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Systematic Review with Meta-Analysis: Efficacy and Safety of Direct-Acting Antivirals for Chronic Hepatitis C Genotypes 5 and 6. BIOMED RESEARCH INTERNATIONAL 2019; 2019:2301291. [PMID: 31815126 PMCID: PMC6877942 DOI: 10.1155/2019/2301291] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 08/14/2019] [Accepted: 09/20/2019] [Indexed: 02/07/2023]
Abstract
Direct-acting antivirals (DAAs) are modern treatments for chronic hepatitis C infection, but majority of available evidence on its treatment effect covers genotypes 1 to 4. Therefore, the efficacy and safety of DAAs for genotypes 5 and 6 need to be analysed. Studies were identified from Medline, Scopus, and CENTRAL and a Chinese database CNKI, from inception until Dec 4, 2018. Clinical trials were included if they enrolled patients with genotypes 5 and/or 6 infection, any type of second-generation DAAs was studied, and sustained virological response was assessed at the 12th week after treatment (SVR12) as outcome measure. Meta-analysis using metaprop statistical program was applied for pooling proportions if data were sufficient (i.e., at least 2 studies). Thirteen studies were included in the analysis. Four studies assessed the efficacy of four DAA regimens in genotype 5 patients, which were mainly sofosbuvir (SOF) plus pegylated-interferon/ribavirin (PR) or other DAAs, with SVR12 ranging from 94.4% to 100%. Twelve studies assessed the efficacy of seven DAA regimens among genotype 6 patients, but only two DAA regimens (i.e., SOF + PR and SOF/ledipasvir) had sufficient data for pooling. The pooled SVR12 rates (95% CI) were 99.6% (92.2 to 100) for SOF + PR and 99.2% (96.5 to 100) for SOF/ledipasvir. No treatment-related serious adverse event was reported, while the nonserious adverse events were comparable to other genotypes. In conclusion, DAAs are effective and may be safe for the treatment of chronic hepatitis C genotypes 5 and 6. However, our evidence is based on noncomparative studies; hence, further larger-scale randomized controlled trials in these genotypes are still required.
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Humanized Mouse Models for the Study of Hepatitis C and Host Interactions. Cells 2019; 8:cells8060604. [PMID: 31213010 PMCID: PMC6627916 DOI: 10.3390/cells8060604] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 06/09/2019] [Accepted: 06/13/2019] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C virus (HCV) infection is commonly attributed as a major cause of chronic hepatotropic diseases, such as, steatosis, cirrhosis and hepatocellular carcinoma. As HCV infects only humans and primates, its narrow host tropism hampers in vivo studies of HCV-mammalian host interactions and the development of effective therapeutics and vaccines. In this context, we will focus our discussion on humanized mice in HCV research. Here, these humanized mice are defined as animal models that encompass either only human hepatocytes or both human liver and immune cells. Aspects related to immunopathogenesis, anti-viral interventions, drug testing and perspectives of these models for future HCV research will be discussed.
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Equivalent Outcomes With Retransplantation and Primary Liver Transplantation in the Direct-acting Antiviral Era. Transplantation 2019; 103:1168-1174. [DOI: 10.1097/tp.0000000000002460] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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Maekawa S, Enomoto N. The "real-world" efficacy and safety of DAAs for the treatment of HCV patients throughout Japan. J Gastroenterol 2018; 53:1168-1169. [PMID: 29980847 DOI: 10.1007/s00535-018-1493-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 07/03/2018] [Indexed: 02/04/2023]
Affiliation(s)
- Shinya Maekawa
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, 1110, Shimokato, Chuo, Yamanashi, 409-3898, Japan.
| | - Nobuyuki Enomoto
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, 1110, Shimokato, Chuo, Yamanashi, 409-3898, Japan
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5
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Orita N, Shimakami T, Sunagozaka H, Horii R, Nio K, Terashima T, Iida N, Kitahara M, Takatori H, Kawaguchi K, Kitamura K, Arai K, Yamashita T, Sakai Y, Yamashita T, Mizukoshi E, Honda M, Kaneko S. Three renal failure cases successfully treated with ombitasvir/paritaprevir/ritonavir for genotype 1b hepatitis C virus reinfection after liver transplantation. Clin J Gastroenterol 2018; 12:63-70. [PMID: 29995231 DOI: 10.1007/s12328-018-0884-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 07/04/2018] [Indexed: 01/16/2023]
Abstract
We report three cases of genotype 1b hepatitis C virus (HCV) reinfection after liver transplantation. When antiviral treatment was considered, all three patients had renal dysfunction and had been treated with immunosuppressive agents for a long time; one with tacrolimus (TAC) and the others with cyclosporine A (CyA). Therefore, the possible antiviral regimens among direct-acting antivirals (DAA) were limited and so we treated all three patients with ombitasvir/paritaprevir/ritonavir (OBV/PTV/r). Because ritonavir is known to markedly increase the blood concentration of TAC and CyA through drug-drug interactions, close monitoring of blood concentrations of TAC or CyA and dose adjustments of immunosuppressive agents were needed. Sustained virus response was achieved in all the patients treated, and there were no adverse effects or transplant rejection. OBV/PTV/r might be a useful DAA regimen for patients with genotype 1 HCV reinfection in the setting of renal dysfunction.
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Affiliation(s)
- Noriaki Orita
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Tetsuro Shimakami
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan.
| | - Hajime Sunagozaka
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Rika Horii
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Kouki Nio
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Tekeshi Terashima
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Noriho Iida
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Masaaki Kitahara
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Hajime Takatori
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Kazunori Kawaguchi
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Kazuya Kitamura
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Kuniaki Arai
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Taro Yamashita
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Yoshio Sakai
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Tatsuya Yamashita
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Eishiro Mizukoshi
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Masao Honda
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan
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6
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Grottenthaler JM, Werner CR, Steurer M, Spengler U, Berg T, Engelmann C, Wedemeyer H, von Hahn T, Stremmel W, Pathil A, Seybold U, Schott E, Blessin U, Sarrazin C, Welker MW, Harrer E, Scholten S, Hinterleitner C, Lauer UM, Malek NP, Berg CP. Successful direct acting antiviral (DAA) treatment of HCV/HIV-coinfected patients before and after liver transplantation. PLoS One 2018; 13:e0197544. [PMID: 29874250 PMCID: PMC5991346 DOI: 10.1371/journal.pone.0197544] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 05/03/2018] [Indexed: 12/15/2022] Open
Abstract
Objectives The aim of this multicenter retrospective study was to investigate safety and efficacy of direct acting antiviral (DAA) treatment in the rare subgroup of patients with HCV/HIV-coinfection and advanced liver cirrhosis on the liver transplant waiting list or after liver transplantation, respectively. Methods When contacting 54 German liver centers (including all 23 German liver transplant centers), 12 HCV/HIV-coinfected patients on antiretroviral combination therapy were reported having received additional DAA therapy while being on the waiting list for liver transplantation (patient characteristics: Child-Pugh A (n = 6), B (n = 5), C (n = 1); MELD range 7–21; HCC (n = 2); HCV genotype 1a (n = 8), 1b (n = 2), 4 (n = 2)). Furthermore, 2 HCV/HIV-coinfected patients were denoted having received DAA therapy after liver transplantation (characteristics: HCV genotype 1a (n = 1), 4 (n = 1)). Results Applied DAA regimens were SOF/DAC (n = 7), SOF/LDV/RBV (n = 3), SOF/RBV (n = 3), PTV/r/OBV/DSV (n = 1), or PTV/r/OBV/DSV/RBV (n = 1), respectively. All patients achieved SVR 12, in the end. In one patient, HCV relapse occurred after 24 weeks of SOF/DAC therapy; subsequent treatment with 12 weeks PTV/r/OBV/DSV achieved SVR 12. One patient underwent liver transplantation while on DAA treatment. Analysis of liver function revealed either stable parameters or even significant improvement during DAA therapy and in follow-up. MELD scores were found to improve in 9/13 therapies in patients on the waiting list for liver transplantation; in only 2 patients a moderate increase of MELD scores persisted at the end of follow-up. Conclusion DAA treatment was safe and highly effective in this nation-wide cohort of patients with HCV/HIV-coinfection awaiting liver transplantation or being transplanted.
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Affiliation(s)
- Julia M. Grottenthaler
- Department of Gastroenterology, Hepatology, and Infectiology, University Hospital Tuebingen, Tuebingen, Germany
- German Center for Infection Research (DZIF) partner site, Tuebingen, Bonn, Hannover, Heidelberg, Munich, Germany
| | - Christoph R. Werner
- Department of Gastroenterology, Hepatology, and Infectiology, University Hospital Tuebingen, Tuebingen, Germany
- German Center for Infection Research (DZIF) partner site, Tuebingen, Bonn, Hannover, Heidelberg, Munich, Germany
| | - Martina Steurer
- Department of Gastroenterology, Hepatology, and Infectiology, University Hospital Tuebingen, Tuebingen, Germany
- German Center for Infection Research (DZIF) partner site, Tuebingen, Bonn, Hannover, Heidelberg, Munich, Germany
| | - Ulrich Spengler
- German Center for Infection Research (DZIF) partner site, Tuebingen, Bonn, Hannover, Heidelberg, Munich, Germany
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Thomas Berg
- Division of Gastroenterology and Hepatology, University Hospital Leipzig, Leipzig, Germany
| | - Cornelius Engelmann
- Division of Gastroenterology and Hepatology, University Hospital Leipzig, Leipzig, Germany
| | - Heiner Wedemeyer
- German Center for Infection Research (DZIF) partner site, Tuebingen, Bonn, Hannover, Heidelberg, Munich, Germany
- Department of Gastroenterology, Hepatology, and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany
| | - Thomas von Hahn
- German Center for Infection Research (DZIF) partner site, Tuebingen, Bonn, Hannover, Heidelberg, Munich, Germany
- Department of Gastroenterology, Hepatology, and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany
| | - Wolfgang Stremmel
- German Center for Infection Research (DZIF) partner site, Tuebingen, Bonn, Hannover, Heidelberg, Munich, Germany
- Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany
| | - Anita Pathil
- German Center for Infection Research (DZIF) partner site, Tuebingen, Bonn, Hannover, Heidelberg, Munich, Germany
- Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany
| | - Ulrich Seybold
- German Center for Infection Research (DZIF) partner site, Tuebingen, Bonn, Hannover, Heidelberg, Munich, Germany
- Division of Infectious Diseases, Medizinische Poliklinik-Innenstadt, University of Munich, Munich, Germany
| | - Eckart Schott
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Usha Blessin
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Christoph Sarrazin
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany
| | - Martin-Walter Welker
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany
| | - Ellen Harrer
- Department of Internal Medicine 3, Institute of Clinical Immunology, University Hospital Erlangen, Erlangen, Germany
| | | | - Clemens Hinterleitner
- German Center for Infection Research (DZIF) partner site, Tuebingen, Bonn, Hannover, Heidelberg, Munich, Germany
- Department of Medical Oncology, Haematology, Immunology, Rheumatology and Pulmology, University Hospital Tuebingen, Tuebingen, Germany
| | - Ulrich M. Lauer
- German Center for Infection Research (DZIF) partner site, Tuebingen, Bonn, Hannover, Heidelberg, Munich, Germany
- Department of Clinical Tumor Biology, University Hospital Tuebingen, Tuebingen, Germany
| | - Nisar P. Malek
- Department of Gastroenterology, Hepatology, and Infectiology, University Hospital Tuebingen, Tuebingen, Germany
- German Center for Infection Research (DZIF) partner site, Tuebingen, Bonn, Hannover, Heidelberg, Munich, Germany
| | - Christoph P. Berg
- Department of Gastroenterology, Hepatology, and Infectiology, University Hospital Tuebingen, Tuebingen, Germany
- German Center for Infection Research (DZIF) partner site, Tuebingen, Bonn, Hannover, Heidelberg, Munich, Germany
- * E-mail:
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7
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Sáez-González E, Vinaixa C, San Juan F, Hontangas V, Benlloch S, Aguilera V, Rubín A, García M, Prieto M, López-Andujar R, Berenguer M. Impact of hepatitis C virus (HCV) antiviral treatment on the need for liver transplantation (LT). Liver Int 2018; 38:1022-1027. [PMID: 29105320 DOI: 10.1111/liv.13618] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 10/26/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND Therapies for hepatitis C virus (HCV) infection have revolutionized the treatment of patients with chronic HCV infection. The effect of these therapies on the epidemiology of liver transplantation (LT) has yet to be elucidated. AIM To establish whether the indications for LT have changed as a result of the introduction of new therapies for HCV. MATERIALS AND METHODS We conducted a retrospective study based on a prospectively maintained registry of patients who undergo LT at La Fe Hospital in Valencia from 1997 to 2016. An analysis of outcome measures over time stratified by LT indications was performed. RESULTS From January 1997 to December 2016, 2379 patients were listed for LT. Of these, 1113 (47%) were listed for HCV cirrhosis±hepatocellular carcinoma (HCC). This percentage varied significantly over time declining from 48.8% in the 1997-2009 initial period (IFN-based regimens) to 33% in the 2014-2016 final period (DAAs regimens) (P = .03). However, during that period, the proportion of those included in the waiting list (WL) due to HCV-HCC increased significantly (P = .001). In addition, among HCV-positive waitlisted patients with decompensated cirrhosis without HCC, the proportion of those with an HCV-alcohol mixed etiology also increased significantly over time (P = .001). Of all HCV-positive waitlisted patients, 203 were eventually removed from the WL due to either clinical improvement (n = 77) or more frequently worsening/death (n = 126). CONCLUSIONS The proportion of patients wait-listed for LT for decompensated HCV cirrhosis has significantly decreased over time. These changes are possibly related to the large-scale use of direct-acting antivirals.
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Affiliation(s)
- Esteban Sáez-González
- Department of Gastroenterology, Hepatology and Liver Transplantation Unit, Hospital Universitari i Politècnic La Fe, Valencia, Spain
| | - Carmen Vinaixa
- Department of Gastroenterology, Hepatology and Liver Transplantation Unit, Hospital Universitari i Politècnic La Fe, Valencia, Spain.,Instituto de Investigación Sanitaria (IIS La Fe), Hospital Universitari i Politècnic La Fe, Valencia, Spain
| | - Fernando San Juan
- Unit of Hepato-Biliary-Pancreatic Surgery and Transplantation, Hospital Universitari i Politècnic La Fe, Valencia, Spain
| | - Vanesa Hontangas
- Department of Gastroenterology, Hepatology and Liver Transplantation Unit, Hospital Universitari i Politècnic La Fe, Valencia, Spain.,Instituto de Investigación Sanitaria (IIS La Fe), Hospital Universitari i Politècnic La Fe, Valencia, Spain
| | - Salvador Benlloch
- Department of Gastroenterology, Hepatology and Liver Transplantation Unit, Hospital Universitari i Politècnic La Fe, Valencia, Spain.,Instituto de Investigación Sanitaria (IIS La Fe), Hospital Universitari i Politècnic La Fe, Valencia, Spain.,Networking Biomedical Research Centre in Hepatic and Digestive Diseases (CIBEREHD), Valencia, Spain
| | - Victoria Aguilera
- Department of Gastroenterology, Hepatology and Liver Transplantation Unit, Hospital Universitari i Politècnic La Fe, Valencia, Spain.,Instituto de Investigación Sanitaria (IIS La Fe), Hospital Universitari i Politècnic La Fe, Valencia, Spain.,Networking Biomedical Research Centre in Hepatic and Digestive Diseases (CIBEREHD), Valencia, Spain
| | - Angel Rubín
- Department of Gastroenterology, Hepatology and Liver Transplantation Unit, Hospital Universitari i Politècnic La Fe, Valencia, Spain.,Instituto de Investigación Sanitaria (IIS La Fe), Hospital Universitari i Politècnic La Fe, Valencia, Spain
| | - María García
- Department of Gastroenterology, Hepatology and Liver Transplantation Unit, Hospital Universitari i Politècnic La Fe, Valencia, Spain.,Instituto de Investigación Sanitaria (IIS La Fe), Hospital Universitari i Politècnic La Fe, Valencia, Spain
| | - Martín Prieto
- Department of Gastroenterology, Hepatology and Liver Transplantation Unit, Hospital Universitari i Politècnic La Fe, Valencia, Spain.,Networking Biomedical Research Centre in Hepatic and Digestive Diseases (CIBEREHD), Valencia, Spain
| | - Rafa López-Andujar
- Unit of Hepato-Biliary-Pancreatic Surgery and Transplantation, Hospital Universitari i Politècnic La Fe, Valencia, Spain
| | - Marina Berenguer
- Department of Gastroenterology, Hepatology and Liver Transplantation Unit, Hospital Universitari i Politècnic La Fe, Valencia, Spain.,Instituto de Investigación Sanitaria (IIS La Fe), Hospital Universitari i Politècnic La Fe, Valencia, Spain.,Networking Biomedical Research Centre in Hepatic and Digestive Diseases (CIBEREHD), Valencia, Spain.,Department of Medicine, Universitat de València, Valencia, Spain
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8
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Impact of sustained virologic response on short-term clinical outcomes in hepatitis C-related cirrhosis. Eur J Gastroenterol Hepatol 2018; 30:296-301. [PMID: 29200006 DOI: 10.1097/meg.0000000000001032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Hepatitis C virus (HCV) is a common cause of cirrhosis, leading to increased morbidity and mortality. Treatment of the underlying etiology has been shown to improve fibrosis and cirrhosis. AIM We sought to evaluate the impact of a sustained virologic response on liver chemistries, model for end stage liver disease (MELD) score, Child-Pugh-Turcotte score (CPT), and fibrosis 4 score (FIB4) in patients with liver cirrhosis secondary to HCV with portal hypertension, with or without decompensation. METHODS Patients with HCV seen in our transplant clinic between June 2013 and September 2015 were identified using ICD-9 code 573.3. Charts were reviewed retrospectively. RESULTS We collected data from 92 patients with a mean pretreatment MELD score of 9.16±2.98. The most common genotype was Ia, n=79 (86%). The mean duration of follow-up was 7.52±2.25 months. Transaminitis improved significantly at follow-up versus pretreatment [mean aspartate transaminase from 81.2±62.9 to 32.4±12.0 (P<0.0001); alanine transaminase 74.7±77.8 to 27.7±19.4 (P<0.0001)]. Albumin, bilirubin, and α-fetoprotein improved significantly. MELD scores improved in patients with pretreatment scores greater than 10 (P<0.0003), but not in patients with pretreatment scores less than 10 (P=0.501). The CPT score decreased from 6.1±0.9 to 5.8±0.9 (P<0.0024). The FIB4 score improved significantly in patients with baseline FIB4 more than 3.24, but not with higher baseline FIB4. CONCLUSION Use of direct antivirals in patients with decompensated cirrhosis because of HCV leads to improved MELD, FIB4, and CPT scores.
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9
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Cholankeril G, Yoo ER, Hu M, Gadiparthi C, Khan MA, Perumpail RB, Bonham CA, Ahmed A. Rates of liver retransplantation in the United States are declining in the era of direct-acting antiviral agents. J Viral Hepat 2017; 24:1194-1195. [PMID: 28685914 DOI: 10.1111/jvh.12750] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2017] [Accepted: 05/30/2017] [Indexed: 12/09/2022]
Affiliation(s)
- G Cholankeril
- Division of Gastroenterology and Hepatology, University of Tennessee Health Sciences Center, Memphis, TN, USA
| | - E R Yoo
- Department of Medicine, University of Illinois College of Medicine, Chicago, IL, USA
| | - M Hu
- Department of Biostatistics, Brown University School of Public Health, Providence, RI, USA
| | - C Gadiparthi
- Division of Gastroenterology and Hepatology, University of Tennessee Health Sciences Center, Memphis, TN, USA
| | - M A Khan
- Division of Gastroenterology and Hepatology, University of Tennessee Health Sciences Center, Memphis, TN, USA
| | - R B Perumpail
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - C A Bonham
- Division of Abdominal Transplantation, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - A Ahmed
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
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10
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Jakobsen JC, Nielsen EE, Feinberg J, Katakam KK, Fobian K, Hauser G, Poropat G, Djurisic S, Weiss KH, Bjelakovic M, Bjelakovic G, Klingenberg SL, Liu JP, Nikolova D, Koretz RL, Gluud C, Cochrane Hepato‐Biliary Group. Direct-acting antivirals for chronic hepatitis C. Cochrane Database Syst Rev 2017; 9:CD012143. [PMID: 28922704 PMCID: PMC6484376 DOI: 10.1002/14651858.cd012143.pub3] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Millions of people worldwide suffer from hepatitis C, which can lead to severe liver disease, liver cancer, and death. Direct-acting antivirals (DAAs), e.g. sofosbuvir, are relatively new and expensive interventions for chronic hepatitis C, and preliminary results suggest that DAAs may eradicate hepatitis C virus (HCV) from the blood (sustained virological response). Sustained virological response (SVR) is used by investigators and regulatory agencies as a surrogate outcome for morbidity and mortality, based solely on observational evidence. However, there have been no randomised trials that have validated that usage. OBJECTIVES To assess the benefits and harms of DAAs in people with chronic HCV. SEARCH METHODS We searched for all published and unpublished trials in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, LILACS, and BIOSIS; the Chinese Biomedical Literature Database (CBM), China Network Knowledge Information (CNKI), the Chinese Science Journal Database (VIP), Google Scholar, The Turning Research into Practice (TRIP) Database, ClinicalTrials.gov, European Medicines Agency (EMA) (www.ema.europa.eu/ema/), WHO International Clinical Trials Registry Platform (www.who.int/ictrp), the Food and Drug Administration (FDA) (www.fda.gov), and pharmaceutical company sources for ongoing or unpublished trials. Searches were last run in October 2016. SELECTION CRITERIA Randomised clinical trials comparing DAAs versus no intervention or placebo, alone or with co-interventions, in adults with chronic HCV. We included trials irrespective of publication type, publication status, and language. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. Our primary outcomes were hepatitis C-related morbidity, serious adverse events, and health-related quality of life. Our secondary outcomes were all-cause mortality, ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, hepatocellular carcinoma, non-serious adverse events (each reported separately), and SVR. We systematically assessed risks of bias, performed Trial Sequential Analysis, and followed an eight-step procedure to assess thresholds for statistical and clinical significance. We evaluated the overall quality of the evidence, using GRADE. MAIN RESULTS We included a total of 138 trials randomising a total of 25,232 participants. The trials were generally short-term trials and designed primarily to assess the effect of treatment on SVR. The trials evaluated 51 different DAAs. Of these, 128 trials employed matching placebo in the control group. All included trials were at high risk of bias. Eighty-four trials involved DAAs on the market or under development (13,466 participants). Fifty-seven trials administered DAAs that were discontinued or withdrawn from the market. Study populations were treatment-naive in 95 trials, had been exposed to treatment in 17 trials, and comprised both treatment-naive and treatment-experienced individuals in 24 trials. The HCV genotypes were genotype 1 (119 trials), genotype 2 (eight trials), genotype 3 (six trials), genotype 4 (nine trials), and genotype 6 (one trial). We identified two ongoing trials.We could not reliably determine the effect of DAAs on the market or under development on our primary outcome of hepatitis C-related morbidity or all-cause mortality. There were no data on hepatitis C-related morbidity and only limited data on mortality from 11 trials (DAA 15/2377 (0.63%) versus control 1/617 (0.16%); OR 3.72, 95% CI 0.53 to 26.18, very low-quality evidence). We did not perform Trial Sequential Analysis on this outcome.There is very low quality evidence that DAAs on the market or under development do not influence serious adverse events (DAA 5.2% versus control 5.6%; OR 0.93, 95% CI 0.75 to 1.15 , 15,817 participants, 43 trials). The Trial Sequential Analysis showed that there was sufficient information to rule out that DAAs reduce the relative risk of a serious adverse event by 20% when compared with placebo. The only DAA that showed a lower risk of serious adverse events when meta-analysed separately was simeprevir (OR 0.62, 95% CI 0.45 to 0.86). However, Trial Sequential Analysis showed that there was not enough information to confirm or reject a relative risk reduction of 20%, and when one trial with an extreme result was excluded, the meta-analysis result showed no evidence of a difference.DAAs on the market or under development may reduce the risk of no SVR from 54.1% in untreated people to 23.8% in people treated with DAA (RR 0.44, 95% CI 0.37 to 0.52, 6886 participants, 32 trials, low quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.Only 1/84 trials on the market or under development assessed the effects of DAAs on health-related quality of life (SF-36 mental score and SF-36 physical score).There was insufficient evidence from trials on withdrawn or discontinued DAAs to determine their effect on hepatitis C-related morbidity and all-cause mortality (OR 0.64, 95% CI 0.23 to 1.79; 5 trials, very low-quality evidence). However, these DAAs seemed to increase the risk of serious adverse events (OR 1.45, 95% CI 1.22 to 1.73; 29 trials, very low-quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.None of the 138 trials provided useful data to assess the effects of DAAs on the remaining secondary outcomes (ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, and hepatocellular carcinoma). AUTHORS' CONCLUSIONS The evidence for our main outcomes of interest come from short-term trials, and we are unable to determine the effect of long-term treatment with DAAs. The rates of hepatitis C morbidity and mortality observed in the trials are relatively low and we are uncertain as to how DAAs affect this outcome. Overall, there is very low quality evidence that DAAs on the market or under development do not influence serious adverse events. There is insufficient evidence to judge if DAAs have beneficial or harmful effects on other clinical outcomes for chronic HCV. Simeprevir may have beneficial effects on risk of serious adverse event. In all remaining analyses, we could neither confirm nor reject that DAAs had any clinical effects. DAAs may reduce the number of people with detectable virus in their blood, but we do not have sufficient evidence from randomised trials that enables us to understand how SVR affects long-term clinical outcomes. SVR is still an outcome that needs proper validation in randomised clinical trials.
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Affiliation(s)
- Janus C Jakobsen
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenSjællandDenmarkDK‐2100
- Holbaek HospitalDepartment of CardiologyHolbaekDenmark4300
| | - Emil Eik Nielsen
- Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention ResearchBlegdamsvej 9CopenhagenDenmark2100
| | - Joshua Feinberg
- Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812Blegdamsvej 9CopenhagenDenmark2100
| | - Kiran Kumar Katakam
- Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812Blegdamsvej 9CopenhagenDenmark2100
| | - Kristina Fobian
- Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention ResearchBlegdamsvej 9CopenhagenDenmark2100
| | - Goran Hauser
- Clinical Hospital Centre RijekaDepartment of GastroenterologyKresimirova 42RijekaCroatia51 000
| | - Goran Poropat
- Clinical Hospital Centre RijekaDepartment of GastroenterologyKresimirova 42RijekaCroatia51 000
| | - Snezana Djurisic
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagenDenmark
| | - Karl Heinz Weiss
- Heidelberg University HospitalInternal Medicine IV: Gastroenterology, Infectious Diseases, ToxicologyIm Neuenheimer Feld 410HeidelbergGermanyD‐69120
| | - Milica Bjelakovic
- University of NisMedical FacultyBoulevard Dr Zorana Djindjica 81NisSerbia18000
| | - Goran Bjelakovic
- Medical Faculty, University of NisDepartment of Internal MedicineZorana Djindjica 81NisSerbia18000
| | - Sarah Louise Klingenberg
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenSjællandDenmarkDK‐2100
| | - Jian Ping Liu
- Beijing University of Chinese MedicineCentre for Evidence‐Based Chinese Medicine11 Bei San Huan Dong Lu, Chaoyang DistrictBeijingChina100029
| | - Dimitrinka Nikolova
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenSjællandDenmarkDK‐2100
| | | | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenSjællandDenmarkDK‐2100
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11
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Jakobsen JC, Nielsen EE, Feinberg J, Katakam KK, Fobian K, Hauser G, Poropat G, Djurisic S, Weiss KH, Bjelakovic M, Bjelakovic G, Klingenberg SL, Liu JP, Nikolova D, Koretz RL, Gluud C. Direct-acting antivirals for chronic hepatitis C. Cochrane Database Syst Rev 2017; 9:CD012143. [PMID: 28922704 PMCID: PMC6484383 DOI: 10.1002/14651858.cd012143.pub2] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Millions of people worldwide suffer from hepatitis C, which can lead to severe liver disease, liver cancer, and death. Direct-acting antivirals (DAAs), e.g. sofosbuvir, are relatively new and expensive interventions for chronic hepatitis C, and preliminary results suggest that DAAs may eradicate hepatitis C virus (HCV) from the blood (sustained virological response). Sustained virological response (SVR) is used by investigators and regulatory agencies as a surrogate outcome for morbidity and mortality, based solely on observational evidence. However, there have been no randomised trials that have validated that usage. OBJECTIVES To assess the benefits and harms of DAAs in people with chronic HCV. SEARCH METHODS We searched for all published and unpublished trials in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, LILACS, and BIOSIS; the Chinese Biomedical Literature Database (CBM), China Network Knowledge Information (CNKI), the Chinese Science Journal Database (VIP), Google Scholar, The Turning Research into Practice (TRIP) Database, ClinicalTrials.gov, European Medicines Agency (EMA) (www.ema.europa.eu/ema/), WHO International Clinical Trials Registry Platform (www.who.int/ictrp), the Food and Drug Administration (FDA) (www.fda.gov), and pharmaceutical company sources for ongoing or unpublished trials. Searches were last run in October 2016. SELECTION CRITERIA Randomised clinical trials comparing DAAs versus no intervention or placebo, alone or with co-interventions, in adults with chronic HCV. We included trials irrespective of publication type, publication status, and language. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. Our primary outcomes were hepatitis C-related morbidity, serious adverse events, and health-related quality of life. Our secondary outcomes were all-cause mortality, ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, hepatocellular carcinoma, non-serious adverse events (each reported separately), and SVR. We systematically assessed risks of bias, performed Trial Sequential Analysis, and followed an eight-step procedure to assess thresholds for statistical and clinical significance. We evaluated the overall quality of the evidence, using GRADE. MAIN RESULTS We included a total of 138 trials randomising a total of 25,232 participants. The trials were generally short-term trials and designed primarily to assess the effect of treatment on SVR. The trials evaluated 51 different DAAs. Of these, 128 trials employed matching placebo in the control group. All included trials were at high risk of bias. Eighty-four trials involved DAAs on the market or under development (13,466 participants). Fifty-seven trials administered DAAs that were discontinued or withdrawn from the market. Study populations were treatment-naive in 95 trials, had been exposed to treatment in 17 trials, and comprised both treatment-naive and treatment-experienced individuals in 24 trials. The HCV genotypes were genotype 1 (119 trials), genotype 2 (eight trials), genotype 3 (six trials), genotype 4 (nine trials), and genotype 6 (one trial). We identified two ongoing trials.We could not reliably determine the effect of DAAs on the market or under development on our primary outcome of hepatitis C-related morbidity or all-cause mortality. There were no data on hepatitis C-related morbidity and only limited data on mortality from 11 trials (DAA 15/2377 (0.63%) versus control 1/617 (0.16%); OR 3.72, 95% CI 0.53 to 26.18, very low-quality evidence). We did not perform Trial Sequential Analysis on this outcome.There is very low quality evidence that DAAs on the market or under development do not influence serious adverse events (DAA 5.2% versus control 5.6%; OR 0.93, 95% CI 0.75 to 1.15 , 15,817 participants, 43 trials). The Trial Sequential Analysis showed that there was sufficient information to rule out that DAAs reduce the relative risk of a serious adverse event by 20% when compared with placebo. The only DAA that showed a lower risk of serious adverse events when meta-analysed separately was simeprevir (OR 0.62, 95% CI 0.45 to 0.86). However, Trial Sequential Analysis showed that there was not enough information to confirm or reject a relative risk reduction of 20%, and when one trial with an extreme result was excluded, the meta-analysis result showed no evidence of a difference.DAAs on the market or under development may reduce the risk of no SVR from 54.1% in untreated people to 23.8% in people treated with DAA (RR 0.44, 95% CI 0.37 to 0.52, 6886 participants, 32 trials, low quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.Only 1/84 trials on the market or under development assessed the effects of DAAs on health-related quality of life (SF-36 mental score and SF-36 physical score).There was insufficient evidence from trials on withdrawn or discontinued DAAs to determine their effect on hepatitis C-related morbidity and all-cause mortality (OR 0.64, 95% CI 0.23 to 1.79; 5 trials, very low-quality evidence). However, these DAAs seemed to increase the risk of serious adverse events (OR 1.45, 95% CI 1.22 to 1.73; 29 trials, very low-quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.None of the 138 trials provided useful data to assess the effects of DAAs on the remaining secondary outcomes (ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, and hepatocellular carcinoma). AUTHORS' CONCLUSIONS The evidence for our main outcomes of interest come from short-term trials, and we are unable to determine the effect of long-term treatment with DAAs. The rates of hepatitis C morbidity and mortality observed in the trials are relatively low and we are uncertain as to how DAAs affect this outcome. Overall, there is very low quality evidence that DAAs on the market or under development do not influence serious adverse events. There is insufficient evidence to judge if DAAs have beneficial or harmful effects on other clinical outcomes for chronic HCV. Simeprevir may have beneficial effects on risk of serious adverse event. In all remaining analyses, we could neither confirm nor reject that DAAs had any clinical effects. DAAs may reduce the number of people with detectable virus in their blood, but we do not have sufficient evidence from randomised trials that enables us to understand how SVR affects long-term clinical outcomes. SVR is still an outcome that needs proper validation in randomised clinical trials.
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Affiliation(s)
| | - Emil Eik Nielsen
- Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention ResearchBlegdamsvej 9CopenhagenDenmark2100
| | - Joshua Feinberg
- Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention ResearchBlegdamsvej 9CopenhagenDenmark2100
| | - Kiran Kumar Katakam
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalBlegdamsvej 9CopenhagenDenmark2100
| | - Kristina Fobian
- Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention ResearchBlegdamsvej 9CopenhagenDenmark2100
| | - Goran Hauser
- Clinical Hospital Centre RijekaDepartment of GastroenterologyKresimirova 42RijekaCroatia51 000
| | - Goran Poropat
- Clinical Hospital Centre RijekaDepartment of GastroenterologyKresimirova 42RijekaCroatia51 000
| | - Snezana Djurisic
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalBlegdamsvej 9CopenhagenDenmark2100
| | - Karl Heinz Weiss
- Heidelberg University HospitalInternal Medicine IV: Gastroenterology, Infectious Diseases, ToxicologyIm Neuenheimer Feld 410HeidelbergGermanyD‐69120
| | - Milica Bjelakovic
- University of NisMedical FacultyBoulevard Dr Zorana Djindjica 81NisSerbia18000
| | - Goran Bjelakovic
- Medical Faculty, University of NisDepartment of Internal MedicineZorana Djindjica 81NisSerbia18000
| | - Sarah Louise Klingenberg
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | - Jian Ping Liu
- Beijing University of Chinese MedicineCentre for Evidence‐Based Chinese Medicine11 Bei San Huan Dong Lu, Chaoyang DistrictBeijingChina100029
| | - Dimitrinka Nikolova
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | | | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
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12
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Moreno-Planas JM, Larrubia-Marfil JR, Sánchez-Ruano JJ, Morillas-Ariño J, Patón-Arenas R, Sáiz-Chumillas RM, Tébar-Romero E, Lucendo-Villarín A, Gancedo-Bringas P, Solera-Muñoz M, Vicente-Gutiérrez MDM, Martínez-Alfaro E. Influence of baseline MELD score in the efficacy of treatment of hepatitis C with simeprevir and sofosbuvir. Enferm Infecc Microbiol Clin 2017. [PMID: 28641865 DOI: 10.1016/j.eimc.2017.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION There are few published studies on predictors of response to treatment with sofosbuvir and simeprevir in HCV patients. OBJECTIVE The objective of the study was to analyse possible predictors of response to simeprevir (SMV) and sofosbuvir (SOF) in patients infected with hepatitis C genotypes 1 or 4. PATIENTS AND METHODS Prospective observational cohort study in 12 hospitals. The primary efficacy endpoint was SVR rate 12 weeks after end of treatment (SVR12). RESULTS 204 patients (62.3% male, mean age 55 years) were included: 186 (91.2%) genotype 1 (60.3% 1b 25% 1a) and 18 (8.8%) genotype 4. 132 (64.7%) cirrhotic (87.9% Child A), 33 (16.2%) F3, 31 (15.2%) F2, 8 (3.9%) F0-1. 80.8% MELD<10. 93 (45.6%) naive. Ribavirin was added in 68 (33.3%). Mean baseline viral load 2,151,549 IU/ml (SD: 2,391,840). Treatment duration 12 weeks in 93.1%. 4 discontinued therapy: suicide, psychotic attack, hyperbilirubinaemia and liver cancer recurrence. 190 (93.1%) achieved SVR12. There were no differences in SVR12 depending on the genotype, treatment duration, ribavirin use, prior therapy, viral load (VL) or baseline platelets. In univariate analysis, undetectable VL at 4 weeks (p=0.042), absence of cirrhosis (p=0.021), baseline albumin ≥ 4g/dl (p=0.001) and MELD<10 (p<0.0001) were associated with higher SVR12. In multivariate analysis, only baseline MELD score <10 patients had higher SVR12 (p<0.001). CONCLUSIONS The combination of simeprevir and sofosbuvir in patients infected with genotype 1 and 4 hepatitis C is highly effective. It is a safe therapy, especially in patients without ribavirin. This combination was more effective in patients with a MELD score below 10.
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Affiliation(s)
- José María Moreno-Planas
- Servicio de Aparato Digestivo, Complejo Hospitalario Universitario de Albacete, Facultad de Medicina, Universidad de Castilla La Mancha, Albacete, España.
| | - Juan Ramón Larrubia-Marfil
- Servicio de Aparato Digestivo, Hospital Universitario de Guadalajara, Guadalajara, España; Facultad de Medicina, Universidad Alcalá de Henares, Alcalá de Henares, Madrid, España
| | | | - Julia Morillas-Ariño
- Servicio de Aparato Digestivo, Hospital Virgen de la Luz de Cuenca, Cuenca, España
| | - Roberto Patón-Arenas
- Servicio de Aparato Digestivo, Hospital General Universitario de Ciudad Real, Ciudad Real, España
| | | | - Emilia Tébar-Romero
- Servicio de Aparato Digestivo, Hospital de Alcázar de San Juan, Ciudad Real, España
| | | | | | - Mario Solera-Muñoz
- Servicio de Medicina Interna, Hospital de Villarrobledo, Albacete, España
| | - María Del Mar Vicente-Gutiérrez
- Servicio de Aparato Digestivo, Complejo Hospitalario Universitario de Albacete, Universidad de Castilla La Mancha, Albacete, España
| | - Elisa Martínez-Alfaro
- Unidad de Enfermedades Infecciosas, Complejo Hospitalario Universitario de Albacete, Universidad de Castilla La Mancha, Albacete, España
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13
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Abstract
Hepatic retransplantation has been surgically challenging since the beginning of liver transplant. Outcomes have improved over time, but patient survival with retransplant continues to be significantly worse than that of primary transplant. Many studies have focused on factors to predict outcomes. Models have been developed to help predict risk, but the decision for retransplant must be a multidisciplinary transplant team decision. The question of "when is too much?" can be guided by recipient and donor factors but is an ethical decision that must be made by the liver transplant team.
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Affiliation(s)
- Jennifer Berumen
- Department of Abdominal Transplantation and Hepatobiliary Surgery, University of California, San Diego, La Jolla, CA 92037, USA.
| | - Alan Hemming
- Department of Abdominal Transplantation and Hepatobiliary Surgery, University of California, San Diego, La Jolla, CA 92037, USA
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14
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Ponziani FR, Mangiola F, Binda C, Zocco MA, Siciliano M, Grieco A, Rapaccini GL, Pompili M, Gasbarrini A. Future of liver disease in the era of direct acting antivirals for the treatment of hepatitis C. World J Hepatol 2017; 9:352-367. [PMID: 28321272 PMCID: PMC5340991 DOI: 10.4254/wjh.v9.i7.352] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Revised: 10/26/2016] [Accepted: 12/01/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection has been a global health problem for decades, due to the high number of infected people and to the lack of effective and well-tolerated therapies. In the last 3 years, the approval of new direct acting antivirals characterized by high rates of virological clearance and excellent tolerability has dramatically improved HCV infection curability, especially for patients with advanced liver disease and for liver transplant recipients. Long-term data about the impact of the new direct acting antivirals on liver fibrosis and liver disease-related outcomes are not yet available, due to their recent introduction. However, previously published data deriving from the use of pegylated-interferon and ribavirin lead to hypothesizing that we are going to observe, in the future, a reduction in mortality and in the incidence of hepatocellular carcinoma, as well as a regression of fibrosis for people previously affected by hepatitis C. In the liver transplant setting, clinical improvement has already been described after treatment with the new direct acting antivirals, which has often led to patients delisting. In the future, this may hopefully reduce the gap between liver organ request and availability, probably expanding liver transplant indications to other clinical conditions. Therefore, these new drugs are going to change the natural history of HCV-related liver disease and the epidemiology of HCV infection worldwide. However, the global consequences will depend on treatment accessibility and on the number of countries that could afford the use of the new direct acting antivirals.
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Affiliation(s)
- Francesca Romana Ponziani
- Francesca Romana Ponziani, Francesca Mangiola, Cecilia Binda, Maria Assunta Zocco, Massimo Siciliano, Antonio Grieco, Maurizio Pompili, Antonio Gasbarrini, Internal Medicine, Gastroenterology and Hepatology, Catholic University Sacred Heart of Rome, Agostino Gemelli Hospital, 00168 Rome, Italy
| | - Francesca Mangiola
- Francesca Romana Ponziani, Francesca Mangiola, Cecilia Binda, Maria Assunta Zocco, Massimo Siciliano, Antonio Grieco, Maurizio Pompili, Antonio Gasbarrini, Internal Medicine, Gastroenterology and Hepatology, Catholic University Sacred Heart of Rome, Agostino Gemelli Hospital, 00168 Rome, Italy
| | - Cecilia Binda
- Francesca Romana Ponziani, Francesca Mangiola, Cecilia Binda, Maria Assunta Zocco, Massimo Siciliano, Antonio Grieco, Maurizio Pompili, Antonio Gasbarrini, Internal Medicine, Gastroenterology and Hepatology, Catholic University Sacred Heart of Rome, Agostino Gemelli Hospital, 00168 Rome, Italy
| | - Maria Assunta Zocco
- Francesca Romana Ponziani, Francesca Mangiola, Cecilia Binda, Maria Assunta Zocco, Massimo Siciliano, Antonio Grieco, Maurizio Pompili, Antonio Gasbarrini, Internal Medicine, Gastroenterology and Hepatology, Catholic University Sacred Heart of Rome, Agostino Gemelli Hospital, 00168 Rome, Italy
| | - Massimo Siciliano
- Francesca Romana Ponziani, Francesca Mangiola, Cecilia Binda, Maria Assunta Zocco, Massimo Siciliano, Antonio Grieco, Maurizio Pompili, Antonio Gasbarrini, Internal Medicine, Gastroenterology and Hepatology, Catholic University Sacred Heart of Rome, Agostino Gemelli Hospital, 00168 Rome, Italy
| | - Antonio Grieco
- Francesca Romana Ponziani, Francesca Mangiola, Cecilia Binda, Maria Assunta Zocco, Massimo Siciliano, Antonio Grieco, Maurizio Pompili, Antonio Gasbarrini, Internal Medicine, Gastroenterology and Hepatology, Catholic University Sacred Heart of Rome, Agostino Gemelli Hospital, 00168 Rome, Italy
| | - Gian Lodovico Rapaccini
- Francesca Romana Ponziani, Francesca Mangiola, Cecilia Binda, Maria Assunta Zocco, Massimo Siciliano, Antonio Grieco, Maurizio Pompili, Antonio Gasbarrini, Internal Medicine, Gastroenterology and Hepatology, Catholic University Sacred Heart of Rome, Agostino Gemelli Hospital, 00168 Rome, Italy
| | - Maurizio Pompili
- Francesca Romana Ponziani, Francesca Mangiola, Cecilia Binda, Maria Assunta Zocco, Massimo Siciliano, Antonio Grieco, Maurizio Pompili, Antonio Gasbarrini, Internal Medicine, Gastroenterology and Hepatology, Catholic University Sacred Heart of Rome, Agostino Gemelli Hospital, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Francesca Romana Ponziani, Francesca Mangiola, Cecilia Binda, Maria Assunta Zocco, Massimo Siciliano, Antonio Grieco, Maurizio Pompili, Antonio Gasbarrini, Internal Medicine, Gastroenterology and Hepatology, Catholic University Sacred Heart of Rome, Agostino Gemelli Hospital, 00168 Rome, Italy
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15
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ARFI elastography: Changes after direct-acting antiviral treatment in transplanted livers with relapse of hepatitis C virus infection. RADIOLOGIA 2017. [DOI: 10.1016/j.rxeng.2016.12.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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16
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Alfageme Zubillaga M, Fontanilla Echeveste T, Pérez González I, Royuela Vicente A, Duca A, Ruiz Peralbo R, González Hernando C. Elastografía tipo ARFI: modificación tras tratamiento antiviral en el trasplante hepático con recidiva por VHC. RADIOLOGIA 2017; 59:139-146. [PMID: 28214021 DOI: 10.1016/j.rx.2016.12.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Revised: 11/29/2016] [Accepted: 12/30/2016] [Indexed: 02/07/2023]
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17
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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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18
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Kumar S, Deo SV, Altarabsheh SE, Dunlay SM, Sarabu N, Sareyyupoglu B, Elgudin Y, Medalion B, ElAmm C, Ginwalla M, Zacharias M, Benatti R, Oliveira GH, Kilic A, Fonarow GC, Park SJ. Effect of Hepatitis C Positivity on Survival in Adult Patients Undergoing Heart Transplantation (from the United Network for Organ Sharing Database). Am J Cardiol 2016; 118:132-137. [PMID: 27189814 DOI: 10.1016/j.amjcard.2016.04.023] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Revised: 04/13/2016] [Accepted: 04/13/2016] [Indexed: 02/07/2023]
Abstract
Concerns exist regarding orthotropic heart transplantation in hepatitis C virus (HCV) seropositive recipients. Thus, a national registry was accessed to evaluate early and late outcome in HCV seropositive recipients undergoing heart transplant. Retrospective analysis of the United Network for Organ Sharing registry (1991 to 2014) was performed to evaluate recipient profile and clinical outcome of patients with HCV seropositive (HCV +ve) and seronegative (HCV -ve). Adjusted results of early mortality and late survival were compared between cohorts. From 23,507 patients (mean age 52 years; 75% men), 481 (2%) were HCV +ve (mean age 52 years; 77% men). Annual proportion of HCV +ve recipients was comparable over the study period (range 1.3% to 2.7%; p = 0.2). The HCV +ve cohort had more African-American (22% vs 17%; p = 0.01), previous left ventricular assist device utilization (21% vs 14%; p <0.01) and more hepatitis B core Ag+ve recipients (17% vs 5%; p <0.01). However, both cohorts were comparable in terms of extracorporeal membrane oxygenator usage (p = 0.7), inotropic support (p = 0.2), intraaortic balloon pump (p = 0.7) support, serum creatinine (p = 0.7), and serum bilirubin (p = 0.7). Proportion of status 1A patients was similar (24% HCV + vs 21% HCV -); however, wait time for HCV +ve recipients were longer (mean 23 vs 19 days; p <0.01). Among donor variables, age (p = 0.8), hepatitis B status (p = 0.4), and Center for Diseases Control high-risk status (p = 0.9) were comparable in both cohorts. At a median follow-up of 4 years, 67% patients were alive, 28% died, and 1.1% were retransplanted (3.4% missing). Overall survival was worse in the HCV+ cohort (64.3% vs 72.9% and 43.2% vs 55% at 5 and 10 years; p <0.01), respectively. Late renal (odds ratio [OR] 1.2 [1 to 1.6]; p = 0.02) and liver dysfunction (odds ratio 4.5 [1.2 to 15.7]; p = 0.01) occurs more frequently in HCV +ve recipients. On adjusted analysis, HCV seropositivity is associated with poorer survival (hazard ratio for mortality 1.4 [1.1 to 1.6]; p <0.001). In conclusion, a small proportion of patients receiving a heart transplant in the United States have hepatitis C. Despite comparable preoperative hepatic function, hepatitis C seropositive recipients demonstrate poorer long-term survival.
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Affiliation(s)
- Sachin Kumar
- Division of Cardiovascular Surgery, Advanced Heart Failure Program, University of Texas Medical Center, Houston, Texas
| | - Salil V Deo
- Divisions of Cardiovascular Surgery and Cardiology, Harrington Heart and Vascular Institute, University Hospitals, Case Western Reserve University, Cleveland, Ohio.
| | - Salah E Altarabsheh
- Department of Cardiovascular Surgery, Queen Alia Heart Institute, Amman, Jordan
| | | | - Nagaraju Sarabu
- Division of Nephrology and Renal Transplantation, University Hospitals, Case Western Reserve University, Cleveland, Ohio
| | - Basar Sareyyupoglu
- Divisions of Cardiovascular Surgery and Cardiology, Harrington Heart and Vascular Institute, University Hospitals, Case Western Reserve University, Cleveland, Ohio
| | - Yakov Elgudin
- Divisions of Cardiovascular Surgery and Cardiology, Harrington Heart and Vascular Institute, University Hospitals, Case Western Reserve University, Cleveland, Ohio
| | - Benjamin Medalion
- Divisions of Cardiovascular Surgery and Cardiology, Harrington Heart and Vascular Institute, University Hospitals, Case Western Reserve University, Cleveland, Ohio
| | - Chantal ElAmm
- Divisions of Cardiovascular Surgery and Cardiology, Harrington Heart and Vascular Institute, University Hospitals, Case Western Reserve University, Cleveland, Ohio
| | - Mahazarin Ginwalla
- Divisions of Cardiovascular Surgery and Cardiology, Harrington Heart and Vascular Institute, University Hospitals, Case Western Reserve University, Cleveland, Ohio
| | - Michael Zacharias
- Divisions of Cardiovascular Surgery and Cardiology, Harrington Heart and Vascular Institute, University Hospitals, Case Western Reserve University, Cleveland, Ohio
| | - Rodolpho Benatti
- Divisions of Cardiovascular Surgery and Cardiology, Harrington Heart and Vascular Institute, University Hospitals, Case Western Reserve University, Cleveland, Ohio
| | - Guilherme H Oliveira
- Divisions of Cardiovascular Surgery and Cardiology, Harrington Heart and Vascular Institute, University Hospitals, Case Western Reserve University, Cleveland, Ohio
| | - Ahmet Kilic
- Division of Cardiothoracic Surgery, Wexner Medical Center, The Ohio State University, Columbus, Ohio
| | - Gregg C Fonarow
- Division of Cardiology, Ahmanson-UCLA Cardiomyopathy Center, University of California, Los Angeles, Los Angeles, California
| | - Soon J Park
- Divisions of Cardiovascular Surgery and Cardiology, Harrington Heart and Vascular Institute, University Hospitals, Case Western Reserve University, Cleveland, Ohio
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Wirth TC, Manns MP. The impact of the revolution in hepatitis C treatment on hepatocellular carcinoma. Ann Oncol 2016; 27:1467-74. [PMID: 27226385 DOI: 10.1093/annonc/mdw219] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Accepted: 05/18/2016] [Indexed: 12/13/2022] Open
Abstract
Hepatitis C infection represents a global health problem affecting ∼200 million chronically infected patients worldwide. Owing to the development of a fibrogenic and inflammatory micromilieu in the liver, hepatitis C virus (HCV)-infected patients are at a high risk of developing fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The advent of direct-acting antiviral agents (DAAs), however, has spurred a revolution in the treatment of HCV patients with sustained viral response (SVR) rates exceeding 90% in real-life settings. Recent clinical trials suggest that these novel treatments will not only alter the epidemiology of HCV infection but also the incidence of HCV-induced complications including hepatic decompensation, liver transplantation and hepatocarcinogenesis. Here, we summarize data from clinical trials carried out in HCV patients with compensated and decompensated cirrhosis and analyze the impact of viral clearance on HCC development and treatment. Finally, we review and discuss current and future treatment options of HCV patients with HCC in pre- and post-transplantation settings.
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Affiliation(s)
- T C Wirth
- Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover
| | - M P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover German Center for Infectious Diseases (DZIF), Hannover-Braunschweig, Germany
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20
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Song ATW, Sobesky R, Vinaixa C, Dumortier J, Radenne S, Durand F, Calmus Y, Rousseau G, Latournerie M, Feray C, Delvart V, Roche B, Haim-Boukobza S, Roque-Afonso AM, Castaing D, Abdala E, D’Albuquerque LAC, Duclos-Vallée JC, Berenguer M, Samuel D. Predictive factors for survival and score application in liver retransplantation for hepatitis C recurrence. World J Gastroenterol 2016; 22:4547-4558. [PMID: 27182164 PMCID: PMC4858636 DOI: 10.3748/wjg.v22.i18.4547] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Accepted: 01/18/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To identify risk factors associated with survival in patients retransplanted for hepatitis C virus (HCV) recurrence and to apply a survival score to this population.
METHODS: We retrospectively identified 108 patients retransplanted for HCV recurrence in eight European liver transplantation centers (seven in France, one in Spain). Data collection comprised clinical and laboratory variables, including virological and antiviral treatment data. We then analyzed the factors associated with survival in this population. A recently published score that predicts survival in retransplantation in patients with hepatitis C was applied. Because there are currently no uniform recommendations regarding selection of the best candidates for retransplantation in this setting, we also described the clinical characteristics of 164 patients not retransplanted, with F3, F4, or fibrosing cholestatic hepatitis (FCH) post-first graft presenting with hepatic decompensation.
RESULTS: Overall retransplantation patient survival rates were 55%, 47%, and 43% at 3, 5, and 10 years, respectively. Patients who were retransplanted for advanced cirrhosis had survival rates of 59%, 52%, and 49% at 3, 5, and 10 years, while those retransplanted for FCH had survival rates of 34%, 29%, and 11%, respectively. Under multivariate analysis, and adjusting for the center effect and the occurrence of FCH, factors associated with better survival after retransplantation were: negative HCV viremia before retransplantation, antiviral therapy after retransplantation, non-genotype 1, a Model for End-stage Liver Disease (MELD) score < 25 when replaced on the waiting list, and a retransplantation donor age < 60 years. Although the numbers were small, in the context of the new antivirals era, we showed that outcomes in patients who underwent retransplantation with undetectable HCV viremia did not depend on donor age and MELD score. The Andrés score was applied to 102 patients for whom all score variables were available, producing a mean score of 43.4 (SD = 6.6). Survival rates after the date of the first decompensation post-first liver transplantation (LT1) in the liver retransplantation (reLT) group (94 patients decompensated) at 3, 5, and 10 years were 62%, 59%, and 51%, respectively, among 78 retransplanted individuals with advanced cirrhosis, and 42%, 32%, and 16% among 16 retransplanted individuals with FCH. In the non-reLT group with hepatic decompensation, survival rates were 27%, 18%, and 9% at 3, 5, and 10 years, respectively (P < 0.0001). Compared with non-retransplanted patients, retransplanted patients were younger at LT1 (mean age 48 ± 8 years compared to 53 ± 9 years in the no reLT group, P < 0.0001), less likely to have human immunodeficiency virus (HIV) co-infection (4% vs 14% among no reLT patients, P = 0.005), more likely to have received corticosteroid bolus therapy after LT1 (25% in reLT vs 12% in the no reLT group, P = 0.01), and more likely to have presented with sustained virological response (SVR) after the first transplantation (20% in the reLT group vs 7% in the no reLT group, P = 0.028).
CONCLUSION: Antiviral therapy before and after retransplantation had a substantial impact on survival in the context of retransplantation for HCV recurrence, and with the new direct-acting antivirals now available, outcomes should be even better in the future.
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Jakobsen JC, Nielsen EE, Feinberg J, Fobian K, Katakam KK, Hauser G, Poropat G, Djurisic S, Weiss KH, Bjelakovic M, Bjelakovic G, Klingenberg SL, Liu JP, Nikolova D, Koretz RL, Gluud C. Direct-acting antivirals for chronic hepatitis C. THE COCHRANE DATABASE OF SYSTEMATIC REVIEWS 2016. [DOI: 10.1002/14651858.cd012143] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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22
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McConachie SM, Wilhelm SM, Kale-Pradhan PB. New direct-acting antivirals in hepatitis C therapy: a review of sofosbuvir, ledipasvir, daclatasvir, simeprevir, paritaprevir, ombitasvir and dasabuvir. Expert Rev Clin Pharmacol 2016; 9:287-302. [DOI: 10.1586/17512433.2016.1129272] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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