|
1
|
Garbuzenko DV. [The role of antiviral therapy in the management of patients with liver cirrhosis associated with chronic HBV and HCV infection]. Vopr Virusol 2021; 66:331-339. [PMID: 34738448 DOI: 10.36233/0507-4088-70] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 11/04/2021] [Indexed: 12/12/2022]
Abstract
The formation of the liver cirrhosis (LC) is an unfavorable event of the natural history of chronic liver diseases being accompanied by complications that often cause a fatal outcome. The study of the effectiveness of drugs that affect various etiopathogenetic mechanisms of this condition is an urgent problem of modern hepatology.The aim of the review was to show the role of antiviral therapy (AVT) in the management of patients with LC associated with chronic HBV (hepatitis B virus) and HCV (hepatitis C virus) infection.PubMed database, Google Scholar search engine, Cochrane Systematic Reviews, eLIBRARY.RU electronic scientific library, as well as the reference lists of articles were used to search for scientific articles. The relevant objectives of the review of the publications were identified for the period since 2000 up to 2021 by the search queries as following: «liver cirrhosis», «liver fibrosis», «chronic HBV infection», «chronic HCV infection», «portal hypertension», «treatment». The inclusion criteria were restricted to the management of patients with LC associated with chronic HBV and HCV infection.Current guidelines recommend indefinite treatment of patients with HBV-associated LC with nucleos(t)ide analogues regardless of serum HBV DNA levels, while the modern concept of using direct-acting antiviral drug combinations has become the standard treatment for HCV-associated cirrhosis. Studies have shown the ability of AVT to inhibit and reverse fibrotic processes in LC associated with chronic HBV and HCV infection. It has also been reported that HBV/HCV eradication prior to orthotopic liver transplantation improves long-term overall survival.This, in turn, can reduce the severity of portal hypertension and decrease the risk of associated complications, as well as normalize liver function. Thus, ensuring the availability of drugs for those in need of AVT will not only help prevent the development of LC, but also improve the quality of life and increase its expectancy of patients suffering from this disease.
Collapse
Affiliation(s)
- D V Garbuzenko
- FSBEI HE «South Ural State Medical University» of the Ministry of the Health of Russia
| |
Collapse
|
|
2
|
Kumada T, Toyoda H, Yasuda S, Tada T, Tanaka J, Chayama K, Johnson PJ, Irving WL. Comparison of the Prognosis of Decompensated Cirrhosis in Patients with and Without Eradication of Hepatitis C Virus. Infect Dis Ther 2021; 10:1001-1013. [PMID: 33881712 PMCID: PMC8116463 DOI: 10.1007/s40121-021-00441-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 03/24/2021] [Indexed: 01/08/2023] Open
Abstract
Introduction In patients with hepatitis C virus (HCV) infection and decompensated cirrhosis (DC), it is uncertain whether viral clearance is clinically meaningful and whether it decreases liver-related and non-liver-related mortality. The aim of this study was to assess whether viral eradication reduced liver-related and non-liver-related mortality in patients with HCV infection and DC. Methods To clarify the impact of viral eradication on liver-related and non-liver-related mortality, 364 patients with DC who received direct-acting antivirals (DAAs) and achieved sustained virological response (SVR) in the UK (DAA group) were compared with 249 patients with DC who did not receive DAAs and who underwent symptomatic treatment in Japan (non-DAA group). Propensity score matching and inverse probability weighting (IPW) were performed to adjust the baseline characteristics in the DAA and non-DAA groups. Liver-related and non-liver-related mortality were analyzed using the competing risks IPW cumulative incidence functions estimator. Results The cumulative all-cause mortality rate in the DAA group was significantly lower than that in the non-DAA group (p < 0.0001, IPW-adjusted log-rank test). The cumulative incidence rates of both liver-related and non-liver-related mortality were significantly lower in the DAA group than those in the non-DAA group (p < 0.0001 for both). Conclusion DAA-mediated viral eradication reduced not only liver-related mortality but also non-liver-related mortality in patients with HCV infection and DC. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-021-00441-7.
Collapse
Affiliation(s)
- Takashi Kumada
- Department of Nursing, Faculty of Nursing, Gifu Kyoritsu University, 5-50, Kitagata-cho, Ogaki-shi, Gifu-ken, Ogaki, Gifu, 503-8550, Japan.
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Gifu, Japan
| | - Satoshi Yasuda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Gifu, Japan
| | - Toshifumi Tada
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Gifu, Japan
| | - Junko Tanaka
- Department of Epidemiology, Infectious Disease Control, and Prevention, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Institute of Biomedical and Health Sciences, Hiroshima University Hospital, Hiroshima, Japan
| | - Philip J Johnson
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK
| | - William L Irving
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, The University of Nottingham, Nottingham, UK
| |
Collapse
|
|
3
|
Ridziauskas M, Zablockienė B, Jančorienė L, Samuilis A, Zablockis R, Jackevičiūtė A. Assessment of Liver Stiffness Regression and Hepatocellular Carcinoma Risk in Chronic Hepatitis C Patients after Treatment with Direct-Acting Antiviral Drugs. ACTA ACUST UNITED AC 2021; 57:medicina57030210. [PMID: 33652777 PMCID: PMC7996730 DOI: 10.3390/medicina57030210] [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] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 02/20/2021] [Accepted: 02/22/2021] [Indexed: 11/23/2022]
Abstract
Background and Objectives: Chronic hepatitis C virus infection affects about 71 million people worldwide. It is one of the most common chronic liver conditions associated with an increased risk of developing liver cirrhosis and cancer. The aim of this study was to evaluate changes in liver fibrosis and the risk of developing hepatocellular carcinoma after direct-acting antiviral drug therapy, and to assess factors, linked with these outcomes. Materials and Methods: 70 chronic hepatitis C patients were evaluated for factors linked to increased risk of de novo liver cancer and ≥ 20% decrease of ultrasound transient elastography values 12 weeks after the end of treatment. Results: The primary outcome was an improvement of liver stiffness at the end of treatment (p = 0.004), except for patients with diabetes mellitus type 2 (p = 0.49). Logistic regression analysis revealed factors associated with ≥ 20% decrease of liver stiffness values: lower degree of steatosis in liver tissue biopsy (p = 0.053); no history of interferon-based therapy (p = 0.045); elevated liver enzymes (p = 0.023–0.036); higher baseline liver stiffness value (p = 0.045) and absence of splenomegaly (p = 0.035). Hepatocellular carcinoma developed in 4 (5.7%) patients, all with high alpha-fetoprotein values (p = 0.0043) and hypoechoic liver mass (p = 0.0001), three of these patients had diabetes mellitus type 2. Conclusions: Liver stiffness decrease was significant as early as 12 weeks after the end of treatment. Patients with diabetes and advanced liver disease are at higher risk of developing non-regressive fibrosis and hepatocellular carcinoma even after successful treatment.
Collapse
Affiliation(s)
- Martynas Ridziauskas
- Vilnius University Faculty of Medicine, M.K. Ciurlionio 21, LT-03101 Vilnius, Lithuania;
- Correspondence: ; Tel.: +370-606-98744
| | - Birutė Zablockienė
- Center of Infectious Diseases, Vilnius University Hospital Santaros Klinikos, LT-08406 Vilnius, Lithuania; (B.Z.); (L.J.)
- Clinic of Infectious Diseases and Dermatovenerology, Institute of Clinical Medicine, Vilnius University Faculty of Medicine, M.K. Ciurlionio 21, LT-03101 Vilnius, Lithuania
| | - Ligita Jančorienė
- Center of Infectious Diseases, Vilnius University Hospital Santaros Klinikos, LT-08406 Vilnius, Lithuania; (B.Z.); (L.J.)
- Clinic of Infectious Diseases and Dermatovenerology, Institute of Clinical Medicine, Vilnius University Faculty of Medicine, M.K. Ciurlionio 21, LT-03101 Vilnius, Lithuania
| | - Artūras Samuilis
- Center of Radiology and Nuclear Medicine, Vilnius University Hospital Santaros Klinikos, LT-08661 Vilnius, Lithuania;
- Department of Radiology, Nuclear Medicine and Medical Physics, Faculty of Medicine, Vilnius University, M.K. Ciurlionio 21, LT-03101 Vilnius, Lithuania
| | - Rolandas Zablockis
- Center of Pulmonology and Allergology, Vilnius University Hospital Santaros Klinikos, Santariskiu 2, LT-08661 Vilnius, Lithuania;
- Clinic of Chest Diseases, Immunology and Allergology, Faculty of Medicine, Institute of Clinical Medicine, Vilnius University, M.K. Ciurlionio 21, LT-03101 Vilnius, Lithuania
| | - Aušrinė Jackevičiūtė
- Vilnius University Faculty of Medicine, M.K. Ciurlionio 21, LT-03101 Vilnius, Lithuania;
| |
Collapse
|
|
4
|
Laursen TL, Sandahl TD, Kazankov K, George J, Grønbæk H. Liver-related effects of chronic hepatitis C antiviral treatment. World J Gastroenterol 2020; 26:2931-2947. [PMID: 32587440 PMCID: PMC7304101 DOI: 10.3748/wjg.v26.i22.2931] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 03/26/2020] [Accepted: 05/29/2020] [Indexed: 02/06/2023] Open
Abstract
More than five years ago, the treatment of hepatitis C virus infection was revolutionized with the introduction of all-oral direct-acting antiviral (DAA) drugs. They proved highly efficient in curing patients with chronic hepatitis C (CHC), including patients with cirrhosis. The new DAA treatments were alleged to induce significant improvements in clinical outcome and prognosis, but the exact cause of the expected benefit was unclear. Further, little was known about how the underlying liver disease would be affected during and after viral clearance. In this review, we describe and discuss the liver-related effects of the new treatments in regards to both pathophysiological aspects, such as macrophage activation, and the time-dependent effects of therapy, with specific emphasis on inflammation, structural liver changes, and liver function, as these factors are all related to morbidity and mortality in CHC patients. It seems clear that antiviral therapy, especially the achievement of a sustained virologic response has several beneficial effects on liver-related parameters in CHC patients with advanced liver fibrosis or cirrhosis. There seems to be a time-dependent effect of DAA therapy with viral clearance and the resolution of liver inflammation followed by more discrete changes in structural liver lesions. These improvements lead to favorable effects on liver function, followed by an improvement in cognitive dysfunction and portal hypertension. Overall, the data provide knowledge on the several beneficial effects of DAA therapy on liver-related parameters in CHC patients suggesting short- and long-term improvements in the underlying disease with the promise of an improved long-term prognosis.
Collapse
Affiliation(s)
- Tea L Laursen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N DK-8200, Denmark
| | - Thomas D Sandahl
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N DK-8200, Denmark
| | - Konstantin Kazankov
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N DK-8200, Denmark
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital, Sydney NSW 2145, Australia
- University of Sydney, Sydney NSW 2145, Australia
| | - Henning Grønbæk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N DK-8200, Denmark
| |
Collapse
|
|
5
|
Hepatitis C: Does Successful Treatment Alter the Natural History and Quality of Life? Gastroenterol Clin North Am 2020; 49:301-314. [PMID: 32389364 DOI: 10.1016/j.gtc.2020.01.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The cure of chronic hepatitis C infection has a major impact on the morbidity and mortality of infected patients. It is now clear that sustained virologic response improves overall survival and significantly reduces the risk of liver failure, fibrosis progression, need of liver transplantation, and incidence of hepatocellular carcinoma. Moreover, hepatitis C eradication improves a broad range of extrahepatic manifestations, such as dermatologic, neoplastic, cardiovascular, and endocrine, and improves quality of life.
Collapse
|
|
6
|
Silva GF, Andrade VGD, Moreira A. WAITING DAAS LIST MORTALITY IMPACT IN HCV CIRRHOTIC PATIENTS. ARQUIVOS DE GASTROENTEROLOGIA 2019; 55:343-345. [PMID: 30785516 DOI: 10.1590/s0004-2803.201800000-76] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2018] [Accepted: 08/30/2018] [Indexed: 12/18/2022]
Abstract
BACKGROUND The infection for the hepatitis C virus (HCV) is a leading cause of liver-related morbidity and mortality through its evolution to liver cirrhosis, end-stage liver complications and hepatocellular carcinoma. Currently, the new drugs for the HCV infection, based on direct antiviral agents, have changed the outcomes in this setting. OBJECTIVE To assess death incidence, during the wait for the treatment with the new drugs, and to analyze which independent variable (age, sex, ascite, HDA, albumin, α-fetoprotein, platelets and Meld score) had relation with death. METHODS Prospective study with cirrhotic patients by HCV. Inclusion: cirrhotic patients by hepatic biopsy (METAVIR), clinic or image, detectable RNA (HCV). Exclusion: Other stages of hepatic fibrosis and hepatocellular carcinoma. Descriptive statistic in continue variables. Fisher Exact and Kaplan Meier and Cox Regression Analysis to assess the association of variables studied with death. P<0.05. RESULTS A total of 129 patients were included. Of this, 73% were men. Mean age was 57.8±12.1, albumin of 3.5±0.6 mg/dL, platelets of 123.4±59.6 and Meld score of 10.59±3.56. The time of observation was 11.2±3.26 months, and the number of death 9/129 (6,9%). The Kaplan-Meier showed association between death with albumin lower than 2.9 (0.0006), MELD score higher than 15 (0.007) and α-fetoprotein higher than 40 ng/mL (<0.0001). Adjusted Cox Regression Analysis showed that α-fetoprotein higher than 40 ng/ml could be considered an independent risk for death. CONCLUSION We conclude that, patients with advanced cirrhosis should be prioritized for treatment with direct antiviral agents.
Collapse
Affiliation(s)
- Giovanni Faria Silva
- Universidade Estadual Paulista (UNESP), Faculdade de Medicina, Departamento de Clínica Médica, Botucatu, SP, Brasil
| | - Vanessa Gutierrez de Andrade
- Universidade Estadual Paulista (UNESP), Faculdade de Medicina, Departamento de Clínica Médica, Botucatu, SP, Brasil
| | - Alecsandro Moreira
- Universidade Estadual Paulista (UNESP), Faculdade de Medicina, Departamento de Clínica Médica, Botucatu, SP, Brasil
| |
Collapse
|
|
7
|
Giannini EG, Crespi M, Demarzo M, Bodini G, Furnari M, Marabotto E, Torre F, Zentilin P, Savarino V. Improvement in hepatitis C virus patients with advanced, compensated liver disease after sustained virological response to direct acting antivirals. Eur J Clin Invest 2019; 49:e13056. [PMID: 30474209 DOI: 10.1111/eci.13056] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 10/18/2018] [Accepted: 11/20/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND The outcome of patients with chronic hepatitis C virus infection (HCV) and advanced, compensated liver disease after sustained virological response (SVR) to direct-acting antivirals (DAAs) has not yet been completely depicted. We aimed to assess the clinical, biochemical and instrumental outcome of patients with advanced, compensated chronic HCV-related liver disease with DAA-induced SVR to DAAs and who had at least 1-year follow-up. MATERIALS AND METHODS Fifty-two patients with cirrhosis (n = 27) and fibrosis stage F3 (n = 25) followed up for a median of 60 weeks after successful DAA treatment were included. Laboratory work-up, including APRI and FIB-4 scores, liver transient elastography and measurement of the spleen bi-polar diameter were carried out before treatment and at the end of follow-up. RESULTS Liver stiffness decreased (P < 0.0001) from a median baseline of 15.2 kPa (12.0-20.0) to 9.3 kPa (7.5-12.0) at follow-up. A liver stiffness value suggestive of the presence (ie, ≥21.0 kPa) of clinically significant portal hypertension was found in 13 patients (25.0%) at baseline and in seven patients (13.5%) at follow-up (P = 0.037). Both APRI (P < 0.0001) and FIB-4 score (P = 0.025) progressively decreased, while platelet count increased (143 × 109 /L [117-176] to 153 × 109 /L [139-186], P = 0.003), and spleen bi-polar diameter decreased (120 mm [112-123] to 110 mm [102-116], P = 0.0009) from baseline to the end of follow-up. CONCLUSIONS In patients advanced, compensated chronic liver disease, liver stiffness significantly improves in the long-term after SVR, and this improvement is accompanied by an amelioration of indirect indices of liver fibrosis and function, and by a decrease in parameters of portal hypertension.
Collapse
Affiliation(s)
- Edoardo G Giannini
- Gastroenterology Unit, Department of Internal Medicine, Ospedale Policlinico San Martino-IRCCS per l'Oncologia, University of Genoa, Genoa, Italy
| | - Mattia Crespi
- Gastroenterology Unit, Department of Internal Medicine, Ospedale Policlinico San Martino-IRCCS per l'Oncologia, University of Genoa, Genoa, Italy
| | - Mariagiulia Demarzo
- Gastroenterology Unit, Department of Internal Medicine, Ospedale Policlinico San Martino-IRCCS per l'Oncologia, University of Genoa, Genoa, Italy
| | - Giorgia Bodini
- Gastroenterology Unit, Department of Internal Medicine, Ospedale Policlinico San Martino-IRCCS per l'Oncologia, University of Genoa, Genoa, Italy
| | - Manuele Furnari
- Gastroenterology Unit, Department of Internal Medicine, Ospedale Policlinico San Martino-IRCCS per l'Oncologia, University of Genoa, Genoa, Italy
| | - Elisa Marabotto
- Gastroenterology Unit, Department of Internal Medicine, Ospedale Policlinico San Martino-IRCCS per l'Oncologia, University of Genoa, Genoa, Italy
| | - Francesco Torre
- Gastroenterology Unit, Department of Internal Medicine, Ospedale Policlinico San Martino-IRCCS per l'Oncologia, University of Genoa, Genoa, Italy
| | - Patrizia Zentilin
- Gastroenterology Unit, Department of Internal Medicine, Ospedale Policlinico San Martino-IRCCS per l'Oncologia, University of Genoa, Genoa, Italy
| | - Vincenzo Savarino
- Gastroenterology Unit, Department of Internal Medicine, Ospedale Policlinico San Martino-IRCCS per l'Oncologia, University of Genoa, Genoa, Italy
| |
Collapse
|
|
8
|
Mücke MM, Mücke VT, Lange CM, Zeuzem S. Managing hepatitis C in patients with the complications of cirrhosis. Liver Int 2018; 38 Suppl 1:14-20. [PMID: 29427491 DOI: 10.1111/liv.13636] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Accepted: 11/16/2017] [Indexed: 12/17/2022]
Abstract
Direct acting antivirals (DAA) have revolutionized the treatment of hepatitis C virus (HCV). Sustained virological response rates of nearly 100% have become common in the general population. However, physicians face the growing problem of managing HCV in patients with the complications of cirrhosis, eg hepatic decompensation or hepatocellular carcinoma (HCC). Safety and efficacy remain a clinical challenge in these difficult-to-treat patients. This review focuses on the current state of knowledge and treatment regimens in patients with decompensated cirrhosis as well as the potential risk of the development of HCC following DAA therapy.
Collapse
Affiliation(s)
- Marcus M Mücke
- Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt, Germany
| | - Victoria T Mücke
- Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt, Germany
| | - Christian M Lange
- Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt, Germany
| | - Stefan Zeuzem
- Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt, Germany
| |
Collapse
|
|
9
|
Ippolito AM, Iacobellis A, Milella M, Conti F, Messina V, Valvano MR, Niro GA, Morisco F, Barone M, Termite AP, Brancaccio G, Andriulli A. Hepatitis C Virus Clearance in Older Adults. J Am Geriatr Soc 2018; 66:85-91. [PMID: 29135030 DOI: 10.1111/jgs.15140] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVES To determine whether older adults with the hepatitis C virus (HCV) achieve a sustained viral response (SVR) after treatment with direct-acting antiviral therapy. PARTICIPANTS Individuals aged 80 and older with chronic HCV infection (N = 253; n = 213 with cirrhosis, n = 40 with advanced fibrosis). MEASUREMENTS We investigated the efficacy, safety, and global clinical effect of treatment with different combinations of direct antiviral agents (DAAs). Participants with cirrhosis were staged according to Child-Pugh-Turcotte class, Model for End-Stage Liver Disease score, and the D'Amico staging system. The type and number of comorbidities at baseline and hepatic and nonhepatic events during follow-up were registered. RESULTS Ninety-five percent of participants with cirrhosis and 95% of those with advanced fibrosis attained SVR. The rate was independent of sex, HCV genotype, and treatment schedule. During a mean follow-up of 14 ± 4 months (range 5-23 months), 34 events occurred in 27 participants: 10 hepatocellular carcinomas, 12 hepatic decompensations, 9 nonhepatic events, 3 deaths. Multivariate analysis of risk factors for experiencing adverse events during follow up showed that participants in D'Amico Stages 4 and 5, with a baseline serum albumin level of 3.5 mg/dL or less, and 3 or more comorbidities were the most at risk. CONCLUSION In a real-world setting, DAAs are safe and effective in older adults with HCV-related advanced fibrosis or cirrhosis. Individuals with preserved albumin synthesis and fewer than 3 comorbidities at baseline have the most to gain from long-term DAA therapy.
Collapse
Affiliation(s)
- Antonio Massimo Ippolito
- Division of Gastroenterology, Casa Sollievo Sofferenza Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, San Giovanni Rotondo, Italy
| | - Angelo Iacobellis
- Division of Gastroenterology, Casa Sollievo Sofferenza Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, San Giovanni Rotondo, Italy
| | - Michele Milella
- Clinics of Infectious Diseases, University of Bari, Bari, Italy
| | - Fabio Conti
- Centre for the Study of Hepatitis, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Vincenzo Messina
- Infectious and Tropical Diseases Unit, S. Anna and S. Sebastiano Hospital, Caserta, Italy
| | - Maria Rosa Valvano
- Division of Gastroenterology, Casa Sollievo Sofferenza Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, San Giovanni Rotondo, Italy
| | - Grazia Anna Niro
- Division of Gastroenterology, Casa Sollievo Sofferenza Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, San Giovanni Rotondo, Italy
| | - Filomena Morisco
- Division of Gastroenterology, Department of Clinical Medicine and Surgery, Federico II University of Napoli, Naples, Italy
| | - Michele Barone
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, Azienda Ospedaliero Universitaria Policlinico, University of Bari, Bari, Italy
| | | | | | - Angelo Andriulli
- Division of Gastroenterology, Casa Sollievo Sofferenza Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, San Giovanni Rotondo, Italy
| |
Collapse
|
|
10
|
Ji F, Wang W, Dang S, Wang S, Li B, Bai D, Zhao W, Deng H, Tian C, Li Z. Outcomes after sofosbuvir-containing regimens for hepatitis C virus in patients with decompensated cirrhosis: a real-world study. Infect Agent Cancer 2017; 12:48. [PMID: 28924449 PMCID: PMC5598030 DOI: 10.1186/s13027-017-0158-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 09/05/2017] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Direct-acting antivirals have been used for decompensated cirrhotic patients with hepatitis C virus (HCV) infection. However, the benefits in Chinese patients with decompensated cirrhosis are unclear. METHODS Thirty patients with HCV infection and decompensated cirrhosis were administered sofosbuvir-containing regimens at our hospital between April and December 2015. The efficacy and safety of the treatments was determined by sustained virological response at week 12 (SVR 12), change of liver function and adverse events. RESULTS The cohort included 13 treatment-experienced and 17 treatment-naïve patients. A total of 27 patients (90%) achieved SVR 12. No baseline characteristics (sex, age, treatment-experience, genotype, viral load, liver function or splenectomy) was association with achievement of SVR 12. Patients achieved SVR 12 had significantly improved liver function by post-treatment week 12 (P < 0.05). Of the 30 patients, six developed anemia, one developed hepatic decompensation, two developed impaired renal function and one developed a severe upper respiratory tract infection during the treatment. There was no death or HCC development during 12 months of follow-up off-therapy. Two patients (7.4%) with SVR 12 experienced new decompensated episodes during the follow-up. CONCLUSION Sofosbuvir-containing regimens are effective in Chinese HCV patients with decompensated cirrhosis, regardless of baseline characteristics, as demonstrated by a high rate of SVR 12, as well as improvement in liver function. Although antiviral therapy is generally well tolerated, a vigilant monitoring of anemia and renal function should be mandatory.
Collapse
Affiliation(s)
- Fanpu Ji
- Department of Infectious Diseases, Second Affiliated Hospital of Xi’an Jiaotong University, 157 Xi Wu Road, Xi’an, 710004 Shaanxi Province People’s Republic of China
- Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Wenjun Wang
- Department of Infectious Diseases, Second Affiliated Hospital of Xi’an Jiaotong University, 157 Xi Wu Road, Xi’an, 710004 Shaanxi Province People’s Republic of China
| | - Shuangsuo Dang
- Department of Infectious Diseases, Second Affiliated Hospital of Xi’an Jiaotong University, 157 Xi Wu Road, Xi’an, 710004 Shaanxi Province People’s Republic of China
| | - Shengbang Wang
- Department of Infectious Diseases, Second Affiliated Hospital of Xi’an Jiaotong University, 157 Xi Wu Road, Xi’an, 710004 Shaanxi Province People’s Republic of China
| | - Burong Li
- Department of Clinical Laboratory, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Dan Bai
- Department of Biochemistry and Molecular Biology, Medical College of Xi’an Jiaotong University, Xi’an, China
| | - Wenxue Zhao
- Department of Infectious Diseases, Second Affiliated Hospital of Xi’an Jiaotong University, 157 Xi Wu Road, Xi’an, 710004 Shaanxi Province People’s Republic of China
| | - Hong Deng
- Department of Infectious Diseases, Second Affiliated Hospital of Xi’an Jiaotong University, 157 Xi Wu Road, Xi’an, 710004 Shaanxi Province People’s Republic of China
| | - Changyin Tian
- Department of Infectious Diseases, Second Affiliated Hospital of Xi’an Jiaotong University, 157 Xi Wu Road, Xi’an, 710004 Shaanxi Province People’s Republic of China
| | - Zongfang Li
- Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| |
Collapse
|
|
11
|
McDonald SA, Innes HA, Aspinall E, Hayes PC, Alavi M, Valerio H, Goldberg DJ, Hutchinson SJ. Prognosis of 1169 hepatitis C chronically infected patients with decompensated cirrhosis in the predirect-acting antiviral era. J Viral Hepat 2017; 24:295-303. [PMID: 27885753 DOI: 10.1111/jvh.12646] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2016] [Accepted: 10/05/2016] [Indexed: 12/19/2022]
Abstract
At a population level, little is known regarding the risk of liver- and nonliver-related mortality and hospitalization and the development of hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-infected patients with decompensated cirrhosis (DC). This large-scale national record-linkage study estimates these outcomes following first hospital admission for DC. Record-linkages between national HCV diagnosis and clinical databases and the national inpatient hospital episode database and mortality register were conducted to follow-up the disease course of all identified HCV-diagnosed and chronically infected persons. The study population consisted of 1169 HCV chronically infected persons who had a first hospital admission for DC within the period 1994-2013. We observed an overall average annual percentage change of 12.6% in new DC patients (from 63 in 1994-1999 to 541 in 2009-2013), with no evidence for any improvement in the relative risks of liver-related or all-cause death over time. Between 1 January 1994 and 31 May 2014, 722 and 95 DC patients had died of a liver- and a nonliver-related cause, respectively, and 106 patients had a subsequent first admission for HCC. The 5-year cumulative incidence of liver-related mortality, nonliver-related mortality and first subsequent HCC admission was 61.3%, 8.2% and 8.8%, respectively. The health burden in HCV-infected patients associated with development of decompensated cirrhosis has increased dramatically over the last 20 years. Our findings establish the baseline mortality and HCC progression rates in DC patients against which the impact of new antiviral therapies can be measured.
Collapse
Affiliation(s)
- S A McDonald
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK.,Health Protection Scotland, Glasgow, UK
| | - H A Innes
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK.,Health Protection Scotland, Glasgow, UK
| | - E Aspinall
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK.,Health Protection Scotland, Glasgow, UK
| | - P C Hayes
- Royal Infirmary of Edinburgh, Edinburgh, UK
| | - M Alavi
- Health Protection Scotland, Glasgow, UK
| | - H Valerio
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK.,Health Protection Scotland, Glasgow, UK
| | - D J Goldberg
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK.,Health Protection Scotland, Glasgow, UK
| | - S J Hutchinson
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK.,Health Protection Scotland, Glasgow, UK
| |
Collapse
|
|
12
|
van Tilborg M, Maan R, van der Meer AJ, de Knegt RJ. Interferon-free antiviral therapy for chronic hepatitis C among patients in the liver transplant setting. Best Pract Res Clin Gastroenterol 2017. [PMID: 28624110 DOI: 10.1016/j.bpg.2017.04.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Chronic hepatitis C (HCV) infection remains a major public health problem with many infected individuals worldwide. The revolutionary discovery of highly effective direct-acting antivirals (DAAs) makes chronic HCV infection a curable disease, even in patients with advanced liver disease. Liver function may improve shortly after initiation of antiviral therapy in patients on the waiting list and could even obviate the need for transplantation. However, whether these short term benefits also result in a favorable prognosis on the long-term remains to be seen and this fuels the discussion whether DAAs should be used prior to liver transplantation in all patients. Following liver transplantation, DAA treatment is also highly effective so that postponing antiviral treatment to the post-transplant setting may be better for certain patients. Furthermore, the discussion whether HCV positive organ donors should be used now viral eradication is achieved in almost all patients has regained interest.
Collapse
Affiliation(s)
| | - Raoel Maan
- Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
| | | | - Robert J de Knegt
- Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
| |
Collapse
|
|
13
|
Favorable Outcomes of Chinese HCV-Related Cirrhotic Patients with Sustained Virological Response after Pegylated Interferon Plus Ribavirin Treatment. BIOMED RESEARCH INTERNATIONAL 2017; 2017:8061091. [PMID: 28232944 PMCID: PMC5292367 DOI: 10.1155/2017/8061091] [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: 10/20/2016] [Revised: 12/08/2016] [Accepted: 01/04/2017] [Indexed: 02/07/2023]
Abstract
Few studies have conducted follow-up investigations of the clinical course in HCV-related cirrhotic patients who achieved a sustained virological response (SVR) with pegylated interferon plus ribavirin treatment (PegIFN + RBV). We investigated the clinical course and laboratory data in a prospective cohort study enrolling HCV-related cirrhotic patients who received PegIFN + RBV between August 2008 and July 2013 in China. Complete blood counts, liver function tests, and HCV-RNA were serially examined. Liver-related complications were recorded. To detect hepatocellular carcinoma (HCC), alpha-fetoprotein assays, and ultrasound scans were repeated at 6-month intervals. Twenty-five patients were enrolled, including 8 patients with decompensation events before treatment. Eighteen patients achieved SVR with a mean follow-up period of 25.78 months. During the follow-up period, only one patient exhibited HCV-RNA positivity and no decompensation events were detected, but 4 patients developed HCC after SVR. APRI decreased more in patients with SVR than in patients with non-SVR (median, -1.33 versus 0.86, P < 0.001). The albumin levels and platelet counts significantly increased during the follow-up period after SVR (44.27 ± 4.09 versus 42.63 ± 4.37, P = 0.037 and 173.89 ± 87.36 versus 160.11 ± 77.97, P = 0.047). These data indicated that HCV-related cirrhotic patients with SVR after PegIFN + RBV may have a favorable clinical course and improvements in laboratory data. Moreover, HCC should be monitored.
Collapse
|
|
14
|
Gwak GY. [Renewed 2015 Clinical Practice Guidelines for Management of Hepatitis C by Korean Association for the Study of the Liver; What Has Been Changed? - Treatment of Patients with Decompensated Cirrhosis]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2017; 67:137-41. [PMID: 26996183 DOI: 10.4166/kjg.2016.67.3.137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
HCV-related decompensated liver cirrhosis is a life-threatening illness with an average 5-year survival rate of 50%. Because these patients have higher risk of morbidity and mortality including development of hepatocellular carcinoma, the benefits of eradicating the virus may be greater than in those with less-advanced disease. Recently, direct-acting antiviral agents (DAAs) are replacing interferon-based regimens that have serious adverse events and low tolerability in the treatment of HCV infection. Many clinical trials using combination of several DAAs with or without ribavirin are now actively on-going in HCV-related decompensated cirrhosis, and encouraging data are beginning to appear. In this review, recent advances in the treatment of HCV-related decompensated cirrhosis are introduced with special focus on new DAAs.
Collapse
Affiliation(s)
- Geum Youn Gwak
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| |
Collapse
|
|
15
|
Kanda T. Interferon-free treatment for HCV-infected patients with decompensated cirrhosis. Hepatol Int 2017; 11:38-44. [PMID: 27282879 DOI: 10.1007/s12072-016-9749-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2016] [Accepted: 05/27/2016] [Indexed: 02/06/2023]
Abstract
Progress in interferon-free treatment against hepatitis C virus (HCV) has remained a challenge in patients with decompensated cirrhosis due to a paucity of information on efficacy and safety profiles. This review illustrates that interferon-free treatment could result in greater than 85 % sustained virological response (SVR) rates in patients with HCV genotype 1 and decompensated cirrhosis. The combination of pangenotypic HCV NS5A inhibitor velpatasvir and HCV NS5B inhibitor sofosbuvir has demonstrated high SVR rates in patients with HCV genotypes 1, 2, 3, 4 or 6 and decompensated cirrhosis. Certain patients discontinued treatment due to adverse events, death or having liver transplantation. Taken together, interferon-free treatment could produce higher SVR rates in decompensated hepatic cirrhosis. However, as adverse events were occasionally observed, liver transplantation should always be considered as well. Further improvements in treatment are called for in patients with decompensated cirrhosis.
Collapse
Affiliation(s)
- Tatsuo Kanda
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 220-8677, Japan.
| |
Collapse
|
|
16
|
Mücke MM, Mücke VT, Lange CM, Zeuzem S. Special populations: treating hepatitis C in patients with decompensated cirrhosis and/or advanced renal impairment. Liver Int 2017; 37 Suppl 1:19-25. [PMID: 28052635 DOI: 10.1111/liv.13279] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 10/14/2016] [Indexed: 12/21/2022]
Abstract
Direct-acting antivirals have revolutionized the treatment of hepatitis C. Sustained virological response rates of at least 95% have become common in the general population. However, along with the ageing of the HCV population, physicians face a growing group of HCV-infected patients with advanced liver and/or renal impairment. The safety and efficacy of treatment remains a clinical challenge in these patients. This review focuses on the current state of knowledge and treatment regimens in patients with decompensated cirrhosis and severe renal impairment. It shows that distinct interferon-free treatments can achieve favourable sustained virological response rates in these difficult-to-treat patients. Moreover, pitfalls and special considerations as well as new emerging challenges in an era of interferon-free regimens will be presented in this article.
Collapse
Affiliation(s)
- Marcus M Mücke
- Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt a.M., Germany
| | - Victoria T Mücke
- Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt a.M., Germany
| | - Christian M Lange
- Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt a.M., Germany
| | - Stefan Zeuzem
- Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt a.M., Germany
| |
Collapse
|
|
17
|
Knop V, Hoppe D, Welzel T, Vermehren J, Herrmann E, Vermehren A, Friedrich-Rust M, Sarrazin C, Zeuzem S, Welker MW. Regression of fibrosis and portal hypertension in HCV-associated cirrhosis and sustained virologic response after interferon-free antiviral therapy. J Viral Hepat 2016; 23:994-1002. [PMID: 27500382 DOI: 10.1111/jvh.12578] [Citation(s) in RCA: 127] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Accepted: 07/07/2016] [Indexed: 02/06/2023]
Abstract
It is still controversial, whether and to what amount cirrhosis and portal hypertension are reversible in patients with hepatitis C virus (HCV)-associated cirrhosis and sustained virologic response (SVR) after interferon-free antiviral therapy. In this study, we prospectively evaluated dynamics of liver and spleen stiffness in HCV-infected patients with advanced liver disease and SVR after interferon-free treatment. A total of 54 patients with HCV-associated cirrhosis and SVR were included. Liver and spleen stiffness was measured at therapy baseline (BL), end of treatment (EOT) and 24 weeks after EOT (FU24) by transient liver elastography (L-TE) as well as by acoustic radiation force impulse of the liver (L-ARFI) and spleen (S-ARFI), as well as biochemical, virologic and clinical data. Improvement of liver and spleen stiffness was found in 44 of 50 (88%), 31 of 54 (57%) and 25 of 54 (46%) of patients assessed by L-TE, L-ARFI and S-ARFI between baseline and FU24. Liver stiffness assessed by L-TE improved between BL [median (range), 32.5 (9.1-75) kPa] and EOT [median (range), 21.3 (6.7-73.5) kPa; (P<.0001)], and between BL and FU24 [median (range), 21.2 (5.4-70) kPa; (P<.0001)]. Liver stiffness assessed by L-ARFI improved between BL [median (range), 2.7 (1.2-4.1) m/s] and FU24 [median (range), 2.4 (1.2-3.9) m/s; P=.002), while spleen stiffness remained unchanged. Our data suggest that improvement of liver stiffness may be rather due to reduced necroinflammation and may be due to a less extent to regression of cirrhosis, as dynamics of liver stiffness improvement was more pronounced between BL and EOT than BL and FU24.
Collapse
Affiliation(s)
- V Knop
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | - D Hoppe
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | - T Welzel
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | - J Vermehren
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | - E Herrmann
- Institut für Biostatistik und mathematische Modellierung, Goethe-Universität Frankfurt, Frankfurt am Main, Germany
| | - A Vermehren
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | - M Friedrich-Rust
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | - C Sarrazin
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | - S Zeuzem
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | - M-W Welker
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| |
Collapse
|
|
18
|
Song L, Ma C, Li Q, Fan A, Wang K. Global dynamics of a viral infection model with full logistic terms and antivirus treatments. INT J BIOMATH 2016. [DOI: 10.1142/s1793524517500127] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
In this paper, mathematical analysis of the global dynamics of a viral infection model in vivo is carried out. Though the model is originally to study hepatitis C virus (HCV) dynamics in patients with high baseline viral loads or advanced liver disease, similar models still hold significance for other viral infection, such as hepatitis B virus (HBV) or human immunodeficiency virus (HIV) infection. By means of Volterra-type Lyapunov functions, we know that the basic reproduction number [Formula: see text] is a sharp threshold para-meter for the outcomes of viral infections. If [Formula: see text], the virus-free equilibrium is globally asymptotically stable. If [Formula: see text], the system is uniformly persistent, the unique endemic equilibrium appears and is globally asymptotically stable under a sufficient condition. Other than that, for the global stability of the unique endemic equilibrium, another sufficient condition is obtained by Li–Muldowney global-stability criterion. Using numerical simulation techniques, we further find that sustained oscillations can exist and different maximum de novo hepatocyte influx rate can induce different global dynamics along with the change of overall drug effectiveness. Finally, some biological implications of our findings are given.
Collapse
Affiliation(s)
- Lijuan Song
- Department of Mathematics, School of Biomedical Engineering, Third Military Medical University, Chongqing 400038, P. R. China
| | - Cui Ma
- Department of Mathematics, School of Biomedical Engineering, Third Military Medical University, Chongqing 400038, P. R. China
| | - Qiang Li
- Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing 400038, P. R. China
- Chongqing Institute of Hypertension, Chongqing 400042, P. R. China
| | - Aijun Fan
- Chongqing Academy of Science and Technology, Chongqing 401123, P. R. China
| | - Kaifa Wang
- Department of Mathematics, School of Biomedical Engineering, Third Military Medical University, Chongqing 400038, P. R. China
| |
Collapse
|
|
19
|
EXP CLIN TRANSPLANTExp Clin Transplant 2016; 14. [DOI: 10.6002/ect.tondtdtd2016.p46] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
|
|
20
|
van der Meer AJ, Berenguer M. Reversion of disease manifestations after HCV eradication. J Hepatol 2016; 65:S95-S108. [PMID: 27641991 DOI: 10.1016/j.jhep.2016.07.039] [Citation(s) in RCA: 133] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2016] [Revised: 07/29/2016] [Accepted: 07/29/2016] [Indexed: 12/13/2022]
Abstract
Chronic infection with the hepatitis C virus (HCV) may lead to hepatic fibrosis and eventually cirrhosis, at which stage, patients have a substantial risk of liver failure, hepatocellular carcinoma (HCC) and liver-related death. Moreover, HCV infection is associated with several extrahepatic manifestations which impact the quality of life and increase the non-liver-related mortality rate. For patients with compensated liver disease, interferon (IFN)-based antiviral therapy has been a treatment option for over two decades. Long-term follow-up studies indicated that among those with sustained virological response (SVR) the extend of hepatic fibrosis can regress and that their risk of cirrhosis-related complications (including HCC) is reduced, also in case of cirrhosis. Recent population-based studies extended these observations for solid extrahepatic outcomes, such as end-stage renal failure and cardiovascular events. Most importantly, SVR has been associated with prolonged overall survival. These results highlight the importance of the development of new direct-acting antivirals (DAAs), by which almost all patients are able to eradicate HCV in a comfortable manner. Based on the excellent first experiences with the DAAs, physicians gained confidence to use these drugs among patients with decompensated cirrhosis on a more regular basis as well. This was not possible with interferon therapy. Also in this high risk population the DAAs show high SVR rates with improvements in biochemical parameters of liver function shortly after therapy, especially in case of SVR. In fact, some patients could actually be removed from the liver transplantation waiting list due to clinical improvement following DAA therapy. How these short-term results translate into a prolonged (long-term) survival has yet to be determined, as well as which patients with decompensated liver disease are likely or not to benefit from viral eradication. Here we review the current data regarding the beneficial clinical outcome with antiviral therapy as well the remaining uncertainties in this field, both for patients with compensated liver disease and patients with decompensated liver disease.
Collapse
Affiliation(s)
- Adriaan J van der Meer
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
| | - Marina Berenguer
- Hepatology and Liver Transplant Unit and Ciberehd, La Fe Univ. Hospital and Univ. Valencia, Spain
| |
Collapse
|
|
21
|
Rutter K, Etschmaier A, Ferlitsch M, Maieron A, Hametner S, Horvatits T, Paternostro R, Salzl P, Reiberger T, Peck-Radosavljevic M, Quehenberger P, Hofer H, Trauner M, Ferenci P, Ferlitsch A. von Willebrand factor antigen (vWF-Ag): A non-invasive predictor of treatment response and serious adverse events in HCV patients with interferon triple therapy. Dig Liver Dis 2016; 48:1194-1199. [PMID: 27476467 DOI: 10.1016/j.dld.2016.06.033] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Revised: 05/26/2016] [Accepted: 06/28/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Treatment of chronic hepatitis C virus (HCV) infection was revolutionized within the last years. Interferon free antiviral regimens are not accessible without limitations. Combination of peginterferon/ribavirin with first generation direct acting antivirals is less effective and associated with serious adverse events. AIM We have shown that vWF-Ag is associated with portal hypertension and treatment response to PEG/RBV and we evaluated if vWF-Ag is a predictive marker for treatment response and safety in patients with triple therapy. METHODS 222 HCV-GT 1 patients and DAA based triple therapy were included in this retrospective, multicenter study. RESULTS Median vWF-Ag levels were 167.0% [IQR: 124.0-210.0%]. Significantly higher levels were seen in patients without SVR; median 190% [IQR: 146.0-259.5%] versus SVR: 142.5% [IQR: 114.3-196.8%], p<0.001. Furthermore levels of vWF-Ag were identified as independent predictor of non SVR; (OR: 1.009; 95%CI: 1.016-1.3, p=0.005). In patients with cirrhosis elevated vWF-Ag levels were associated with increased incidence of SAEs (OR: 1.016; 95%CI: 1.004-1.028; p=0.007). Best cut off for prediction of SAEs was vWF-Ag>281.5% with a sensitivity of 78% and a specificity of 90%. CONCLUSION Baseline vWF-Ag levels predict outcome of DAA based treatment in HCV-1 patients and identify patients with a risk of SAEs. Therefore vWF-Ag may be an additional marker for selecting patients for interferon free therapeutic regimens.
Collapse
Affiliation(s)
- Karoline Rutter
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria; Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Alexandra Etschmaier
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Monika Ferlitsch
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | | | | | - Thomas Horvatits
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria; Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Rafael Paternostro
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Petra Salzl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Markus Peck-Radosavljevic
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Peter Quehenberger
- Department of Laboratory Medicine, Medical University of Vienna, Austria
| | - Harald Hofer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Peter Ferenci
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Arnulf Ferlitsch
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria.
| |
Collapse
|
|
22
|
Vandenbulcke H, Moreno C, Colle I, Knebel JF, Francque S, Sersté T, George C, de Galocsy C, Laleman W, Delwaide J, Orlent H, Lasser L, Trépo E, Van Vlierberghe H, Michielsen P, van Gossum M, de Vos M, Marot A, Doerig C, Henrion J, Deltenre P. Alcohol intake increases the risk of HCC in hepatitis C virus-related compensated cirrhosis: A prospective study. J Hepatol 2016; 65:543-51. [PMID: 27180899 DOI: 10.1016/j.jhep.2016.04.031] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2015] [Revised: 04/05/2016] [Accepted: 04/27/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Whether alcohol intake increases the risk of complications in patients with HCV-related cirrhosis remains unclear. The aim of this study was to determine the impact of alcohol intake and viral eradication on the risk of hepatocellular carcinoma (HCC), decompensation of cirrhosis and death. METHODS Data on alcohol intake and viral eradication were prospectively collected in 192 patients with compensated HCV-related cirrhosis. RESULTS 74 patients consumed alcohol (median alcohol intake: 15g/day); 68 reached viral eradication. During a median follow-up of 58months, 33 patients developed HCC, 53 experienced at least one decompensation event, and 39 died. The 5-year cumulative incidence rate of HCC was 10.6% (95% CI: 4.6-16.6) in abstainers vs. 23.8% (95% CI: 13.5-34.1) in consumers (p=0.087), and 2.0% (95% CI: 0-5.8) vs. 21.7% (95% CI: 14.2-29.2) in patients with and without viral eradication (p=0.002), respectively. The lowest risk of HCC was observed for patients without alcohol intake and with viral eradication (0%) followed by patients with alcohol intake and viral eradication (6.2% [95% CI: 0-18.4]), patients without alcohol intake and no viral eradication (15.9% [95% CI: 7.1-24.7]), and patients with alcohol intake and no viral eradication (29.2% [95% CI: 16.5-41.9]) (p=0.009). In multivariate analysis, lack of viral eradication and alcohol consumption were associated with the risk of HCC (hazard ratio for alcohol consumption: 3.43, 95% CI: 1.49-7.92, p=0.004). Alcohol intake did not influence the risk of decompensation or death. CONCLUSIONS Light-to-moderate alcohol intake increases the risk of HCC in patients with HCV-related cirrhosis. Patient care should include measures to ensure abstinence. LAY SUMMARY Whether alcohol intake increases the risk of complications in patients with HCV-related cirrhosis remains unclear. In this prospective study, light-to-moderate alcohol intake was associated with the risk of hepatocellular carcinoma in multivariate analysis. No patients who did not use alcohol and who reached viral eradication developed hepatocellular carcinoma during follow-up. The risk of hepatocellular carcinoma increased with alcohol intake or in patients without viral eradication and was highest when alcohol intake was present in the absence of viral eradication. Patients with HCV-related cirrhosis should be strongly advised against any alcohol intake. Patient care should include measures to ensure abstinence.
Collapse
Affiliation(s)
- Hélène Vandenbulcke
- Departement of Gastroenterology and Hepatology, Hôpital de Jolimont, Haine-Saint-Paul, Belgium
| | - Christophe Moreno
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
| | - Isabelle Colle
- Departement of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
| | - Jean-François Knebel
- Laboratory for Investigative Neurophysiology (The LINE), Department of Radiology and Department of Clinical Neurosciences, University Hospital Center and University of Lausanne, 1011 Lausanne, Switzerland; EEG Brain Mapping Core, Centre for Biomedical Imaging (CIBM), 1011 Lausanne, Switzerland
| | - Sven Francque
- Departement of Gastroenterology and Hepatology, UZ Antwerpen, Edegem, Belgium
| | - Thomas Sersté
- Departement of Gastroenterology and Hepatology, CHU Saint-Pierre, Brussels, Belgium
| | - Christophe George
- Departement of Gastroenterology and Hepatology, AZ Groeninge, Kortrijk, Belgium
| | - Chantal de Galocsy
- Departement of Gastroenterology and Hepatology, Hôpitaux Iris Sud Bracops, Brussels, Belgium
| | - Wim Laleman
- Departement of Gastroenterology and Hepatology, KUL, Leuven, Belgium
| | - Jean Delwaide
- Departement of Gastroenterology and Hepatology, CHU Liège, Liège, Belgium
| | - Hans Orlent
- Departement of Gastroenterology and Hepatology, AZ St Jan, Brugge, Belgium
| | - Luc Lasser
- Departement of Gastroenterology and Hepatology, CHU Brugmann, Brussels, Belgium
| | - Eric Trépo
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
| | - Hans Van Vlierberghe
- Departement of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
| | - Peter Michielsen
- Departement of Gastroenterology and Hepatology, UZ Antwerpen, Edegem, Belgium
| | - Marc van Gossum
- Departement of Gastroenterology and Hepatology, CHU Saint-Pierre, Brussels, Belgium
| | - Marie de Vos
- Departement of Gastroenterology and Hepatology, Hôpital de Jolimont, Haine-Saint-Paul, Belgium
| | - Astrid Marot
- Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Christopher Doerig
- Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Jean Henrion
- Departement of Gastroenterology and Hepatology, Hôpital de Jolimont, Haine-Saint-Paul, Belgium
| | - Pierre Deltenre
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium; Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
| |
Collapse
|
|
23
|
Fan X, Wen M, Shen Y, Wang W, Yang X, Yang L. Does adding variceal status to the Child-Turcotte-Pugh score improve its performance in predicting mortality in cirrhosis? Medicine (Baltimore) 2016; 95:e4884. [PMID: 27661030 PMCID: PMC5044900 DOI: 10.1097/md.0000000000004884] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
The Child-Turcotte-Pugh (CTP) score is widely used worldwide to predict outcomes across a broad spectrum of liver diseases, mainly cirrhosis. Portal hypertension and variceal bleed are significant causes of morbidity and mortality in cirrhotic patients, although the variceal status is not incorporated into the classical CTP score. We sought to determine whether the inclusion of variceal status, specifically the Child-Turcotte-Pugh-Kumar (CTPK) score, would improve the utility of the classical CTP score to predict the clinical outcomes of cirrhotic patients in a single but high-volume center in China.We retrospectively analyzed the records of 253 patients from January 1, 2014 to December 31, 2014 and performed follow-up for at least 12 months. The CTPK score and the CTP score were obtained as soon as possible after the patient's admission. Telephone follow-up was performed to assess survival situations.At 3 and 12 months, the cumulative number of deaths was 9.1% (n = 23) and 13.8% (n = 35), respectively. In the multivariate Cox proportional hazards models, the CTPK score was independently associated with death within 3 and 12 months after adjusting for potential confounders. The predictive ability related to the 2 scores was evaluated by the area under the receiver operating characteristic curve (AUC-ROC) respectively. At 3 months of enrollment, the AUCs of CTPK and CTP were 0.814 and 0.838, respectively. At 12 months of enrollment, the AUCs of CTPK and CTP were 0.825 and 0.840, respectively. No significant difference between time points was observed. Both the CTPK score and the CTP score displayed prognostic value in cirrhotic patients, as the Kaplan-Meier analysis showed that the CTPK score could clearly discriminate patients in the intermediate term (P < 0.001).The CTPK score provides reliable prediction of mortality in Chinese cirrhotic patients for both short-term and medium-term prognoses, although it is not superior to the CTP score. Therefore, the CTP score remains an excellent tool for outcome prediction in patients with cirrhosis, and greater attention to variceal status may be in veins, even for patients with a history of variceal bleed or medium/large varices.
Collapse
Affiliation(s)
| | | | | | | | | | - Li Yang
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
- Correspondence: Li Yang, Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, 37 Guoxue Lane, Chengdu 610041, Sichuan, People's Republic of China (e-mail: )
| |
Collapse
|
|
24
|
Velosa J. Why is viral eradication so important in patients with HCV-related cirrhosis? Antivir Ther 2016; 22:1-12. [PMID: 27553973 DOI: 10.3851/imp3077] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/18/2016] [Indexed: 02/07/2023]
Abstract
Approximately one-third of patients infected with chronic HCV have cirrhosis, and this is likely to increase in the near future. The risk of complications, mainly the development of hepatocellular carcinoma, depends on the presence of cirrhosis, and a significant increase in the incidence of cirrhosis-related events, including mortality, is likely in the following years. All-oral therapy with direct-acting antivirals (DAAs) offers a safe and short treatment, with cure rates over 90% in compensated cirrhosis. Cirrhotic patients should be given high priority for treatment because viral clearance has a significant impact on the natural history of HCV infection, halting the progression of the disease and inducing the regression of fibrosis, as well as reducing the need for liver transplantation and improving survival. The benefit of DAAs is great in patients with decompensated cirrhosis, up until recently a population for whom no alternative therapy was available. The efficacy of all-oral therapy has been reported to improve liver function in about 50% of Child-Pugh class C patients. The regression of cirrhosis observed in more than half of patients achieving viral eradication on prior interferon-based regimens still has to be demonstrated in patients treated with DAAs, although there is reason to believe that this will happen. Advanced cirrhosis will eventually become the last boundary of antiviral therapy that will soon be conquered with new drugs currently pending approval.
Collapse
Affiliation(s)
- José Velosa
- Hospital de Santa Maria - Gastroenterology and Hepatology, Lisbon, Portugal
| |
Collapse
|
|
25
|
Majumdar A, Kitson MT, Roberts SK. Systematic review: current concepts and challenges for the direct-acting antiviral era in hepatitis C cirrhosis. Aliment Pharmacol Ther 2016; 43:1276-92. [PMID: 27087015 DOI: 10.1111/apt.13633] [Citation(s) in RCA: 122] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Revised: 10/06/2015] [Accepted: 03/29/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND The burden of HCV cirrhosis is high and projected to increase significantly over the next decade. While interferon therapy is problematic in HCV cirrhosis, the era of direct-acting anti-viral (DAA) therapy provides effective treatment for patients with cirrhosis. AIM To systematically review the results of DAA therapy to date in patients with HCV cirrhosis, and highlight the ongoing challenges for DAA therapy in this population. METHODS A structured Medline search was conducted to obtain phase II and III HCV trials in patients with cirrhosis. Citations from review articles were cross-referenced and conference abstracts from EASL and AASLD liver meetings for the preceding 3 years were reviewed manually. Keywords used included hepatitis C, cirrhosis and the DAA's: sofosbuvir, ledipasvir, velpatasvir, grazoprevir, elbasvir, daclatasvir, beclabuvir, asunaprevir, simeprevir, paritaprevir, ombitasvir and dasabuvir. RESULTS Successful direct-acting anti-viral treatment is now possible in patients with HCV-related cirrhosis including those with liver decompensation with several regimens now offering sustained virological response (SVR) of 90-95%. Overall success rates in GT1 cirrhosis are excellent while GT3-infected patients with cirrhosis remain hard to cure. The pangenotypic combination of sofosbuvir and velpatasvir holds promise for GT3 cirrhosis achieving SVR of ~90%. CONCLUSIONS Potent DAA therapies provide much needed, safe and highly effective treatment options for persons with HCV cirrhosis including those previously deemed unsuitable for treatment. Combination therapy with two or more classes of drug is essential to achieve high efficacy and minimise viral resistance, with the role of ribavirin still under evaluation. However, several challenges remain including the hard-to-cure groups of GT3 cirrhosis and direct-acting anti-viral failures, and managing drug-drug interactions.
Collapse
Affiliation(s)
- A Majumdar
- Department of Gastroenterology, Alfred Hospital, Melbourne, Vic., Australia.,UCL Institute for Liver and Digestive Health and Sheila Sherlock Liver Centre Royal Free Hospital, London, UK
| | - M T Kitson
- Department of Gastroenterology, Alfred Hospital, Melbourne, Vic., Australia
| | - S K Roberts
- Department of Gastroenterology, Alfred Hospital, Melbourne, Vic., Australia
| |
Collapse
|
|
26
|
Carrion AF, Martin P. Safety and efficacy of elbasvir and grazoprevir for treatment of hepatitis C. Expert Opin Drug Saf 2016; 15:883-890. [PMID: 27091555 DOI: 10.1080/14740338.2016.1179278] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Accepted: 04/13/2016] [Indexed: 02/07/2023]
Abstract
INTRODUCTION The combination of elbasvir and grazoprevir in a single co-formulated tablet is highly effective for treatment of hepatitis C virus (HCV) infection. This regimen affords profound inhibition of NS3/4A protease and NS5A activity, resulting in potent activity against HCV genotypes 1, 4, and 6 with high rates of sustained virological response. AREAS COVERED This review covers the mechanism of action, pharmacokinetics, clinical applications, efficacy and safety profile of elbasvir/grazoprevir including special populations such as individuals with compensated and decompensated cirrhosis, HCV/HIV co-infection, advanced chronic kidney disease, and those that previously failed antiviral therapy. EXPERT OPINION Elbasvir/grazoprevir is an effective antiviral regimen for treatment of genotypes 1 and 4 and has a very favorable safety profile based on extensive data from several pre-licensure clinical trials that included patient subgroups at increased risk of toxicity. This regimen is currently the only one licensed for use in individuals with advanced chronic kidney disease requiring hemodialysis.
Collapse
Affiliation(s)
- Andres F Carrion
- a Division of Gastroenterology and Hepatology, Texas Tech University Health Sciences Center , Paul L. Foster School of Medicine , El Paso , TX , USA
| | - Paul Martin
- b Division of Hepatology , University of Miami Miller School of Medicine , Miami , FL , USA
| |
Collapse
|
|
27
|
Dresch KFN, Mattos AAD, Tovo CV, Onofrio FQD, Casagrande L, Feltrin AA, Barros ICD, Almeida PRLD. IMPACT OF THE PEGYLATED-INTERFERON AND RIBAVIRIN THERAPY ON THE TREATMENT-RELATED MORTALITY OF PATIENTS WITH CIRRHOSIS DUE TO HEPATITIS C VIRUS. Rev Inst Med Trop Sao Paulo 2016; 58:37. [PMID: 27253739 PMCID: PMC4879994 DOI: 10.1590/s1678-9946201658037] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2015] [Accepted: 11/17/2015] [Indexed: 12/15/2022] Open
Abstract
UNLABELLED Although the protease inhibitors have revolutionized the therapy of chronic hepatitis C (CHC), the concomitant use of pegylated-interferon (PEG-IFN) and ribavirin (RBV) is associated to a high rate of adverse effects. In this study, we evaluated the consequences of PEG-IFN and RBV and their relationship with mortality in patients with cirrhosis. METHODS Medical records of CHC who underwent treatment with PEG-IFN and RBV in a public hospital in Brazil were evaluated. All the patients with cirrhosis were selected, and their clinical and laboratory characteristics, response to treatment, side effects and mortality were evaluated. RESULTS From the 1,059 patients with CHC, 257 cirrhotic patients were evaluated. Of these, 45 (17.5%) achieved sustained viral response (SVR). Early discontinuation of therapy occurred in 105 (40.8%) patients, of which 39 (15.2%) were due to serious adverse effects. The mortality rate among the 257 cirrhotic patients was 4.3%, occurring in 06/242 (2.4%) of the Child-A, and in 05/15 (33.3%) of the Child-B patients. In conclusion, the treatment of patients with cirrhosis due to HCV with PEG-IFN and RBV shows a low SVR rate and a high mortality, especially in patients with liver dysfunction.
Collapse
Affiliation(s)
| | | | | | | | - Leandro Casagrande
- Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brasil
| | | | | | | |
Collapse
|
|
28
|
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.
Collapse
|
|
29
|
Llovet LP, Rodríguez-Tajes S, Londoño MC. Tratamiento de la hepatitis C en el pre- y postrasplante hepático. GASTROENTEROLOGIA Y HEPATOLOGIA 2016; 39:344-51. [DOI: 10.1016/j.gastrohep.2015.09.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Revised: 08/31/2015] [Accepted: 09/04/2015] [Indexed: 01/28/2023]
|
|
30
|
Abstract
BACKGROUND Hepatitis B virus (HBV)- and hepatitis C virus (HCV)-associated liver cirrhosis is a major indication for liver transplantation. This concise review gives an overview about current interferon (IFN)-free treatment options before and after liver transplantation in HBV- or HCV-associated liver disease. METHODS A PubMed database search using the terms hepatitis B, hepatitis C, cirrhosis, and liver transplantation was performed to identify significant clinical studies as well as national and international guidelines. RESULTS Studies investigating IFN-free treatment in patients with decompensated HBV as well as in HCV-associated cirrhosis are scarce. Hepatic recompensation during antiviral therapy seems more frequent in patients with HBV than in those with HCV-associated cirrhosis. Graft hepatitis B or C is characterized by an accelerated and unfavorable course. Graft infection prophylaxis is safe and efficacious in HBV-related liver transplantation. Eradication of HCV prior to liver transplantation prevents HCV graft infection, and IFN-free treatment of established HCV graft infection is safe and associated with high sustained virologic response rates. CONCLUSION Patients with HBV-associated cirrhosis should be treated prior to liver transplantation, and receive a continuing graft infection prophylaxis thereafter. Patients with HCV-associated decompensated cirrhosis may be considered as candidates for antiviral therapy prior to liver transplantation or may be treated subsequently.
Collapse
Affiliation(s)
- Martin-Walter Welker
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | | |
Collapse
|
|
31
|
Treatment of hepatitis C in patients with cirrhosis: remaining challenges for direct-acting antiviral therapy. Drugs 2016; 75:823-34. [PMID: 25943281 DOI: 10.1007/s40265-015-0401-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Chronic hepatitis C virus (HCV) infection is a major global health concern, resulting in significant morbidity and mortality. Treatment using interferon-based therapy in patients with HCV-related cirrhosis has been problematic due to toxicity and poor tolerability. Furthermore, interferon therapy is contraindicated in those with advanced cirrhosis or clinical decompensation, who are arguably the group most in need of viral eradication. The arrival of the direct-acting antiviral (DAA) era has resulted in the development of well-tolerated and highly effective interferon-free drug regimens that promise to dramatically change the therapeutic landscape for those with advanced HCV-related liver disease, including patients with clinical decompensation or pre-liver transplantation. Many successful DAA combinations have emerged; however, a number of challenges remain including the establishment of the optimal treatment duration, the ideal combination of drug classes and determining the role of ribavirin. Moreover, the identification of treatment-experienced patients with genotype 3 HCV cirrhosis as a difficult-to-treat subgroup is a significant impediment to overcome, as are those who have failed prior DAA therapy. Despite these barriers, the ongoing prolific development of safe and effective DAA combinations indicates the future is optimistic for the ultimate goal of HCV eradication.
Collapse
|
|
32
|
Asahina Y, Izumi N, Hiromitsu K, Kurosaki M, Koike K, Suzuki F, Takikawa H, Tanaka A, Tanaka E, Tanaka Y, Tsubouchi H, Hayashi N, Hiramatsu N, Yotsuyanagi H. JSH Guidelines for the Management of Hepatitis C Virus Infection: A 2016 update for genotype 1 and 2. Hepatol Res 2016; 46:129-165. [PMID: 26876581 DOI: 10.1111/hepr.12645] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Yasuhiro Asahina
- Department of Gastroenterology and Hepatology, School of Medicine, Tokyo Medical and Dental University
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital
| | | | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo
| | | | - Hajime Takikawa
- Department of Medicine, Teikyo University School of Medicine
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine
| | - Eiji Tanaka
- The Second Department of Internal Medicine, Shinshu University School of Medicine
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Science
| | | | | | - Naoki Hiramatsu
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine
| | - Hiroshi Yotsuyanagi
- Department of Infectious Diseases, Graduate School of Medicine, The University of Tokyo
| |
Collapse
|
|
33
|
Abstract
Patients with chronic hepatitis C virus (HCV) infection frequently present with extrahepatic manifestations covering a large spectrum, involving different organ systems leading to the concept of systemic HCV infection. These manifestations include autoimmune phenomena and frank autoimmune and/or rheumatic diseases and may dominate the course of chronic HCV infection. Chronic HCV infection causes liver inflammation affecting the development of hepatic diseases. HCV is also a lymphotropic virus that triggers B cells and promotes favorable conditions for B lymphocyte proliferation, including mixed cryoglobulinemia (MC) and MC vasculitis, which is the most prominent extrahepatic manifestation of chronic HCV infection. HCV may also promote a low-grade chronic systemic inflammation that may affect the development of some extrahepatic manifestations, particularly cardiovascular and cerebral vascular diseases. Recognition of extrahepatic symptoms of HCV infection could facilitate early diagnosis and treatment. The development of direct-acting antiviral agents (DDAs) has revolutionized HCV treatment. DDAs, as well as new B-cell-depleting or B-cell-modulating monoclonal antibodies, will expand the panorama of treatment options for HCV-related extrahepatic manifestations including cryoglobulinemic vasculitis. In this context, a proactive, integrated approach to HCV therapy should maximize the benefits of HCV therapy, even when liver disease is mild.
Collapse
Affiliation(s)
- E Rosenthal
- Service de Médecine Interne, Hôpital de l'Archet, CHU de Nice, Nice; Université de Nice-Sophia Antipolis, Nice, France COREVIH PACA EST, CHU de Nice, France
| | - P Cacoub
- Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France INSERM, UMR_S 959, Paris, France CNRS, FRE3632, Paris, France AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France
| |
Collapse
|
|
34
|
Saxena V, Terrault N. Current Management of Hepatitis C Virus: Regimens for Peri-Liver Transplant Patients. Clin Liver Dis 2015; 19:669-88, vi. [PMID: 26466655 PMCID: PMC8115933 DOI: 10.1016/j.cld.2015.06.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Chronic hepatitis C virus (HCV) infection currently remains the leading indication for liver transplant in the United States. However, recurrent HCV infection after transplant is universal in those who enter transplant with viremia resulting in reduced posttransplant graft and patient survival rates, caused in large part by progressive recurrent HCV disease. Therefore, successful treatment of HCV in the peri-transplant period, either before or after transplant, is paramount in ensuring improved posttransplant outcomes. This article reviews the experience to date treating HCV in wait-listed patients and liver transplant recipients and the unique challenges encountered when treating this population.
Collapse
Affiliation(s)
- Varun Saxena
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Norah Terrault
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
| |
Collapse
|
|
35
|
12 weeks of interferon-based therapy is feasible in patients with hepatitis C-related cirrhosis and thrombocytopenia: A post hoc analysis of eltrombopag studies. Dig Liver Dis 2015; 47:864-8. [PMID: 26187555 DOI: 10.1016/j.dld.2015.06.006] [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: 03/16/2015] [Revised: 05/29/2015] [Accepted: 06/21/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND A 24-48-week course of interferon-based therapy poorly tolerated in hepatitis C virus (HCV) cirrhosis patients with thrombocytopenia. Aim of the study was to identify patients at low-risk of liver-related complications over a 12-week course of interferon-based therapy. METHODS We assessed the rate of complications and death during the first 12 weeks of interferon-based therapy in HCV cirrhotics with thrombocytopenia (platelets ≤75×10(9)/L) enrolled in the ENABLE-1 and -2 phase 3 randomised controlled trials. RESULTS Overall, among 1441 patients, 89 complications (6.9%) and 10 deaths (0.7%) were observed within the first 12 weeks of therapy. At univariate analysis baseline albumin levels and Model for End Stage Liver Disease (MELD) score (≤35 g /L, p<0.001, and ≥10, p<0.001, respectively) were the only predictors associated with occurrence of complications and death. Of the 1026 patients with serum albumin >35 g/L (71.2%), one patient died (0.1%) and 17 experienced liver-related complications (1.7%). Among 667 patients with serum albumin >35 g/L and MELD score <10, no deaths occurred and 4 experienced liver-related complications (0.6%). CONCLUSION Among HCV cirrhotic patients with thrombocytopenia, albumin levels and MELD score can identify patients who may safely receive a 12-week course of interferon-based therapy with a low risk of complications.
Collapse
|
|
36
|
Ferenci P, Kozbial K, Mandorfer M, Hofer H. HCV targeting of patients with cirrhosis. J Hepatol 2015; 63:1015-1022. [PMID: 26100497 DOI: 10.1016/j.jhep.2015.06.003] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Revised: 06/09/2015] [Accepted: 06/10/2015] [Indexed: 12/15/2022]
Abstract
Interferon (IFN)-free treatments are now the treatment of choice for patients with chronic hepatitis C. Previously difficult to treat patients by IFN-containing treatments can now be treated safely by IFN-free therapies. More than 90% of hepatitis C genotype 1 and 4 patients with compensated cirrhosis or after orthotopic liver transplantation (OLT) can be cured by sofosbuvir combined with simeprevir, daclatasvir or ledipasvir, or by the paritaprevir/ritona-vir/ombitasvir/±dasabuvir (3D) combination. Addition of ribavirin confers to a minimal, if any, benefit to increase SVR. The need for ribavirin is controversial and remains to be studied. The optimal length of treatment is still unknown, and an individual approach may be needed. Most patients require only 12weeks of therapy. The safety of these drugs is not fully explored in patients with decompensated cirrhosis (Child-Pugh C), who should not be treated with protease inhibitors. In cirrhosis hepatitis C virus eradication does not necessarily mean a cure of the disease and patients regularly require follow-up. Drug-drug interactions with immunosuppressant in patients after OLT are easier to manage but still require attention. Better drugs are needed for genotype 3 patients.
Collapse
Affiliation(s)
- Peter Ferenci
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
| | - Karin Kozbial
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Mattias Mandorfer
- 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
| |
Collapse
|
|
37
|
Mandorfer M, Kozbial K, Freissmuth C, Schwabl P, Stättermayer AF, Reiberger T, Beinhardt S, Schwarzer R, Trauner M, Ferlitsch A, Hofer H, Peck-Radosavljevic M, Ferenci P. Interferon-free regimens for chronic hepatitis C overcome the effects of portal hypertension on virological responses. Aliment Pharmacol Ther 2015; 42:707-718. [PMID: 26179884 DOI: 10.1111/apt.13315] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2015] [Revised: 03/14/2015] [Accepted: 06/22/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Portal hypertension is the strongest predictor of virological response to pegylated interferon (IFN)/ribavirin in patients with chronic hepatitis C (CHC)-related cirrhosis. AIM To investigate the effects of portal pressure assessed by hepatic venous pressure gradient (HVPG) measurement on virological responses in patients treated with IFN-free regimens outside of clinical trials. METHODS Fifty-six patients with CHC and cirrhosis who underwent HVPG measurement before starting an IFN-free therapy were retrospectively studied. Patients were treated with sofosbuvir in combination with daclatasvir (n = 32), ribavirin (n = 12) or simeprevir (n = 11), or the combination of simeprevir/daclatasvir (n = 1), for 12-24 weeks. RESULTS Hepatic venous pressure gradient values ≥10 mmHg and ≥16 mmHg were observed in 41 (73%) and 31 (55%) patients respectively. The distributions of treatment regimens and durations were comparable between patients with or without portal hypertension. Patients with portal hypertension had lower platelet counts and albumin levels, while bilirubin levels, INR, MELD and Child-Pugh scores were higher than in patients without portal hypertension. Importantly, rates of on-treatment virological response and viral kinetics, as well as the rates of sustained virological response 12 weeks after the end of therapy [96% (54/56)] were not affected by portal hypertension. Anti-viral therapy improved liver stiffness, platelet count, serum albumin and bilirubin levels, as well as prothrombin time. CONCLUSIONS This is the first study to demonstrate that IFN-free regimens overcome the negative effect of portal hypertension on virological responses and viral kinetics. Improvements in liver stiffness and platelet count might reflect an anti-portal hypertensive effect of IFN-free treatments.
Collapse
Affiliation(s)
- M Mandorfer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - K Kozbial
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - C Freissmuth
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - P Schwabl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - A F Stättermayer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - T Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - S Beinhardt
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - R Schwarzer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - M Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - A Ferlitsch
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - H Hofer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - M Peck-Radosavljevic
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - P Ferenci
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| |
Collapse
|
|
38
|
Barsa JE, Branch AD, Schiano TD. A pleasant dilemma to have: to treat the HCV patient on the waiting list or to treat post-liver transplantation? Clin Transplant 2015; 29:859-65. [DOI: 10.1111/ctr.12596] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/15/2015] [Indexed: 12/13/2022]
|
|
39
|
Khullar V, Firpi RJ. Hepatitis C cirrhosis: New perspectives for diagnosis and treatment. World J Hepatol 2015; 7:1843-1855. [PMID: 26207166 PMCID: PMC4506942 DOI: 10.4254/wjh.v7.i14.1843] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Revised: 02/24/2015] [Accepted: 07/08/2015] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C infection is the leading cause of chronic liver disease, cirrhosis, hepatocellular carcinoma as well as the primary indication for liver transplantation in the United States. Despite recent advances in drugs for the treatment of hepatitis C, predictive models estimate the incidence of cirrhosis due to hepatitis C infection will to continue to rise for the next two decades. There is currently an immense interest in the treatment of patients with fibrosis and early-stage cirrhosis as treatment can lead to decrease in the rates of decompensated cirrhosis, hepatocellular carcinoma and need for liver transplantation in these patients. The goal of this paper is to provide clinicians and health care professionals further information about the treatment of patients with hepatitis C infection and cirrhosis. Additionally, the paper focuses on the disease burden, epidemiology, diagnosis and the disease course from infection to treatment. We provide an overview of multiple studies for the treatment of chronic hepatitis C infection that have included patients with cirrhosis. We also discuss the advantages and disadvantages of treatment in cirrhotic patients and focus on the most up to date guidelines available for treatment.
Collapse
|
|
40
|
Price JC, Terrault NA. Treatment of hepatitis C in liver transplant patients: interferon out, direct antiviral combos in. Liver Transpl 2015; 21:423-34. [PMID: 25604355 DOI: 10.1002/lt.24080] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Revised: 11/20/2014] [Accepted: 01/11/2015] [Indexed: 12/14/2022]
Abstract
Although chronic infection with hepatitis C virus (HCV) is the leading indication for liver transplantation in the United States, graft and patient survival rates are reduced because of HCV recurrence after transplant. Interferon-based antiviral treatment administered either before or after transplant to prevent or treat HCV recurrence, respectively, is limited because of poor tolerability and low efficacy. However, the treatment of HCV in the transplant setting is changing considerably with the availability of newer direct-acting antivirals and interferon-free regimens. This article will review the experience to date with treating HCV in the setting of cirrhosis and liver transplantation and will discuss the unique challenges encountered when this population is being treated.
Collapse
Affiliation(s)
- Jennifer C Price
- Department of Medicine, University of California San Francisco, San Francisco, CA
| | | |
Collapse
|
|
41
|
Dienstag JL, Delemos AS. Viral Hepatitis. MANDELL, DOUGLAS, AND BENNETT'S PRINCIPLES AND PRACTICE OF INFECTIOUS DISEASES 2015:1439-1468.e7. [DOI: 10.1016/b978-1-4557-4801-3.00119-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
42
|
Gambato M, Lens S, Navasa M, Forns X. Treatment options in patients with decompensated cirrhosis, pre- and post-transplantation. J Hepatol 2014; 61:S120-31. [PMID: 25443340 DOI: 10.1016/j.jhep.2014.07.020] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2014] [Revised: 07/03/2014] [Accepted: 07/11/2014] [Indexed: 12/21/2022]
Abstract
Interferon-based treatments have a poor safety profile and limited efficacy in patients with advanced liver disease and in patients with hepatitis C (HCV) recurrence after liver transplantation (LT). Despite the recent approval of the first interferon-free regimen, which will be followed by several other interferon-free combinations in 2014 and 2015, data in patients with advanced cirrhosis and hepatitis C after LT are still limited. One study has already proven the concept that graft HCV infection can be prevented in a significant proportion of patients by treating them with sofosbuvir and ribavirin while awaiting LT. Two interferon-free regimens have also demonstrated a high efficacy in patients with hepatitis C recurrence after transplantation. Before these treatment strategies can be implemented in clinical practice, a few issues need to be addressed: (1) safety and efficacy of new antivirals in patients with decompensated cirrhosis, (2) the impact of viral clearance on liver function, (3) the potential consequences of virological failure (and the selection of multi-drug resistant HCV strains) in patients with decompensated cirrhosis or with severe hepatitis C recurrence after LT, and (4) drug-drug interactions (DDI) profiles. Finally, in the transplant setting it is also relevant to learn which strategy is most cost-effective in minimizing the negative impact of hepatitis C: preventing graft infection by treating patients before transplantation or treating hepatitis C recurrence after LT.
Collapse
Affiliation(s)
- Martina Gambato
- Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, University of Barcelona, Spain
| | - Sabela Lens
- Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, University of Barcelona, Spain
| | - Miquel Navasa
- Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, University of Barcelona, Spain
| | - Xavier Forns
- Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, University of Barcelona, Spain.
| |
Collapse
|
|
43
|
Iacobellis A, Cozzolongo R, Minerva N, Valvano MR, Niro GA, Fontana R, Palmieri O, Ippolito A, Andriulli A. Feasibility of pegylated interferon and ribavirin in hepatitis C-related cirrhosis with neutropenia or thrombocytopenia. Dig Liver Dis 2014; 46:621-4. [PMID: 24675038 DOI: 10.1016/j.dld.2014.02.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2013] [Revised: 01/19/2014] [Accepted: 02/04/2014] [Indexed: 12/11/2022]
Abstract
AIM To investigate the feasibility of pegylated interferon plus ribavirin treatment in cirrhotic patients who presented with, or developed while on-treatment, platelet counts ≤ 80,000/μL and/or neutrophil counts ≤ 1,500/μL. METHODS A retrospective analysis of prospectively gathered data on 123 cirrhotic patients treated with pegylated interferon and ribavirin. Adverse effects and haematological changes were monitored: bleeding and infectious events were registered and related to platelet and absolute neutrophil counts. RESULTS Among the 58 patients (47.2%) with nadir platelets ≤ 50,000/μL during therapy, 6 (10.3%) experienced a bleeding episode; of the remaining 65 patients with platelets constantly >50,000/μL, 3 (4.6%) bled. Of the 11 bleedings, 3 manifested during an infection, while patients had platelets >50,000/μL. Nadir neutrophils ≤ 750/μL occurred in 45 patients (38.2%) during treatment, and 14 of them (29.8%) had an infectious event. Infections were also documented in 18 of the 76 patients (23.7%) with neutrophils constantly >750/μL. CONCLUSIONS The study reveals the feasibility of treating cirrhotic patients with cytopenia with pegylated interferon and ribavirin, as bleeding or infectious events under therapy were unrelated to platelet and neutrophil counts. Withdrawal of therapy or variations in the pre-assigned dosages of either pegylated interferon or ribavirin owing to abnormally low haematological parameters seems to no longer be tenable.
Collapse
Affiliation(s)
- Angelo Iacobellis
- Division of Gastroenterology, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo 71013, Italy.
| | - Raffaele Cozzolongo
- Division of Gastroenterology, De Bellis Hospital, IRCCS, Castellana Grotte 70013, Italy
| | - Nicola Minerva
- Division of Internal Medicine, General Hospital, Canosa 76012, Italy
| | - Maria Rosa Valvano
- Division of Gastroenterology, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo 71013, Italy
| | - Grazia Anna Niro
- Division of Gastroenterology, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo 71013, Italy
| | - Rosanna Fontana
- Division of Gastroenterology, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo 71013, Italy
| | - Orazio Palmieri
- Division of Gastroenterology, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo 71013, Italy
| | - Antonio Ippolito
- Division of Gastroenterology, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo 71013, Italy
| | - Angelo Andriulli
- Division of Gastroenterology, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo 71013, Italy
| |
Collapse
|
|
44
|
Canini L, DebRoy S, Mariño Z, Conway JM, Crespo G, Navasa M, D’Amato M, Ferenci P, Cotler SJ, Forns X, Perelson AS, Dahari H. Severity of liver disease affects HCV kinetics in patients treated with intravenous silibinin monotherapy. Antivir Ther 2014; 20:149-155. [PMID: 24912382 PMCID: PMC4262731 DOI: 10.3851/imp2806] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/21/2014] [Indexed: 01/22/2023]
Abstract
BACKGROUND HCV kinetic analysis and modelling during antiviral therapy have not been performed in decompensated cirrhotic patients awaiting liver transplantation. Here, viral and host parameters were compared in three groups of patients treated with daily intravenous silibinin (SIL) monotherapy for 7 days according to the severity of their liver disease. METHODS Data were obtained from 25 patients, 12 non-cirrhotic, 8 with compensated cirrhosis and 5 with decompensated cirrhosis. The standard-biphasic model with time-varying SIL effectiveness (from 0 to final effectiveness [εmax]) was fitted to viral kinetic data. RESULTS Baseline viral load and age were significantly associated with the severity of liver disease (P<0.0001). A biphasic viral decline was observed in most patients with a higher first phase decline in patients with less severe liver disease. The εmax was significantly (P≤0.032) associated with increasing severity of liver disease (non-cirrhotic εmax [se]=0.86 [0.05], compensated cirrhotic εmax=0.69 [0.06] and decompensated cirrhotic εmax=0.59 [0.1]). The second phase decline slope was not significantly different among groups (mean 1.88 ±0.15 log10 IU/ml/week, P=0.75) as was the rate of change of SIL effectiveness (k=2.12/day [se=0.18/day]). HCV-infected cell loss rate (δ [se]=0.62/day [0.05/day]) was high and similar among groups. CONCLUSIONS The high loss rate of HCV-infected cells suggests that sufficient dose and duration of SIL might achieve viral suppression in advanced liver disease.
Collapse
Affiliation(s)
- Laetitia Canini
- Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA
| | - Swati DebRoy
- Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA
- Department of Mathematics and Computational Science, University of South Carolina-Beaufort, Bluffton, SC, USA
| | - Zoe Mariño
- Liver Unit, Hospital Clinic, CIBERehd, IDIBAPS, Barcelona, Spain
| | - Jessica M Conway
- Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA
| | - Gonzalo Crespo
- Liver Unit, Hospital Clinic, CIBERehd, IDIBAPS, Barcelona, Spain
| | - Miquel Navasa
- Liver Unit, Hospital Clinic, CIBERehd, IDIBAPS, Barcelona, Spain
| | | | - Peter Ferenci
- Internal Medicine 3, Department of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Scott J Cotler
- Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA
| | - Xavier Forns
- Liver Unit, Hospital Clinic, CIBERehd, IDIBAPS, Barcelona, Spain
| | - Alan S Perelson
- Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA
| | - Harel Dahari
- Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA
- Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA
| |
Collapse
|
|
45
|
Ikeda K, Kawamura Y, Kobayashi M, Fukushima T, Sezaki H, Hosaka T, Akuta N, Saitoh S, Suzuki F, Suzuki Y, Arase Y, Kumada H. Prevention of disease progression with anti-inflammatory therapy in patients with HCV-related cirrhosis: a Markov model. Oncology 2014; 86:295-302. [PMID: 24924385 DOI: 10.1159/000357713] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2013] [Accepted: 11/26/2013] [Indexed: 01/13/2023]
Abstract
BACKGROUND The significance of anti-inflammatory therapy has not been fully evaluated in hepatitis C virus (HCV)-related cirrhosis. PATIENTS AND METHODS We analyzed stepwise progression rates from cirrhosis to hepatocellular carcinoma (HCC) and to death using a Markov model in 1,280 patients with HCV-related cirrhosis. During the observation period, 303 patients received interferon and 736 received glycyrrhizin injections as anti-inflammatory therapy. RESULTS In the entire group, annual progression rates from cirrhosis to HCC and from cirrhosis to death were 6.8 and 1.9%, and the rate from HCC to death was 19.0%. When sustained virological response (SVR) or biochemical response (BR) was attained with interferon, the annual rate to HCC decreased to 2.6%. On the contrary, the progression rates to HCC and to death in the patients without SVR and BR were 7.2 and 2.0%, respectively (p < 0.0001). Continuous interferon administration significantly decreased the carcinogenesis rate to 5.5% (p = 0.0087). In the analysis of the remaining patients with high alanine transaminase of 75 IU/l or more but without interferon response or without interferon administration, glycyrrhizin injection significantly decreased annual non-progression probability (no glycyrrhizin 88.0% vs. glycyrrhizin therapy 92.3%, p = 0.00055). CONCLUSION Glycyrrhizin injection therapy is useful in the prevention of disease progression in interferon-resistant or intolerant patients with HCV-related cirrhosis.
Collapse
Affiliation(s)
- Kenji Ikeda
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Schmidt-Martin D, Houlihan D, McCormick A. From the CUPIC study: great times are not coming(?). J Hepatol 2014; 60:899-900. [PMID: 24374294 DOI: 10.1016/j.jhep.2013.11.035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Accepted: 11/22/2013] [Indexed: 12/04/2022]
|
|
47
|
Giannini EG. Eltrombopag in patients with chronic hepatitis C and thrombocytopenia. Future Virol 2014. [DOI: 10.2217/fvl.13.115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
ABSTRACT: Eltrombopag is a thrombopoietic drug that acts by interacting with the TPO receptor and stimulates megakaryocytopoiesis and platelet production. Thrombocytopenia is a fairly frequent hematological abnormality in patients with chronic liver disease, and may represent an obstacle to interferon-based antiviral therapy in patients with chronic HCV infection who are otherwise good candidates for treatment. In large, multicenter, randomized, placebo-controlled studies, eltrombopag consistently enabled thrombocytopenic chronic hepatitis C patients to be treated with interferon-based therapy and, as an adjunct to antiviral therapy, has shown to be able to increase the sustained virologic response rate to treatment. The safety profile of the drug, with particular attention to the risk of thromboembolic events and the potential for hepatic decompensation, should be taken into account when planning treatment. The aim of this article is to review the information currently available regarding the pharmacokinetics, clinical efficacy and side-effect profile of eltrombopag, and to assess the role of this drug into the current and future hepatitis C treatment paradigm.
Collapse
Affiliation(s)
- Edoardo G Giannini
- Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Viale Benedetto XV, no.6, 16132, Genoa, Italy
| |
Collapse
|
|
48
|
Ogata T, Okuda K, Sato T, Hirakawa Y, Yasunaga M, Horiuchi H, Nomura Y, Kage M, Ide T, Kuromatsu R, Kinoshita H, Tanaka H. Long-term outcome of splenectomy in advanced cirrhotic patients with hepatocellular carcinoma and thrombocytopenia. Kurume Med J 2013; 60:37-45. [PMID: 24064764 DOI: 10.2739/kurumemedj.ms62010] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Splenectomy may be a treatment option in hepatocellular carcinoma (HCC) and cirrhosis when there is no potential donor for liver transplantation. We retrospectively investigated the long-term outcome of splenectomy on survival in advanced cirrhotic patients with HCC and thrombocytopenia. Between 1999 and 2009, 46 cirrhotic patients with thrombocytopenia (Child-Pugh class B or C) who underwent splenectomy for the simultaneous or secondary treatment of HCC at our institute were evaluated. The 1-, 3-, and 5-year survival rates were 93.5, 76.0, and 37.9%, respectively. Splenectomy resulted in a significant reduction in mean portal venous pressure from 21.2 to 16.8 mmHg and improvements in liver function tests such as total bilirubin, prothrombin time, platelet count, Child-Pugh score for 3 years, and albumin for 2 years. The mean frequency of treatment for HCC recurrence after surgery was 3.0 times (range 1-11). Seven patients out of 16 scheduled for Interferon (IFN) therapy after surgery achieved a sustained virological response (SVR). Multivariate analysis identified SVR after IFN therapy as an independent significant prognostic factor (Hazard ratio 0.18, 95%CI 0.03-0.65, P=0.006). Postoperative complications including liver failure (n=1), portal thrombosis (n=7), ascites (n=5), and bacterial infections (n=4) were observed in 14 patients (30%). Splenectomy can be a feasible supportive therapy for the continuation of anticancer therapy and completion of IFN therapy based on improvements in liver function and thrombocytopenia with minimum complications in patients with HCC and advanced cirrhosis with no potential donor.
Collapse
Affiliation(s)
- Toshiro Ogata
- Department of Surgery, Kurume University School of Medicine
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
49
|
Ji F, Zhang S, Huang N, Deng H, Li Z. Splenectomy prior to antiviral therapy in patients with hepatitis C virus related decompensated cirrhosis. Braz J Infect Dis 2013; 17:601-605. [PMID: 23830054 PMCID: PMC9425127 DOI: 10.1016/j.bjid.2013.02.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2012] [Revised: 02/04/2013] [Accepted: 02/06/2013] [Indexed: 12/22/2022] Open
Abstract
Patients with hepatitis C virus-related decompensated cirrhosis can benefit from interferon-based antiviral therapy, but the common complication of cytopenia is a contraindication for this treatment. Splenectomy prior to interferon therapy may alleviate this problem. To investigate whether splenectomy improves the efficacy of antiviral therapy, 13 interferon-naïve hepatitis C virus decompensated cirrhotic patients underwent splenectomy between January 2008 and January 2011, followed 1-3 months later by an interferon-based therapeutic regimen (pegylated/standard interferon-α combined with ribavirin for 48 weeks). Ten (76.9%) of the patients developed postoperative complications, which included minor portal vein thrombosis (2/13, 15.4%) and transient ascites (8/13, 61.5%). At one-month post-splenectomy, the patients showed significantly increased platelet (pre-surgery: 48.2±15.9 vs. 186.0±70.6×10(3)μL(-1), p<0.001) and leukocyte (2.1±0.5 vs. 5.7±1.4×10(3)μL(-1), p<0.001) counts. Eight (61.5%) of the patients achieved sustained virological response, including all HCV genotype 2a-infected patients (4/4, 100%) and some of the genotype 1b-infected patients (4/9, 44.4%). Temporary interferon-α suspension was required for one patient to address severe intestinal infection. These results indicate that splenectomy prior to interferon-based therapy was safe and may facilitate adherence to subsequent antiviral therapy in selected HCV cirrhotic patients with portal hypertension and hypersplenism.
Collapse
Affiliation(s)
- Fanpu Ji
- Department of Hepatology and Surgery, College of Medicine, Xi’an Jiaotong University, Shaanxi Province, China
- Department of Infectious Disease, College of Medicine, Xi’an Jiaotong University, Shaanxi Province, China
| | - Shu Zhang
- Department of Hepatology and Surgery, College of Medicine, Xi’an Jiaotong University, Shaanxi Province, China
| | - Na Huang
- Department of Laboratory Medicine, College of Medicine, Xi’an Jiaotong University, Shaanxi Province, China
| | - Hong Deng
- Department of Infectious Disease, College of Medicine, Xi’an Jiaotong University, Shaanxi Province, China
| | - Zongfang Li
- Department of Hepatology and Surgery, College of Medicine, Xi’an Jiaotong University, Shaanxi Province, China
| |
Collapse
|
|
50
|
Hézode C, Fontaine H, Dorival C, Larrey D, Zoulim F, Canva V, de Ledinghen V, Poynard T, Samuel D, Bourlière M, Zarski JP, Raabe JJ, Alric L, Marcellin P, Riachi G, Bernard PH, Loustaud-Ratti V, Métivier S, Tran A, Serfaty L, Abergel A, Causse X, Di Martino V, Guyader D, Lucidarme D, Grando-Lemaire V, Hillon P, Feray C, Dao T, Cacoub P, Rosa I, Attali P, Petrov-Sanchez V, Barthe Y, Pawlotsky JM, Pol S, Carrat F, Bronowicki JP. Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) - NCT01514890. J Hepatol 2013; 59:434-441. [PMID: 23669289 DOI: 10.1016/j.jhep.2013.04.035] [Citation(s) in RCA: 362] [Impact Index Per Article: 30.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2013] [Revised: 04/05/2013] [Accepted: 04/25/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS In phase III trials, the safety profile of triple therapy (pegylated interferon/ribavirin with boceprevir or telaprevir) seems to be similar in HCV treatment-experienced cirrhotic and non-cirrhotic patients, but few cirrhotics were included. We report the week 16 safety and efficacy analysis in a cohort of compensated cirrhotics treated in the French Early Access Programme. METHODS 674 genotype 1 patients, prospectively included, received 48 weeks of triple therapy. The analysis is restricted to 497 patients reaching week 16. RESULTS A high incidence of serious adverse events (40.0%), and of death and severe complications (severe infection or hepatic decompensation) (6.4%), and a difficult management of anaemia (erythropoietin and transfusion use in 50.7% and 12.1%) were observed. Independent predictors of anaemia < 8 g/dl or blood transfusion were: female gender (OR 2.19, 95% CI 1.11-4.33, p=0.024), no lead-in phase (OR 2.25, 95% CI 1.15-4.39, p=0.018), age ≥ 65 years (OR 3.04, 95% CI 1.54-6.02, p=0.0014), haemoglobin level (≤ 12 g/dl for females, ≤ 13 g/dl for males) (OR 5.30, 95% CI 2.49-11.5, p=0.0001). Death or severe complications were related to platelets count ≤ 100,000/mm(3) (OR 3.11, 95% CI 1.30-7.41, p=0.0105) and albumin <35 g/dl (OR 6.33, 95% CI 2.66-15.07, p=0.0001), with a risk of 44.1% in patients with both. However, the on-treatment virological response was high. CONCLUSIONS The safety profile was poor and patients with platelet count ≤ 100,000/mm(3) and serum albumin <35 g/L should not be treated with the triple therapy.
Collapse
Affiliation(s)
- Christophe Hézode
- Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, AP-HP, Université Paris-Est, INSERM U955, Créteil, France
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|