent Di Martino
- Service d'Hépatologie, CHRU Jean Minjoz et Université de Franche-Comté, Besançon, France
| | - Sylvie Radenne
- Service d'Hépatologie, HCL, Hôpital de la Croix-Rousse, 69205 Lyon, France
| | - Nassim Kamar
- Département de Néphrologie et Transplantation d'Organes, CHU Rangueil, INSERM U1043, IFR-BMT, Université Paul Sabatier, Toulouse, France
| | | | - Vincent Leroy
- Clinique Universitaire d'Hépato-Gastroentérologie, Pôle Digidune, CHU de Grenoble, France
| | - Valérie Canva
- CHRU de Lille, Service d'Hépatologie, Hôpital Huriez, CHRU Lille, 59037 Lille, France
| | - Pascal Lebray
- Service d'Hépatologie et de Transplantation Hépatique, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
| | - Christophe Moreno
- Département de Gastroenterologie, d'Hépatopancréatologie et Cancérologie Digestive, CUB Hôpital Erasme, Université Libre de Bruxelles, Bruxelles, Belgium
| | - Jérôme Dumortier
- Unité de Transplantation Hépatique, Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices Civils de Lyon et Université Claude Bernard Lyon 1, Lyon, France
| | | | - Camille Besch
- Centre de Chirurgie Digestive et Transplantation Hépatique, Université de Strasbourg, France
| | - Philippe Perre
- Service de MPU Infectiologie CHD Vendée, 85925 La Roche sur Yon, France
| | | | - Rodolphe Anty
- Hôpital universitaire de Nice, Service d'Hépato-gastroentérologie, INSERM, U1065, Equipe 8, Université de Nice-Sophia-Antipolis, Faculté de Médecine, Nice F-06107, Cedex 2, France
| | - Claire Francoz
- Service d'Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France
| | - Armando Abergel
- Service d'Hépato-gastroentérologie, CHU Estaing Clermont-Ferrand, Clermont-Ferrand, France
| | | | - Filomena Conti
- Service d'Hépatologie et de Transplantation Hépatique, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
| | - François Habersetzer
- Hôpitaux Universitaires de Strasbourg, Inserm U 1110, LabEx HepSYS, Université de Strasbourg, Strasbourg, France
| | - Alexandra Rohel
- Unité de recherché Clinique et Fondamentale sur les Hépatites Virales, Agence Nationale de Recherche sur le Sida et les Hépatites Virales, Paris, France
| | - Emilie Rossignol
- Hôpital Universitaire de Pontchaillou, Service de Pharmacologie, Rennes, France; INSERM, CIC 1414 Clinical Investigation Centre, Rennes, France
| | - Hélène Danjou
- Hôpital Universitaire de Pontchaillou, Service de Pharmacologie, Rennes, France; INSERM, CIC 1414 Clinical Investigation Centre, Rennes, France
| | - Anne-Marie Roque-Afonso
- AP-HP Hôpital Paul-Brousse, Service de Virologie, Villejuif F-94800, France; Université Paris Sud, Université Paris Sud-Saclay, UMR-S 1193, Villejuif F-94800, France; INSERM, Unité 1193, Villejuif F-94800, France; DHU Hepatinov, Villejuif F-94800, France
| | - Didier Samuel
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif F-94800, France; Université Paris Sud, Université Paris Sud-Saclay, UMR-S 1193, Villejuif F-94800, France; INSERM, Unité 1193, Villejuif F-94800, France; DHU Hepatinov, Villejuif F-94800, France
| | - Jean-Charles Duclos-Vallée
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif F-94800, France; Université Paris Sud, Université Paris Sud-Saclay, UMR-S 1193, Villejuif F-94800, France; INSERM, Unité 1193, Villejuif F-94800, France; DHU Hepatinov, Villejuif F-94800, France
| | - Georges-Philippe Pageaux
- Département d'Hépato-gastroentérologie et de Transplantation Hépatique, CHU Saint-Eloi, Université de Montpellier, Montpellier F-34295, France
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24
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You Y, Kim HS, Bae IH, Lee SG, Jee MH, Keum G, Jang SK, Kim BM. New potent biaryl sulfate-based hepatitis C virus inhibitors. Eur J Med Chem 2016; 125:87-100. [PMID: 27657807 DOI: 10.1016/j.ejmech.2016.09.031] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Revised: 09/08/2016] [Accepted: 09/09/2016] [Indexed: 10/21/2022]
Abstract
The discovery of a new series of potent hepatitis C virus (HCV) NS5A inhibitors containing biaryl sulfone or sulfate cores is reported. Structure-activity relationship (SAR) studies on inhibitors containing various substitution patterns of the sulfate or sulfone core structure established that m-,m'- substituted biaryl sulfate core-based inhibitors containing an amide moiety (compound 20) or an imidazole moiety (compound 24) showed extremely high potency. Compound 20 demonstrated double-digit pM potencies against both genotype 1b (GT-1b) and 2a (GT-2a). Compound 24 also exhibited double-digit pM potencies against GT-1b and sub nM potencies against GT-2a. Furthermore, compounds 20 and 24 exhibited no cardiotoxicity in an hERG ligand binding assay and showed acceptable plasma stability and no mutagenic potential in the Ames test. In addition, these compounds showed distinctive additive effects in combination treatment with the NS5B targeting drug sofosbuvir (Sovaldi®). The results of this study showed that the compounds 20 and 24 could be effective HCV inhibitors.
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Affiliation(s)
- Youngsu You
- Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, South Korea
| | - Hee Sun Kim
- Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, South Korea
| | - Il Hak Bae
- Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, South Korea
| | - Seung Gi Lee
- Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, South Korea
| | - Min Hyeok Jee
- Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, South Korea
| | - Gyochang Keum
- Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, South Korea
| | - Sung Key Jang
- Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, South Korea.
| | - B Moon Kim
- Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, South Korea.
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25
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Seifert LL, Heinzow H, Kabar I, Christensen S, Hüsing A, Schmidt HHJ. Successful Anti-HCV Therapy of a Former Intravenous Drug User with Sofosbuvir and Daclatasvir in a Peritranspant Setting: A Case Report. AMERICAN JOURNAL OF CASE REPORTS 2016; 17:605-10. [PMID: 27554644 PMCID: PMC4999016 DOI: 10.12659/ajcr.895839] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Accepted: 04/22/2016] [Indexed: 02/02/2023]
Abstract
BACKGROUND Direct-acting antivirals (DAAs) represent a new hallmark in antiviral therapy of hepatitis C virus (HCV). DAAs have been shown to be safe and effective after liver transplantation (LT), but there is little information about their use in peritransplant settings. Former intravenous drug users represent an increasing group seeking HCV treatment. This case report demonstrates the successful peritransplant antiviral treatment of a former intravenous drug user who had been treated in a methadone maintenance program. CASE REPORT The patient was diagnosed with Child B cirrhosis for the first time in 2009. He had a Model for End-stage Liver Disease (MELD) score of 21 and started antiviral therapy with sofosbuvir (SOF) and daclatasvir (DCV) in March 2014. Due to hepatic decompensation, he received a LT in April 2014. Immunosuppression was performed with tacrolimus (TAC) and mycophenolate-mofetil (MMF), and boosted with prednisolone in the initial stage. Four weeks after his LT, the patient presented with an acute renal injury. The patient was discharged one week later after sufficient hydration, discontinuation of non-steroidal anti-phlogistics therapy, and adjustments to his immunosuppressive regimen. At the beginning of his therapy, the number of RNA copies was 13,000 IU/mL. He received 24 weeks of anti-HCV treatment with SOF and DCV; the antiviral treatment was successful and his LT was well tolerated. CONCLUSIONS Treatment of HCV is feasible in a peritransplant setting. The antiviral regimen we used did not seem to have any relevant interactions with the patient's immunosuppressive regimens. Still, the peritransplant setting is a very demanding environment for anti-HCV therapy, and further studies are needed.
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Affiliation(s)
- Leon Louis Seifert
- Department of Transplantation Medicine, University Hospital Münster, Münster, Germany
| | - Hauke Heinzow
- Department of Transplantation Medicine, University Hospital Münster, Münster, Germany
| | - Iyad Kabar
- Department of Transplantation Medicine, University Hospital Münster, Münster, Germany
| | - Stefan Christensen
- Center for Interdisciplinary Medicine (CIM) Infectious Diseases, Münster, Germany
| | - Anna Hüsing
- Department of Transplantation Medicine, University Hospital Münster, Münster, Germany
| | - Hartmut H.-J. Schmidt
- Department of Transplantation Medicine, University Hospital Münster, Münster, Germany
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26
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Meanwell NA. 2015 Philip S. Portoghese Medicinal Chemistry Lectureship. Curing Hepatitis C Virus Infection with Direct-Acting Antiviral Agents: The Arc of a Medicinal Chemistry Triumph. J Med Chem 2016; 59:7311-51. [PMID: 27501244 DOI: 10.1021/acs.jmedchem.6b00915] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The development of direct-acting antiviral agents that can cure a chronic hepatitis C virus (HCV) infection after 8-12 weeks of daily, well-tolerated therapy has revolutionized the treatment of this insidious disease. In this article, three of Bristol-Myers Squibb's HCV programs are summarized, each of which produced a clinical candidate: the NS3 protease inhibitor asunaprevir (64), marketed as Sunvepra, the NS5A replication complex inhibitor daclatasvir (117), marketed as Daklinza, and the allosteric NS5B polymerase inhibitor beclabuvir (142), which is in late stage clinical studies. A clinical study with 64 and 117 established for the first time that a chronic HCV infection could be cured by treatment with direct-acting antiviral agents alone in the absence of interferon. The development of small molecule HCV therapeutics, designed by medicinal chemists, has been hailed as "the arc of a medical triumph" but may equally well be described as "the arc of a medicinal chemistry triumph".
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Affiliation(s)
- Nicholas A Meanwell
- Department of Discovery Chemistry, Bristol-Myers Squibb Research & Development , Wallingford, Connecticut 06492, United States
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27
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Sasaki R, Kanda T, Ohtsuka M, Yasui S, Haga Y, Nakamura M, Yokoyama M, Wu S, Nakamoto S, Arai M, Maruyama H, Miyazaki M, Yokosuka O. Successful Management of Graft Reinfection of HCV Genotype 2 in Living Donor Liver Transplantation from a Hepatitis B Core Antibody-Positive Donor with Sofosbuvir and Ribavirin. Case Rep Gastroenterol 2016; 10:366-372. [PMID: 27721720 PMCID: PMC5043295 DOI: 10.1159/000447423] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Accepted: 05/04/2016] [Indexed: 12/16/2022] Open
Abstract
Direct-acting antivirals (DAAs) are relatively safe and highly effective for the eradication of hepatitis C virus (HCV) in liver transplant recipients. In this case study, we present a female with a graft reinfected with HCV genotype 2 who was treated with a combination of sofosbuvir and ribavirin after living donor liver transplantation (LDLT). Because the graft was from a hepatitis B core antibody-positive donor, passive immunization with hyperimmune hepatitis B immunoglobulin (HBIG) and entecavir were also provided to prevent hepatitis B virus (HBV) reactivation. It became clear that the combination of sofosbuvir and ribavirin promptly led to a sustained virologic response and that this combination was safe to treat graft reinfection with HCV genotype 2 after LDLT. Adverse events caused by DAAs were not observed, except for slight anemia. HBIG and entecavir were useful in the prevention of HBV reactivation. In conclusion, the present case indicated that DAA treatment for graft reinfection with HCV is safe and effective in LDLT from hepatitis B core antibody-positive donors.
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Affiliation(s)
- Reina Sasaki
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tatsuo Kanda
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masayuki Ohtsuka
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Shin Yasui
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yuki Haga
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masato Nakamura
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masayuki Yokoyama
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Shuang Wu
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Shingo Nakamoto
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Makoto Arai
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hitoshi Maruyama
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masaru Miyazaki
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Osamu Yokosuka
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
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28
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Bifano M, Adamczyk R, Hwang C, Kandoussi H, Marion A, Bertz RJ. An open-label investigation into drug-drug interactions between multiple doses of daclatasvir and single-dose cyclosporine or tacrolimus in healthy subjects. Clin Drug Investig 2016; 35:281-9. [PMID: 25896946 PMCID: PMC4544506 DOI: 10.1007/s40261-015-0279-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Background and Objective Chronic hepatitis C virus (HCV) infection is a major cause of liver transplantation. Drug–drug interactions (DDIs) with cyclosporine and tacrolimus hindered the use of first-generation protease inhibitors in transplant recipients. The current study investigated DDIs between daclatasvir—a pan-genotypic HCV NS5A inhibitor with clinical efficacy in multiple regimens (including all-oral)—and cyclosporine or tacrolimus in healthy subjects. Methods Healthy fasted subjects (aged 18–49 years; body mass index 18–32 kg/m2) received single oral doses of cyclosporine 400 mg on days 1 and 9, and daclatasvir 60 mg once daily on days 4–11 (group 1, n = 14), or a single oral dose of tacrolimus 5 mg on days 1 and 13, and daclatasvir 60 mg once daily on days 8–19 (group 2, n = 14). Blood samples for pharmacokinetic analysis [by liquid chromatography with tandem mass spectrometry (LC–MS/MS)] were collected on days 1 and 9 for cyclosporine (72 h), on days 1 and 13 for tacrolimus (168 h) and on days 8 and 9 (group 1) or on days 12 and 13 (group 2) for daclatasvir (24 h). Plasma concentrations were determined by validated LC–MS/MS methods. Results Daclatasvir did not affect the pharmacokinetic parameters of cyclosporine or tacrolimus, and tacrolimus did not affect the pharmacokinetic parameters of daclatasvir. Co-administration of cyclosporine resulted in a 40 % increase in the area under the concentration–time curve of daclatasvir but did not affect its maximum observed concentration. Conclusion On the basis of these observations in healthy subjects, no clinically relevant DDIs between daclatasvir and cyclosporine or tacrolimus are anticipated in liver transplant recipients infected with HCV; dose adjustments during co-administration are unlikely to be required.
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Affiliation(s)
- Marc Bifano
- />Bristol-Myers Squibb Research and Development, 311 Pennington Rock Hill Road, Hopewell, NJ 08534 USA
| | - Robert Adamczyk
- />Bristol-Myers Squibb Research and Development, 311 Pennington Rock Hill Road, Hopewell, NJ 08534 USA
| | - Carey Hwang
- />Bristol-Myers Squibb Research and Development, 311 Pennington Rock Hill Road, Hopewell, NJ 08534 USA
| | - Hamza Kandoussi
- />Bristol-Myers Squibb Research and Development, Lawrenceville, NJ USA
| | | | - Richard J. Bertz
- />Bristol-Myers Squibb Research and Development, 311 Pennington Rock Hill Road, Hopewell, NJ 08534 USA
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Treatment efficacy and tolerability of Sofosbuvir and Ribavirin for chronic hepatitis C infection in post renal transplant patients – A retrospective single centre study. INDIAN JOURNAL OF TRANSPLANTATION 2016. [DOI: 10.1016/j.ijt.2016.05.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
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Felmlee DJ, Coilly A, Chung RT, Samuel D, Baumert TF. New perspectives for preventing hepatitis C virus liver graft infection. THE LANCET. INFECTIOUS DISEASES 2016; 16:735-745. [PMID: 27301929 PMCID: PMC4911897 DOI: 10.1016/s1473-3099(16)00120-1] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Revised: 01/29/2016] [Accepted: 02/15/2016] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) infection is a leading cause of end-stage liver disease that necessitates liver transplantation. The incidence of virus-induced cirrhosis and hepatocellular carcinoma continues to increase, making liver transplantation increasingly common. Infection of the engrafted liver is universal and accelerates progression to advanced liver disease, with 20-30% of patients having cirrhosis within 5 years of transplantation. Treatments of chronic HCV infection have improved dramatically, albeit with remaining challenges of failure and access, and therapeutic options to prevent graft infection during liver transplantation are emerging. Developments in directed use of new direct-acting antiviral agents (DAAs) to eliminate circulating HCV before or after transplantation in the past 5 years provide renewed hope for prevention and treatment of liver graft infection. Identification of the ideal regimen and use of DAAs reveals new ways to treat this specific population of patients. Complementing DAAs, viral entry inhibitors have been shown to prevent liver graft infection in animal models and delay graft infection in clinical trials, which shows their potential for use concomitant to transplantation. We review the challenges and pathology associated with HCV liver graft infection, highlight current and future strategies of DAA treatment timing, and discuss the potential role of entry inhibitors that might be used synergistically with DAAs to prevent or treat graft infection.
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Affiliation(s)
- Daniel J Felmlee
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France; Hepatology Research Group, Peninsula School of Medicine and Dentistry, University of Plymouth, Plymouth, UK
| | - Audrey Coilly
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France; University Paris-Sud, UMR-S 1193, Villejuif, France; Inserm Unit 1193, Villejuif F-94800, France
| | - Raymond T Chung
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Didier Samuel
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France; University Paris-Sud, UMR-S 1193, Villejuif, France; Inserm Unit 1193, Villejuif F-94800, France.
| | - Thomas F Baumert
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France; Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
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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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Poordad F, Schiff ER, Vierling JM, Landis C, Fontana RJ, Yang R, McPhee F, Hughes EA, Noviello S, Swenson ES. Daclatasvir with sofosbuvir and ribavirin for hepatitis C virus infection with advanced cirrhosis or post-liver transplantation recurrence. Hepatology 2016; 63:1493-505. [PMID: 26754432 PMCID: PMC5069651 DOI: 10.1002/hep.28446] [Citation(s) in RCA: 341] [Impact Index Per Article: 37.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Accepted: 01/07/2016] [Indexed: 12/16/2022]
Abstract
UNLABELLED Chronic hepatitis C virus (HCV) infection with advanced cirrhosis or post-liver transplantation recurrence represents a high unmet medical need with no approved therapies effective across all HCV genotypes. The open-label ALLY-1 study assessed the safety and efficacy of a 60-mg once-daily dosage of daclatasvir (pan-genotypic NS5A inhibitor) in combination with sofosbuvir at 400 mg once daily (NS5B inhibitor) and ribavirin at 600 mg/day for 12 weeks with a 24-week follow-up in two cohorts of patients with chronic HCV infection of any genotype and either compensated/decompensated cirrhosis or posttransplantation recurrence. Patients with on-treatment transplantation were eligible to receive 12 additional weeks of treatment immediately after transplantation. The primary efficacy measure was sustained virologic response at posttreatment week 12 (SVR12) in patients with a genotype 1 infection in each cohort. Sixty patients with advanced cirrhosis and 53 with posttransplantation recurrence were enrolled; HCV genotypes 1 (76%), 2, 3, 4, and 6 were represented. Child-Pugh classifications in the advanced cirrhosis cohort were 20% A, 53% B, and 27% C. In patients with cirrhosis, 82% (95% confidence interval [CI], 67.9%-92.0%) with genotype 1 infection achieved SVR12, whereas the corresponding rates in those with genotypes 2, 3, and 4 were 80%, 83%, and 100%, respectively; SVR12 rates were higher in patients with Child-Pugh class A or B, 93%, versus class C, 56%. In transplant recipients, SVR12 was achieved by 95% (95% CI, 83.5%-99.4%) and 91% of patients with genotype 1 and 3 infection, respectively. Three patients received peritransplantation treatment with minimal dose interruption and achieved SVR12. There were no treatment-related serious adverse events. CONCLUSION The pan-genotypic combination of daclatasvir, sofosbuvir, and ribavirin was safe and well tolerated. High SVR rates across multiple HCV genotypes were achieved by patients with post-liver transplantation recurrence or advanced cirrhosis.
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Affiliation(s)
- Fred Poordad
- The Texas Liver InstituteUniversity of Texas Health Science CenterSan AntonioTX
| | - Eugene R. Schiff
- Schiff Center for Liver DiseasesUniversity of Miami Miller School of MedicineMiamiFL
| | - John M. Vierling
- Division of Abdominal TransplantationBaylor College of MedicineHoustonTX
| | - Charles Landis
- Division of Gastroenterology and Hepatology, Department of MedicineUniversity of WashingtonSeattleWA
| | - Robert J. Fontana
- University Division of Gastroenterology, Department of Internal MedicineUniversity of Michigan Medical CenterAnn ArborMI
| | - Rong Yang
- Bristol‐Myers SquibbLawrence TownshipNJ
| | - Fiona McPhee
- Discovery VirologyBristol‐Myers Squibb Research and DevelopmentWallingfordCT
| | | | | | - Eugene S. Swenson
- Discovery VirologyBristol‐Myers Squibb Research and DevelopmentWallingfordCT
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Abstract
Recurrence of hepatitis C after liver transplantation is a major problem; it is characterized by high hepatitis C virus (HCV)-RNA, rapid progression, and cholestatic hepatitis. Treatment for HCV infection with peginterferon and ribavirin has been administered to prevent progression of hepatitis C after liver transplantation. However, it has low efficacy and causes many adverse events, including immune-mediated graft dysfunction. Interferon-containing regimens with direct-acting antivirals (DAAs) improve treatment efficacy but DAAs cause serious adverse events and drug-drug interactions. Recent studies have demonstrated the efficacy and safety of interferon-free therapy with DAAs before and after liver transplantation, which has ushered in a new era in the strategy for treating HCV in transplant recipients. Interferon-free therapies are safe and effective in patients before and after liver transplantation as well as in those with severe cholestatic hepatitis C. Several obstacles must be overcome before the widespread adoption of interferon-free therapy, including drug-drug interactions, DAA-resistant HCV, treatment for decompensated cirrhosis, and treatment for renal failure. These problems are expected to be solved in the near future, and the poor prognosis of HCV-positive recipients will improve.
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Ajlan A, Al-Jedai A, Elsiesy H, Alkortas D, Al-Hamoudi W, Alarieh R, Al-Sebayel M, Broering D, Aba Alkhail F. Sofosbuvir-Based Therapy for Genotype 4 HCV Recurrence Post-Liver Transplant Treatment-Experienced Patients. Can J Gastroenterol Hepatol 2016; 2016:2872371. [PMID: 27446833 PMCID: PMC4904700 DOI: 10.1155/2016/2872371] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Accepted: 11/10/2015] [Indexed: 12/20/2022] Open
Abstract
Background and Aim. This is an open label prospective cohort study conducted at a tertiary care hospital. The primary endpoint is SVR12 in patients treated with sofosbuvir-based therapy in post-liver transplant patients with genotype 4 HCV recurrence. Methodology. Thirty-six treatment-experienced liver transplant patients with HCV recurrence received sofosbuvir and ribavirin ± peginterferon. Results. We report here safety and efficacy data on 36 patients who completed the follow-up period. Mean age was 56 years, and the cohort included 24 males and one patient had cirrhosis. Mean baseline HCV RNA was 6.2 log10 IU/mL. The majority of patients had ≥ stage 2 fibrosis. Twenty-eight patients were treated with pegylated interferon plus ribavirin in addition to sofosbuvir for 12 weeks and the remaining were treated with sofosbuvir plus ribavirin only for 24 weeks. By week 4, only four (11.1%) patients had detectable HCV RNA. Of the 36 patients, 2 (5.5%) relapsed and one died (2.75%). Conclusion. Our results suggest that sofosbuvir + ribavirin ± pegylated interferon can be utilized successfully to treat liver transplant patients with HCV recurrence.
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Affiliation(s)
- A. Ajlan
- Pharmaceutical Care Division, King Faisal Specialist Hospital and Research Centre, MBC-11, P.O. Box 3354, Riyadh 11211, Saudi Arabia
| | - A. Al-Jedai
- Pharmaceutical Care Division, King Faisal Specialist Hospital and Research Centre, MBC-11, P.O. Box 3354, Riyadh 11211, Saudi Arabia
- Alfaisal University, College of Medicine, Riyadh, Saudi Arabia
| | - H. Elsiesy
- Alfaisal University, College of Medicine, Riyadh, Saudi Arabia
- Liver & Small Bowel Transplant and Hepatobiliary and Pancreatic Surgery-Organ Transplant Center, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - D. Alkortas
- Pharmaceutical Care Division, King Faisal Specialist Hospital and Research Centre, MBC-11, P.O. Box 3354, Riyadh 11211, Saudi Arabia
| | - W. Al-Hamoudi
- Liver & Small Bowel Transplant and Hepatobiliary and Pancreatic Surgery-Organ Transplant Center, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
- King Saud University, College of Medicine, Riyadh, Saudi Arabia
| | - R. Alarieh
- Liver & Small Bowel Transplant and Hepatobiliary and Pancreatic Surgery-Organ Transplant Center, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - M. Al-Sebayel
- Liver & Small Bowel Transplant and Hepatobiliary and Pancreatic Surgery-Organ Transplant Center, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - D. Broering
- Liver & Small Bowel Transplant and Hepatobiliary and Pancreatic Surgery-Organ Transplant Center, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - F. Aba Alkhail
- Alfaisal University, College of Medicine, Riyadh, Saudi Arabia
- Liver & Small Bowel Transplant and Hepatobiliary and Pancreatic Surgery-Organ Transplant Center, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
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Hesamizadeh K, Sharafi H, Rezaee-Zavareh MS, Behnava B, Alavian SM. Next Steps Toward Eradication of Hepatitis C in the Era of Direct Acting Antivirals. HEPATITIS MONTHLY 2016; 16:e37089. [PMID: 27275164 PMCID: PMC4893415 DOI: 10.5812/hepatmon.37089] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Accepted: 02/21/2016] [Indexed: 12/11/2022]
Abstract
CONTEXT After the introduction of safe and highly effective hepatitis C virus (HCV) treatments, eradication of HCV in the next 20 years is the ultimate goal. Since 2011, the advent of first generation direct acting antivirals (DAAs) were started and followed by the introduction of a new wave of DAAs in 2013 which exhibit outstanding efficacy. It is obvious that the eradication of hepatitis C is not restricted to development of DAAs. EVIDENCE ACQUISITION An electronic search of available literature published was conducted in all peer-reviewed journal indexed in PubMed, Scopus and Google scholar. The literature search was done among articles related treatment of hepatitis C with DAAs in different patient groups with mass screening of the patients and cost benefit of new treatments as main key words. RESULTS There are major steps that should be taken to eradicate HCV, including (1) the development of screening strategies, particularly for groups such as intravenous drug users and recipients of blood or blood products before the introduction of HCV screening in donors; (2) the development of strategies to overcome issues with the high cost of recently introduced treatments; (3) special attention to special patient groups, such as HIV/HCV co-infection, hemophilia, thalassemia, hemodialysis, and liver-transplant patients; and (4) development of preventive strategies, such as the development of an efficient HCV vaccine, special attention to harm reduction in high-risk groups, and promotion of mass awareness of HCV. CONCLUSIONS The eradication of HCV will require significant governmental financial investment for screening, prevention, and treatment of infected patients. Although, we have a long way to eradication of HCV, the next steps could be including proper planning to patient finding, availability of new treatments to all patients and development of HCV prevention strategies such as vaccines.
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Affiliation(s)
- Khashayar Hesamizadeh
- Middle East Liver Disease (MELD) Center, Tehran, IR Iran
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| | - Heidar Sharafi
- Middle East Liver Disease (MELD) Center, Tehran, IR Iran
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| | - Mohammad Saeid Rezaee-Zavareh
- Middle East Liver Disease (MELD) Center, Tehran, IR Iran
- Students’ Research Committee, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| | - Bita Behnava
- Middle East Liver Disease (MELD) Center, Tehran, IR Iran
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| | - Seyed Moayed Alavian
- Middle East Liver Disease (MELD) Center, Tehran, IR Iran
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, IR Iran
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Fontana RJ, Brown RS, Moreno-Zamora A, Prieto M, Joshi S, Londoño MC, Herzer K, Chacko KR, Stauber RE, Knop V, Jafri SM, Castells L, Ferenci P, Torti C, Durand CM, Loiacono L, Lionetti R, Bahirwani R, Weiland O, Mubarak A, ElSharkawy AM, Stadler B, Montalbano M, Berg C, Pellicelli AM, Stenmark S, Vekeman F, Ionescu-Ittu R, Emond B, Reddy KR. Daclatasvir combined with sofosbuvir or simeprevir in liver transplant recipients with severe recurrent hepatitis C infection. Liver Transpl 2016; 22:446-458. [PMID: 26890629 DOI: 10.1002/lt.24416] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Revised: 01/12/2016] [Accepted: 01/24/2016] [Indexed: 12/11/2022]
Abstract
Daclatasvir (DCV) is a potent, pangenotypic nonstructural protein 5A inhibitor with demonstrated antiviral efficacy when combined with sofosbuvir (SOF) or simeprevir (SMV) with or without ribavirin (RBV) in patients with chronic hepatitis C virus (HCV) infection. Herein, we report efficacy and safety data for DCV-based all-oral antiviral therapy in liver transplantation (LT) recipients with severe recurrent HCV. DCV at 60 mg/day was administered for up to 24 weeks as part of a compassionate use protocol. The study included 97 LT recipients with a mean age of 59.3 ± 8.2 years; 93% had genotype 1 HCV and 31% had biopsy-proven cirrhosis between the time of LT and the initiation of DCV. The mean Model for End-Stage Liver Disease (MELD) score was 13.0 ± 6.0, and the proportion with Child-Turcotte-Pugh (CTP) A/B/C was 51%/31%/12%, respectively. Mean HCV RNA at DCV initiation was 14.3 × 6 log10 IU/mL, and 37% had severe cholestatic HCV infection. Antiviral regimens were selected by the local investigator and included DCV+SOF (n = 77), DCV+SMV (n = 18), and DCV+SMV+SOF (n = 2); 35% overall received RBV. At the end of treatment (EOT) and 12 weeks after EOT, 88 (91%) and 84 (87%) patients, respectively, were HCV RNA negative or had levels <43 IU/mL. CTP and MELD scores significantly improved between DCV-based treatment initiation and last contact. Three virological breakthroughs and 2 relapses occurred in patients treated with DCV+SMV with or without RBV. None of the 8 patient deaths (6 during and 2 after therapy) were attributed to therapy. In conclusion, DCV-based all-oral antiviral therapy was well tolerated and resulted in a high sustained virological response in LT recipients with severe recurrent HCV infection. Most treated patients experienced stabilization or improvement in their clinical status.
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Affiliation(s)
- Robert J Fontana
- Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI
| | - Robert S Brown
- College of Physicians and Surgeons, Columbia University, New York, NY
| | | | - Martin Prieto
- Hospital Universitario y Politécnico La Fe and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Valencia, Spain
| | - Shobha Joshi
- Department of Gastroenterology, Ochsner Health System, New Orleans, LA
| | | | - Kerstin Herzer
- Department for General, Viszeral and Transplantation Surgery and Department of Gastroenterology and Hepatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Kristina R Chacko
- Einstein Center for Transplantation, Montefiore Medical Center, New York, NY
| | - Rudolf E Stauber
- Department of Internal Medicine, Karl-Franzens-University, Graz, Austria
| | - Viola Knop
- Department of Internal Medicine, University Hospital-Goethe University, Frankfurt, Germany
| | - Syed-Mohammed Jafri
- Department of Gastroenterology and Hepatology, Henry Ford Hospital, Detroit, MI
| | - Lluís Castells
- Internal Medicine Department, Hospital Universitary Vall Hebron, University of Barcelona, Barcelona, Spain
| | - Peter Ferenci
- Department of Internal Medicine IV, Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Carlo Torti
- Unit of Infectious and Tropical Diseases, Magna Graecia University, Cantanzaro, Italy
| | - Christine M Durand
- Department of Medicine Infectious Diseases, Johns Hopkins Medical Institution, Baltimore, MD
| | | | - Raffaella Lionetti
- Liver Unit, IRCCS Lazzaro Spallanzani, National Institute for Infectious Diseases, Rome, Italy
| | - Ranjeeta Bahirwani
- Division of Gastroenterology, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Ola Weiland
- Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Abdullah Mubarak
- Department of Hepatology, Dallas Medical Physicians Group, Dallas, TX
| | - Ahmed M ElSharkawy
- University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Medical Centre, Birmingham, United Kingdom
| | | | - Marzia Montalbano
- Liver Unit, IRCCS Lazzaro Spallanzani, National Institute for Infectious Diseases, Rome, Italy
| | - Christoph Berg
- Department of Internal Medicine, Hepatology, Gastroenterology, Infectious Diseases, University Hospital of Tübingen, Tübingen, Germany
| | | | | | | | | | - Bruno Emond
- Analysis Group, Inc, Montreal, Quebec, Canada
| | - K Rajender Reddy
- Division of Gastroenterology, Hospital of the University of Pennsylvania, Philadelphia, PA
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Herzer K, Papadopoulos-Köhn A, Walker A, Achterfeld A, Paul A, Canbay A, Timm J, Gerken G. Daclatasvir, Simeprevir and Ribavirin as a Promising Interferon-Free Triple Regimen for HCV Recurrence after Liver Transplant. Digestion 2016; 91:326-33. [PMID: 25999053 DOI: 10.1159/000382075] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2015] [Accepted: 03/31/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND Recurrent hepatitis C infection after liver transplantation (LT) is associated with lower rates of graft and patient survival. METHODS Here we describe the first use of daclatasvir, simeprevir, and ribavirin (RBV) as an all-oral triple regimen administered to 6 liver transplant recipients with recurrent hepatitis C, one with GT 1a and 5 with GT 1b. All patients were treated for 24 weeks. Trough levels of immunosuppression, laboratory measures, and potential adverse effects were closely monitored. RESULTS For all patients, viral load became undetectable between treatment weeks 4 and 12. One patient experienced a viral breakthrough at the 10th week of treatment; this was associated with the selection of resistance-associated variants (D168Y in NS3 and ΔP32 in NS5A). For the other 5 patients, end-of-treatment response and for 4 patients SVR24 was achieved. Viremia recurred in one patient 4 weeks after the end of treatment, which was again associated with the selection of resistance-associated variants (D168V in NS3 and ΔP32 in NS5A). Clinical measures of liver function improved substantially for all patients. Adverse events were few and limited to moderate anemia caused by RBV. Importantly, adjustments to the immunosuppressant dosage were not required. CONCLUSIONS The described regimen appears to be safe and effective for liver transplant patients and will be a promising treatment regimen for post-LT patients.
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Affiliation(s)
- Kerstin Herzer
- Departments of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
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Pol S, Corouge M, Vallet-Pichard A. Daclatasvir-sofosbuvir combination therapy with or without ribavirin for hepatitis C virus infection: from the clinical trials to real life. Hepat Med 2016; 8:21-6. [PMID: 27019602 PMCID: PMC4786064 DOI: 10.2147/hmer.s62014] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The treatment of hepatitis C virus has changed dramatically with the rapid advent of numerous new antiviral agents, including direct-acting antivirals and agents with non-viral targets (cyclophilin inhibitors, interferon-lambda, vaccine therapy). Given the better safety profile and high antiviral potency of direct-acting antivirals, their combination in interferon-free oral regimens is becoming the standard of care for hepatitis C virus infection, tailored to individual patients according to the degree of disease progression (fibrosis), hepatitis C virus genotype and subtype, resistance profile, and prior therapeutic history. Results from clinical studies as well as preliminary real-life data regarding the combination of sofosbuvir (a nucleotide polymerase inhibitor) and daclatasvir, a first-in-class NS5A replication complex inhibitor, demonstrate that it is one of the most promising antiviral therapies, with once-daily oral dosing, a low pill burden, good tolerability, and limited drug-drug interactions, in addition to high antiviral potency, with >90% sustained virologic response rates. This combination has high pangenotypic antiviral potency regardless of the severity and patient characteristics. The combination of sofosbuvir and an NS5A inhibitor with ribavirin for 12 weeks appears to be a very good further treatment option in both cirrhotic and treatment-experienced patients whatever the stage of fibrosis.
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Affiliation(s)
- Stanislas Pol
- Université Paris Descartes, Liver Department, Assistance Publique Hôpitaux de Paris, Cochin Hospital, French Institute of Health and Medical Research UMS20, Institut Pasteur, Paris, France
| | - Marion Corouge
- Université Paris Descartes, Liver Department, Assistance Publique Hôpitaux de Paris, Cochin Hospital, French Institute of Health and Medical Research UMS20, Institut Pasteur, Paris, France
| | - Anaïs Vallet-Pichard
- Université Paris Descartes, Liver Department, Assistance Publique Hôpitaux de Paris, Cochin Hospital, French Institute of Health and Medical Research UMS20, Institut Pasteur, Paris, France
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Burra P, De Martin E, Zanetto A, Senzolo M, Russo FP, Zanus G, Fagiuoli S. Hepatitis C virus and liver transplantation: where do we stand? Transpl Int 2016; 29:135-152. [PMID: 26199060 DOI: 10.1111/tri.12642] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Revised: 03/06/2015] [Accepted: 07/15/2015] [Indexed: 12/14/2022]
Abstract
The hepatitis C virus (HCV) infects more than 180 million people globally, with increasing incidence, especially in developing countries. HCV infection frequently progresses to liver cirrhosis leading to liver transplantation or death, and HCV recurrence still constitutes a major challenge for the transplant team. Antiviral therapy is the only available instrument to slow down this process, although its actual impact on liver histology, in responders and nonresponders, is still controversial. We are now facing a "new era" of direct antiviral agents that is already changing the approach to HCV burden both in the pre- and in the post-liver transplantation settings. Available data on sofosbuvir/ledipasvir and sofosbuvir/simeprevir in patients with decompensated cirrhosis sustain a SVR12 of 89% , but one-third of patients do not clinically improved. The sofosbuvir/ribavirin treatment in stable cirrhotic patients with HCC before liver transplantation is associated with 2% recurrence rate if liver transplantation is performed at least one month after undetectable HCV-RNA is achieved. The treatment of recurrence with the new antiviral drugs is associated with a SVR that ranges between 60 and 90%. In this review, we have focused on the evolution of antiviral therapy for HCV recurrence from the "old" interferon-based therapy to the "new" interferon-free regimens, highlighting useful information to aid the transplant hepatologist in the clinical practice.
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Affiliation(s)
- Patrizia Burra
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Eleonora De Martin
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
- Centre Hepato-Biliaire Paul Brousse, Villejuif, France
| | - Alberto Zanetto
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Marco Senzolo
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Francesco Paolo Russo
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Giacomo Zanus
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Stefano Fagiuoli
- Gastroenterology and Transplant Hepatology, Papa Giovanni XXIII Hospital, Bergamo, Italy
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40
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Brown RS, O’Leary JG, Reddy KR, Kuo A, Morelli GJ, Burton JR, Stravitz RT, Durand C, Di Bisceglie AM, Kwo P, Frenette CT, Stewart TG, Nelson DR, Fried MW, Terrault NA. Interferon-free therapy for genotype 1 hepatitis C in liver transplant recipients: Real-world experience from the hepatitis C therapeutic registry and research network. Liver Transpl 2016; 22:24-33. [PMID: 26519873 PMCID: PMC5208040 DOI: 10.1002/lt.24366] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 09/29/2015] [Accepted: 10/21/2015] [Indexed: 12/13/2022]
Abstract
Recurrent infection with the hepatitis C virus (HCV) after liver transplantation (LT) is associated with decreased graft and patient survival. Achieving sustained virological response (SVR) with antiviral therapy improves survival. Because interferon (IFN)-based therapy has limited efficacy and is poorly tolerated, there has been rapid transition to IFN-free direct-acting antiviral (DAA) regimens. This article describes the experience with DAAs in the treatment of posttransplant genotype (GT) 1 HCV from a consortium of community and academic centers (Hepatitis C Therapeutic Registry and Research Network [HCV-TARGET]). Twenty-one of the 54 centers contributing to the HCV-TARGET consortium participated in this study. Enrollment criteria included positive posttransplant HCV RNA before treatment, HCV GT 1, and documentation of use of a simeprevir (SMV)/sofosbuvir (SOF) containing DAA regimen. Safety and efficacy were assessed. SVR was defined as undetectable HCV RNA 64 days or later after cessation of treatment. A total of 162 patients enrolled in HCV-TARGET started treatment with SMV+SOF with or without ribavirin (RBV) following LT. The study population included 151 patients treated with these regimens for whom outcomes and safety data were available. The majority of the 151 patients were treated with SOF and SMV alone (n = 119; 79%) or with RBV (n = 32; 21%), The duration of therapy was 12 weeks for most patients, although 15 patients received 24 weeks of treatment. Of all patients receiving SOF/SMV with or without RBV, 133/151 (88%) achieved sustained virological response at 12 weeks after therapy and 11 relapsed (7%). One patient had virological breakthrough (n = 1), and 6 patients were lost to posttreatment follow-up. Serious adverse events occurred in 11.9%; 3 patients (all cirrhotic) died due to aspiration pneumonia, suicide, and multiorgan failure. One experienced LT rejection. IFN-free DAA treatment represents a major improvement over prior IFN-based therapy. Broader application of these and other emerging DAA regimens in the treatment of posttransplant hepatitis C is warranted.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Paul Kwo
- Indiana University, Indianapolis, IN
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41
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Focaccia R, de Mello RF, Montes PS, Conti FM. Management of Hepatitis C Infection with Direct Action Antiviral Drugs (DAA). ACTA ACUST UNITED AC 2015. [DOI: 10.17352/ahr.000003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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42
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Ueda Y, Kaido T, Hatano E, Ohtsuru S, Uemoto S. Safe and effective treatment with daclatasvir and asunaprevir in a liver transplant recipient with severe cholestatic hepatitis C. Hepatol Res 2015; 45:1360-2. [PMID: 25704315 DOI: 10.1111/hepr.12509] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2014] [Revised: 02/16/2015] [Accepted: 02/16/2015] [Indexed: 02/08/2023]
Abstract
Severe cholestatic hepatitis C (SCH) is a unique variant of recurrent hepatitis C that occurs after liver transplantation. Unfortunately, the prognosis of SCH is poor, and interferon (IFN) therapy has been reported to not improve the prognosis. We herein report a case of progressive SCH with acute cellular rejection (ACR) and bacterial infection, which was successfully treated using IFN-free therapy with daclatasvir and asunaprevir. A 43-year-old man was diagnosed with SCH and mild ACR at day 48 after liver transplantation, and IFN-free therapy with daclatasvir and asunaprevir was started. Although he experienced catheter-related bacteremia on the first day, the IFN-free therapy was safely continued, which immediately caused his liver function to improve. His bilirubin levels decreased from 11.1 to 2.1 mg/dL and serum hepatitis C virus RNA levels became undetectable after 4 weeks of the treatment. This case indicates that IFN-free therapy for progressive SCH with acute cellular rejection and bacterial infection is safe and effective, and may improve the outcomes of hepatitis C virus positive transplant recipients.
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Affiliation(s)
- Yoshihide Ueda
- Department of Gastroenterology and Hepatology, Kyoto, Japan
| | - Toshimi Kaido
- Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Etsuro Hatano
- Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | | | - Shinji Uemoto
- Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Degasperi E, Aghemo A, Colombo M. Daclatasvir for the treatment of chronic hepatitis C. Expert Opin Pharmacother 2015; 16:2679-88. [DOI: 10.1517/14656566.2015.1109631] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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44
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Kim H, Lee KW, Yi NJ, Lee HW, Choi Y, Suh SW, Jeong J, Suh KS. Response-Guided Therapy for Hepatitis C Virus Recurrence Based on Early Protocol Biopsy after Liver Transplantation. J Korean Med Sci 2015; 30:1577-83. [PMID: 26539000 PMCID: PMC4630472 DOI: 10.3346/jkms.2015.30.11.1577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 07/29/2015] [Indexed: 11/20/2022] Open
Abstract
Hepatitis C virus (HCV) recurrence after liver transplantation (LT) is universal and progressive. Here, we report recent results of response-guided therapy for HCV recurrence based on early protocol biopsy after LT. We reviewed patients who underwent LT for HCV related liver disease between 2010 and 2012. Protocol biopsies were performed at 3, 6, and 12 months after LT in HCV recurrence (positive HCV-RNA). For any degree of fibrosis, ≥ moderate inflammation on histology or HCV hepatitis accompanying with abnormal liver function, we treated with pegylated interferon and ribavirin. We adjusted treatment period according to individual response to treatment. Among 41 HCV related recipients, 25 (61.0%) who underwent protocol biopsies more than once were enrolled in this study. The mean follow-up time was 43.1 (range, 23-55) months after LT. Genotype 1 and 2 showed in 56.0% and 36.0% patients, respectively. Of the 25 patients, 20 (80.0%) started HCV treatment after LT. Rapid or early virological response was observed in 20 (100%) patients. Fifteen (75.0%) patients finished the treatment with end-of-treatment response. Sustained virological response (SVR) was in 11 (55.0%) patients, including 5 (41.7%) of 12 genotype 1 and 6 (75.0%) of 8 non-genotype 1 (P = 0.197). Only rapid or complete early virological response was a significant predictor for HCV treatment response after LT (100% in SVR group vs. 55.6% in non-SVR group, P = 0.026). Overall 3-yr survival rate was 100%. In conclusion, response-guided therapy for HCV recurrence based on early protocol biopsy after LT shows encouraging results.
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Affiliation(s)
- Hyeyoung Kim
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Kwang-Woong Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Nam-Joon Yi
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Hae Won Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - YoungRok Choi
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Suk-Won Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Jaehong Jeong
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Kyung-Suk Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
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45
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Pockros PJ. Genotype 3: Treat now or wait for something better? Clin Liver Dis (Hoboken) 2015; 6:129-131. [PMID: 31041008 PMCID: PMC6490668 DOI: 10.1002/cld.510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2015] [Revised: 10/05/2015] [Accepted: 10/10/2015] [Indexed: 02/04/2023] Open
Affiliation(s)
- Paul J Pockros
- Division of Gastroenterology and Hepatology Scripps Clinic La Jolla CA
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46
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Leroy V, Dumortier J, Coilly A, Sebagh M, Fougerou-Leurent C, Radenne S, Botta D, Durand F, Silvain C, Lebray P, Houssel-Debry P, Kamar N, D'Alteroche L, Petrov-Sanchez V, Diallo A, Pageaux GP, Duclos-Vallee JC, Duclos-Vallée JC, Coilly A, Bellissant E, Botta-Fridlund D, Diallo A, Dumortier J, Durand F, Duvoux C, Fougerou-Leurent C, Leroy V, Petrov-Sanchez V, Renault A, Rohel A, Roque AM, Taburet AM, Veislinger A. Efficacy of Sofosbuvir and Daclatasvir in Patients With Fibrosing Cholestatic Hepatitis C After Liver Transplantation. Clin Gastroenterol Hepatol 2015; 13:1993-2001.e1-2. [PMID: 26044317 DOI: 10.1016/j.cgh.2015.05.030] [Citation(s) in RCA: 87] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Revised: 05/20/2015] [Accepted: 05/20/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Fibrosing cholestatic hepatitis (FCH) is a life-threatening disorder that develops in patients with recurrent hepatitis C virus (HCV) infection after liver transplantation. Until recently, therapeutic options have been limited. We evaluated the efficacy and safety of sofosbuvir- and daclatasvir-based regimens. METHODS We analyzed data from 23 patients with FCH who participated in a prospective cohort study in France and Belgium of the effects of antiviral agents in patients with recurrence of HCV infection after liver transplantation, from October 2013 through April 2014. Most of the patients had genotype 1 infections that had not responded to previous treatment; 4 patients also were infected with human immunodeficiency virus. Eight patients (37%) had ascites and 15 patients (65%) had bilirubin levels greater than 100 mmol/L; their median serum level of HCV RNA was 7 log IU/mL. The median time between transplantation and treatment initiation was 5 months. Subjects were given either sofosbuvir and daclatasvir (n = 15) or sofosbuvir and ribavirin (n = 8) for 24 weeks. The primary outcome was complete clinical response (survival without re-transplantation, bilirubin level <34 μmol/L, and no ascites or hepatic encephalopathy 36 weeks after treatment began). RESULTS All patients survived, without re-transplantation, until week 36. Rapid and dramatic improvements in clinical status were observed. The patients' median bilirubin concentration decreased from 122 μmol/L at baseline to a normal value at week 12 of treatment. Twenty-two patients (96%) had a complete clinical response at week 36. Despite the low rate of rapid virologic response, 22 patients (96%) achieved a sustained virologic response at week 12. The only relapse of HCV infection occurred in a patient with human immunodeficiency virus infection who received sofosbuvir and ribavirin. Tolerance was satisfactory, with no grade 3 or 4 adverse events related to sofosbuvir or daclatasvir and no significant interactions among drugs. CONCLUSIONS Sofosbuvir therapy with daclatasvir or ribavirin leads to major clinical improvement and high rates of sustained virologic response at week 12 in most patients with recurrence of HCV infection and FCH after liver transplantation. ClinicalTrial.gov no: NCT01944527.
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Affiliation(s)
- Vincent Leroy
- Clinique Universitaire d'Hépato-Gastroentérologie, Pôle Digidune, Centre Hospitalier Universitaire de Grenoble, Grenoble, France; Unité INSERM/Université Grenoble Alpes U823, Immunologie Analytique des Pathologies Chroniques Institut Albert Bonniot, Grenoble, France.
| | - Jérôme Dumortier
- Hôpital Edouard Herriot, Unité de Transplantation Hépatique, Lyon, France; Université Claude Bernard Lyon 1, Lyon, France
| | - Audrey Coilly
- Assistance Publique-Hôpitaux de Paris Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif, France; Université Paris-Sud, UMR-S 1193, Villejuif, France; Inserm, Unité 1193, Villejuif, France; DHU Hepatinov, Villejuif, France
| | - Mylène Sebagh
- Assistance Publique-Hôpitaux de Paris Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif, France; Université Paris-Sud, UMR-S 1193, Villejuif, France; Inserm, Unité 1193, Villejuif, France; DHU Hepatinov, Villejuif, France
| | - Claire Fougerou-Leurent
- Unit of Clinical Pharmacology, Rennes University Hospital, Rennes, France; INSERM Clinical Investigation Centre 1414, Rennes, France
| | - Sylvie Radenne
- Hôpital de la Croix Rousse, Service de Transplantation Hépatique et INSERM 1052, Lyon, France
| | - Danielle Botta
- Centre Hospitalier Universitaire Conception, Service d'Hépato-Gastroentérologie, Marseille, France
| | - François Durand
- Département d'Hépatologie, Hôpital Beaujon-Assistance Publique-Hôpitaux de Paris, Clichy, France; Université Paris Diderot et INSERM U1149, Centre de Recherche sur l'Inflammation, Clichy, France
| | - Christine Silvain
- Département d'Hépato-Gastroentérologie, Centre Hospitalier Universitaire de Poitiers, Poitiers, France; EA 4331, Pôle Biologie Santé, Poitiers, France
| | - Pascal Lebray
- Departement of d'Hépatologie et de Gastroenterologie, Groupe Hospitalier Pitié-Salpétrière, Assistance Publique-Hôpitaux de Paris, Université Pierre et Marie Curie Paris 6, Paris, France
| | - Pauline Houssel-Debry
- Service des Maladies du Foie, Centre Hospitalier Universitaire Rennes, Rennes, France
| | - Nassim Kamar
- Département de Néphrologie et de Transplantation d'Organes, Centre Hospitalier Universitaire Rangueil, Toulouse, France; Université Paul Sabatier, Toulouse, France; INSERM U1043, IFR-BMT, Centre Hospitalier Universitaire Purpan, Toulouse, France
| | - Louis D'Alteroche
- Service d'Hépato-Gastroentérologie, Centre Hospitalier Universitaire Trousseau, Tours, France
| | - Ventzislava Petrov-Sanchez
- Unit for Basic and Clinical Research on Viral Hepatitis, ANRS (France Recherche Nord and Sud Sida-HIV Hépatites FRENSH), Paris, France
| | - Alpha Diallo
- Unit for Basic and Clinical Research on Viral Hepatitis, ANRS (France Recherche Nord and Sud Sida-HIV Hépatites FRENSH), Paris, France
| | - Georges-Philippe Pageaux
- Département d'Hépato-Gastroentérologie et de Transplantation Hépatique, Centre Hospitalier Universitaire Saint-Eloi, Montpellier, France; Université Montpellier 1, Montpellier, France
| | - Jean-Charles Duclos-Vallee
- Assistance Publique-Hôpitaux de Paris Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif, France; Université Paris-Sud, UMR-S 1193, Villejuif, France; Inserm, Unité 1193, Villejuif, France; DHU Hepatinov, Villejuif, France
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47
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Giard JM, Terrault NA. Severe Cholestatic Hepatitis C in Transplant Recipients: No Longer a Threat to Graft Survival. Clin Gastroenterol Hepatol 2015; 13:2002-4. [PMID: 26192143 PMCID: PMC4615527 DOI: 10.1016/j.cgh.2015.07.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Accepted: 07/13/2015] [Indexed: 02/07/2023]
Affiliation(s)
- Jeanne-Marie Giard
- Division of Gastroenterology, University of California-San Francisco, San Francisco, California
| | - Norah A Terrault
- Division of Gastroenterology, University of California-San Francisco, San Francisco, California
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48
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Ofosu A, Durand CM, Saberi B, Alqahtani S, Ucbilek E, Belden M, Cameron AM, Gurakar A. Implications of Treating Hepatitis C Virus Infection Among Patients Awaiting Cadaveric Liver Transplant: A Single-Center Experience. EXP CLIN TRANSPLANT 2015; 13 Suppl 3:7-10. [PMID: 26640901 DOI: 10.6002/ect.tdtd2015.l16] [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] [Indexed: 11/05/2022]
Abstract
OBJECTIVES We examined hepatitis C virus positivity among the donors in our center to investigate whether hepatitis C treatment affected liver transplant Model for End-Stage Liver Disease. MATERIALS AND METHODS We retrospectively reviewed all deceased-donor liver transplants performed between January 2013 and December 2014 at our center, with the primary indication of hepatitis C virus. Baseline demographic and laboratory characteristics of recipients and donors were collected. Statistical analyses were done with P values ≤ .05 considered significant. RESULTS Seventy-five liver transplants were performed, and 62 of them were hepatitis C virus RNA-positive at the time of liver transplant donor offer. In 2013, during the Pre-Direct Antiviral Agents era, 14 of 33 hepatitis C virus RNA-positive recipients (42%) were matched to hepatitis C virus-positive donors. During the Direct Antiviral Agents era in 2014, this ratio was 38% (11/29) (P = .72). The mean Model for End-Stage Liver Disease at transplant of the 62 hepatitis C virus RNA-positive recipients was 29, whereas the mean Model for End-Stage Liver Disease of 13 hepatitis C virus RNA-negative recipients was 31. This was not statistically significant (P = .25). CONCLUSIONS Although hepatitis C virus treatment before liver transplant is an attractive option to eliminate the risk of complications because of recurrent hepatitis C virus after liver transplant, its potential effect on limiting the donor pool for the recipient must also be considered. In our observation, 40% of our donor pool consists of hepatitis C virus-positive donors. Further multiregional studies are warranted to verify this observation and to see the potential effect of direct antiviral agent treatment into waiting times and the Model for End-Stage Liver Disease at organ allocation.
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Affiliation(s)
- Andrew Ofosu
- From the Johns Hopkins University School of Medicine, Division of Gastroenterology, Baltimore, MD, United States
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49
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Vitale A, Spolverato G, Burra P, De Feo TM, Belli L, Donato F, Baroni GS, Marianelli T, Picciotto A, Toniutto P, Bhoori S, Passigato N, Lucà MG, Russo FP, Cillo U, Fagiuoli S. Cost-effectiveness of pretransplant sofosbuvir for preventing recurrent hepatitis C virus infection after liver transplantation. Transpl Int 2015; 28:1055-1065. [PMID: 25865602 DOI: 10.1111/tri.12591] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2014] [Revised: 02/06/2015] [Accepted: 04/07/2015] [Indexed: 02/06/2023]
Abstract
There are reports of pretransplant sofosbuvir (SOF) plus ribavirin being effective in preventing recurrent hepatitis C virus (HCV) infection after liver transplantation (LT). The aim of this study was to assess the cost-effectiveness of this strategy in the area served by the North Italy Transplant program. We retrospectively assessed the impact of HCV infection on post-LT survival in 2376 consecutive adult patients (MELD ≤ 25, unknown genotype, period 2004-2009) and the prevalence costs of conventional standard of care (SOC) antiviral therapy (pegylated interferon plus ribavirin) after LT. A Markov model was developed to compare two strategies: 12-24 weeks of SOF+ ribavirin for pre-LT anti-HCV treatment versus on-demand post-LT SOC antiviral therapy. Among the 1794 patients undergoing LT, 860 (48%) were HCV+ and 50% of them were given SOC therapy after LT (mean cost of drugs and adverse effect management = 14,421€ per patient). HCV etiology had a strong impact on post-LT survival (hazard ratio = 1.59, 95% CI = 1.22-2.09, P = 0.0007). After Monte Carlo simulation, pre-LT SOF therapy showed a median survival benefit of 1.5 quality-adjusted life years and an Incremental cost-effectiveness ratio (ICER) of 30,663€/QALY, proving cost-effective in our particular Italian scenario. The costs of SOF therapy, sustained viral response rate 12 weeks after LT, and recipient's age were the main ICER predictors at multivariate analysis. This study proposes a dynamic model based on real-life data from northern Italy for adjusting the costs of pre-LT direct-acting antiviral therapies to the actual sustained virological response reached after LT.
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Affiliation(s)
| | | | | | | | - Luca Belli
- Hepatology and Gastroenterology, Ospedale Niguarda Ca' Granda, Milan, Italy
| | - Francesca Donato
- Gastroenterology Unit, Ospedale Maggiore Policlinico, Milan, Italy
| | | | | | | | | | | | | | - Maria Grazia Lucà
- Gastroenterology and Transplant Hepatology, Ospedale Papa Giovanni XXIII, Bergamo, Italy
| | | | | | - Stefano Fagiuoli
- Gastroenterology and Transplant Hepatology, Ospedale Papa Giovanni XXIII, Bergamo, Italy
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50
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Beinhardt S, Peck-Radosavljevic M, Hofer H, Ferenci P. Interferon-free antiviral treatment of chronic hepatitis C in the transplant setting. Transpl Int 2015; 28:1011-1024. [PMID: 25864369 DOI: 10.1111/tri.12577] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Revised: 03/03/2015] [Accepted: 04/02/2015] [Indexed: 12/16/2022]
Abstract
Interferon-based regimens with first-generation protease inhibitors have a limited efficacy and an unfavorable safety profile. Combination therapies with two or more second-generation direct-acting antivirals plus/minus ribavirin revolutionized treatment strategies in patients chronically infected with hepatitis C virus. In this rapidly evolving era, patients in the transplant setting benefit from interferon-free treatment regimens. Scientific societies can barely keep up with this development, making it necessary to update the clinical guidelines by the American and European Associations for the Study of Liver Diseases within short periods. This review presents and discusses the currently available data of the use of interferon-free treatment in the setting of liver transplantation. However, costs, different reimbursement strategies, and health-care options cannot be answered by guidelines and recommendations from scientific societies. Further investigator-initiated trials are needed to individualize treatment concepts.
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Affiliation(s)
- Sandra Beinhardt
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Markus Peck-Radosavljevic
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Harald Hofer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Peter Ferenci
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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