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Albillos A, Bañares R, Hernández-Gea V. Portal hypertension: recommendations for diagnosis and treatment. Consensus document sponsored by the Spanish Association for the Study of the Liver (AEEH) and the Biomedical Research Network Center for Liver and Digestive Diseases (CIBERehd). REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2025; 117:14-57. [PMID: 39350672 DOI: 10.17235/reed.2024.10805/2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2025]
Abstract
Portal hypertension is a hemodynamic abnormality that complicates the course of cirrhosis, as well as other diseases that affect the portal venous circulation. The development of portal hypertension compromises prognosis, especially when it rises above a certain threshold known as clinically significant portal hypertension (CSPH). In the consensus conference on Portal Hypertension promoted by the Spanish Association for the Study of the Liver and the Hepatic and Digestive diseases area of the Biomedical Research Networking Center (CIBERehd), different aspects of the diagnosis and treatment of portal hypertension caused by cirrhosis or other diseases were discussed. The outcome of this discussion was a set of recommendations that achieved varying degrees of consensus among panelists and are reflected in this consensus document. The six areas under discussion were: the relevance of clinically significant portal hypertension and the non-invasive methods used for its diagnosis and that of cirrhosis, the prevention of the first episode of decompensation and its recurrence, the treatment of acute variceal bleeding and other complications of portal hypertension, the indications for the use of TIPS, and finally, the diagnosis and treatment of liver vascular diseases.
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Affiliation(s)
- Agustín Albillos
- Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, España
| | - Rafael Bañares
- Servicio de Medicina de Aparato Digestivo, Hospital General Universitario Gregorio Marañón
| | - Virginia Hernández-Gea
- Servicio de Hepatología, Hospital Clínic. Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
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2
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Wu M, Vadlakonda S, El-Kattan Y, Ghosh A, Lin TH, Chambers-Wilson R, Cheng X, Bantia S, Kellogg-Yelder D, Chand P, Babu YS, Kotian PL. Synthesis and biological evaluation of Ribo 7-N/O/S pyrimidine 9-deaza C-nucleoside analogs as new antiviral agents for inhibiting HCV RNA-dependent RNA polymerases. Eur J Med Chem 2024; 264:115991. [PMID: 38118393 DOI: 10.1016/j.ejmech.2023.115991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 11/20/2023] [Accepted: 11/21/2023] [Indexed: 12/22/2023]
Abstract
Hepatitis C infection is caused by the bloodborne pathogen hepatitis C virus (HCV) and can lead to serious liver diseases and, ultimately, death if the treatment is ineffective. This work reports the synthesis and preclinical evaluation of 7 novel 9-O/N/S pyrimidine nucleosides, including compound 12, the triphosphate of known compound 7b. The nucleosides are 9-deaza modifications of adenosine and guanosine with β-2'-C-methyl substituent on the ribose. Within this series of compounds, a 9-deaza furopyrimidine analog of adenosine, compound 7b, showed high anti-HCV activity in vitro, good stability, low toxicity, and low genotoxicity when administrated in low doses, and an adequate pharmacokinetics profile. An improved synthesis of compound 7b compared to a previous study is also reported. Compound 12 was synthesized as a control to verify phosphorylation of 7b occurred in vivo.
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Affiliation(s)
- Minwan Wu
- BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center, Building 200, Suite 200, Birmingham, Alabama 35244, USA
| | - Satish Vadlakonda
- BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center, Building 200, Suite 200, Birmingham, Alabama 35244, USA
| | - Yahya El-Kattan
- BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center, Building 200, Suite 200, Birmingham, Alabama 35244, USA
| | - Ajit Ghosh
- BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center, Building 200, Suite 200, Birmingham, Alabama 35244, USA.
| | - Tsu-Hsing Lin
- BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center, Building 200, Suite 200, Birmingham, Alabama 35244, USA
| | - Ramanda Chambers-Wilson
- BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center, Building 200, Suite 200, Birmingham, Alabama 35244, USA
| | - Xiaogang Cheng
- BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center, Building 200, Suite 200, Birmingham, Alabama 35244, USA
| | - Shanta Bantia
- BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center, Building 200, Suite 200, Birmingham, Alabama 35244, USA.
| | - Debra Kellogg-Yelder
- BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center, Building 200, Suite 200, Birmingham, Alabama 35244, USA
| | - Pooran Chand
- BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center, Building 200, Suite 200, Birmingham, Alabama 35244, USA.
| | - Y S Babu
- BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center, Building 200, Suite 200, Birmingham, Alabama 35244, USA
| | - Pravin L Kotian
- BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center, Building 200, Suite 200, Birmingham, Alabama 35244, USA.
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Oliveira Correa JD, Zambra FMB, Michita RT, Álvares-da-Silva MR, Simon D, Chies JAB. HLA-G 3'UTR haplotype analyses in HCV infection and HCV-derived cirrhosis, hepatocellular carcinoma and fibrosis. Int J Immunogenet 2023; 50:249-255. [PMID: 37658479 DOI: 10.1111/iji.12636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 08/17/2023] [Accepted: 08/23/2023] [Indexed: 09/03/2023]
Abstract
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease. Chronic HCV infection is also an important cause of hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC). HCV has the capacity to evade immune surveillance by altering the host immune response. Moreover, variations in immune-related genes can lead to differential susceptibility to HCV infection as well as interfere on the susceptibility to the development of hepatic fibrosis, cirrhosis and HCC. The human leucocyte antigen G (HLA-G) gene codes for an immunomodulatory protein known to be expressed in the maternal-foetal interface and in immune-privileged tissues. The HLA-G 3' untranslated region (3'UTR) is important for mRNA stability, and variants in this region are known to impact gene expression. Studies, mainly focusing in a 14 bp insertion/deletion polymorphism, have correlated HLA-G 3'UTR with susceptibility to viral infections, but other polymorphic variants in the HLA-G 3'UTR might also affect HCV infection as they are inherited as haplotypes. The present study evaluated HLA-G 3'UTR polymorphisms and performed linkage disequilibrium test and haplotype assembly in 286 HCV infected patients who have developed fibrosis, cirrhosis or HCC, as well as in 129 healthy control subjects. Haplotypes UTR-1, UTR-2 and UTR-3 were the most observed in HCV+ patients, in the frequencies of 0.276, 0.255 and 0.121, respectively. No statistically significant difference was observed between HCV+ and control subjects, even when patients were grouped according to outcome (HCC, cirrhosis or fibrosis). Despite that, some trends in the results were observed, and therefore, we cannot rule out the possibility that variants associated to high HLA-G expression can be involved in HCV infection susceptibility.
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Affiliation(s)
- Julio Daimar Oliveira Correa
- Departamento de Genética, Instituto de Biociências, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | | | - Rafael Tomoya Michita
- Departamento de Genética, Instituto de Biociências, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | | | - Daniel Simon
- Laboratório de Genética Molecular Humana, Universidade Luterana do Brasil (ULBRA), Canoas, Brazil
| | - José Artur Bogo Chies
- Departamento de Genética, Instituto de Biociências, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
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Martinez-Castillo M, Altamirano-Mendoza I, Sánchez-Valle S, García-Islas L, Sánchez-Barragán M, Hernández-Santillán M, Hernández-Barragán A, Pérez-Hernández J, Higuera-de la Tijera F, Gutierrez-Reyes G. Desregulación inmunológica y fisiopatología del consumo de alcohol y la enfermedad hepática alcohólica. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2023; 88:136-154. [DOI: 10.1016/j.rgmx.2023.01.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Liu TW, Huang CF, Tsai PC, Yeh ML, Jang TY, Huang JF, Dai CY, Yu ML, Chuang WL. The compound annual growth rate of the fibrosis-4 index in chronic hepatitis B patients. Kaohsiung J Med Sci 2022; 38:686-693. [PMID: 35403363 DOI: 10.1002/kjm2.12543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 02/25/2022] [Accepted: 03/22/2022] [Indexed: 09/11/2023] Open
Abstract
Chronic hepatitis B (CHB) patients with low disease activity are at risk of liver fibrosis. The age-adjusted fibrosis-4 index (FIB4-AA), developed in our previous publication, and was implemented to evaluate the tendency of liver fibrosis in these patients. We aimed to investigate the rate of liver fibrosis in CHB patients with low disease activity. Resuming our previous study, the FIB-4 changes of 244 antiviral treatment-naïve CHB patients, with a total of 1243.48 person-years, were reviewed. Among the cohort, patients were categorized as FIB4-AA positive or negative according to the results of their last FIB4-AA minus their initial FIB-4 during at least 18 months of observation time. The compound annual growth rate (CAGR) of FIB-4 was calculated for the FIB4-AA positive and negative groups. The assumed healthy controls had an FIB-4 CAGR calculated to be 2.34% for both men and women, while the FIB-4 CAGR of the whole study cohort was 2.84% ± 6.01%. FIB4-AA positive effectively identifies CHB patients with higher mean FIB-4 CAGR (7.11% ± 3.88% vs. -2.36% ± 3.52%, p < 0.0001). Overweight CHB patients had 10 times smaller mean FIB-4 CAGR than lean ones (0.38% ± 10.35% vs. 3.83% ± 8.88%, p = 0.009). An increase in FIB4-AA over at least 18 months in CHB patients with relatively low disease activity meant they were at greater risk of liver fibrosis, and these patients had a mean FIB-4 CAGR of 7.11%. The FIB-4 CAGR was compatible with the findings of previous studies on the collagen proportionate area in viral hepatitis patients.
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Affiliation(s)
- Ta-Wei Liu
- Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
| | - Chung-Feng Huang
- Division of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Pei-Chien Tsai
- Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ming-Lun Yeh
- Division of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Tyng-Yuan Jang
- Division of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Pingtung Hospital, Ministry of Health and Welfare, Pingtung, Taiwan
| | - Jee-Fu Huang
- Division of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Division of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- Division of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Wan-Long Chuang
- Division of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
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6
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Mezina A, Krishnan A, Woreta TA, Rubenstein KB, Watson E, Chen PH, Rodriguez-Watson C. Longitudinal assessment of liver stiffness by transient elastography for chronic hepatitis C patients. World J Clin Cases 2022; 10:5566-5576. [PMID: 35979107 PMCID: PMC9258363 DOI: 10.12998/wjcc.v10.i17.5566] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 12/16/2021] [Accepted: 04/21/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Liver fibrosis is a common pathway of liver injury and is a feature of most chronic liver diseases. Fibrosis progression varies markedly in patients with hepatitis C virus (HCV). Liver stiffness has been recommended as a parameter of fibrosis progression/regression in patients with HCV.
AIM To investigate changes in liver stiffness measured by transient elastography (TE) in a large, racially diverse cohort of United States patients with chronic hepatitis C (CHC).
METHODS We evaluated the differences in liver stiffness between patients treated with direct-acting antiviral (DAA) therapy and untreated patients. Patients had ≥ 2 TE measurements and no prior DAA exposure. We used linear regression to measure the change in liver stiffness between first and last TE in response to treatment, controlling for age, sex, race, diabetes, smoking status, human immunodeficiency virus status, baseline alanine aminotransferase, and baseline liver stiffness. Separate regression models analyzed the change in liver stiffness as measured by kPa, stratified by cirrhosis status.
RESULTS Of 813 patients, 419 (52%) initiated DAA treatment. Baseline liver stiffness was 12 kPa in 127 (16%). Median time between first and last TE was 11.7 and 12.7 mo among treated and untreated patients, respectively. There was no significant change in liver stiffness observed over time in either the group initiating DAA treatment (0.016 kPa/month; CI: -0.051, 0.084) or in the untreated group (0.001 kPa/mo; CI: -0.090, 0.092), controlling for covariates. A higher baseline kPa score was independently associated with decreased liver stiffness.
CONCLUSION DAA treatment was not associated with a differential change in liver stiffness over time in patients with CHC compared to untreated patients.
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Affiliation(s)
- Anya Mezina
- Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21287, United States
| | - Arunkumar Krishnan
- Division of Gastroenterology and Hepatology, Johns Hopkins School of Medicine, Baltimore, MD 21231, United States
| | - Tinsay A Woreta
- Division of Gastroenterology and Hepatology, Johns Hopkins School of Medicine, Baltimore, MD 21231, United States
| | - Kevin B Rubenstein
- Mid-Atlantic Permanente Research Institute, Kaiser Permanente Mid-Atlantic States, Rockville 20852, United States
| | - Eric Watson
- Mid-Atlantic Permanente Research Institute, Kaiser Permanente Mid-Atlantic States, Rockville 20852, United States
| | - Po-Hung Chen
- Division of Gastroenterology and Hepatology, Johns Hopkins School of Medicine, Baltimore, MD 21231, United States
| | - Carla Rodriguez-Watson
- Mid-Atlantic Permanente Research Institute, Kaiser Permanente Mid-Atlantic States, Rockville 20852, United States
- Department of Health Policy and Management, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21287, United States
- Innovation in Medical Evidence Development and Surveillance (IMEDS) Program, Reagan-Udall Foundation for the FDA, Washington, 20036, United States
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7
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Cuesta-Sancho S, Márquez-Coello M, Illanes-Álvarez F, Márquez-Ruiz D, Arizcorreta A, Galán-Sánchez F, Montiel N, Rodriguez-Iglesias M, Girón-González JA. Hepatitis C: Problems to extinction and residual hepatic and extrahepatic lesions after sustained virological response. World J Hepatol 2022; 14:62-79. [PMID: 35126840 PMCID: PMC8790402 DOI: 10.4254/wjh.v14.i1.62] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 08/02/2021] [Accepted: 12/10/2021] [Indexed: 02/06/2023] Open
Abstract
Loss of follow-up or reinfections hinder the expectations of hepatitis C eradication despite the existence of highly effective treatments. Moreover, the elimination of the infection does not imply the reversion of those chronic alterations derived from the previous infection by hepatitis C virus (HCV). This review analyzes the risk factors associated with loss to follow-up in diagnosis or treatment, and the possibility of reinfection. Likewise, it assesses the residual alterations induced by chronic HCV infection considering the liver alterations (inflammation, fibrosis, risk of decompensation, hepatocellular carcinoma, liver transplantation) and, on the other hand, the comorbidities and extrahepatic manifestations (cryoglobulinemia, non-Hodgkin lymphoma, peripheral insulin resistance, and lipid, bone and cognitive alterations). Peculiarities present in subjects coinfected with human immunodeficiency virus are analyzed in each section.
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Affiliation(s)
- Sara Cuesta-Sancho
- Medicina Interna, Hospital Universitario Puerta del Mar, Facultad de Medicina, Universidad de Cádiz, Instituto para la Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), Cádiz 11009, Spain
| | - Mercedes Márquez-Coello
- Medicina Interna, Hospital Universitario Puerta del Mar, Facultad de Medicina, Universidad de Cádiz, Instituto para la Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), Cádiz 11009, Spain
| | - Francisco Illanes-Álvarez
- Medicina Interna, Hospital Universitario Puerta del Mar, Facultad de Medicina, Universidad de Cádiz, Instituto para la Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), Cádiz 11009, Spain
| | - Denisse Márquez-Ruiz
- Medicina Interna, Hospital Universitario Puerta del Mar, Facultad de Medicina, Universidad de Cádiz, Instituto para la Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), Cádiz 11009, Spain
| | - Ana Arizcorreta
- Medicina Interna, Hospital Universitario Puerta del Mar, Facultad de Medicina, Universidad de Cádiz, Instituto para la Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), Cádiz 11009, Spain
| | - Fátima Galán-Sánchez
- Microbiología, Hospital Universitario Puerta del Mar, Facultad de Medicina, Universidad de Cádiz, Instituto para la Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), Cádiz 11009, Spain
| | - Natalia Montiel
- Microbiología, Hospital Universitario Puerta del Mar, Facultad de Medicina, Universidad de Cádiz, Instituto para la Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), Cádiz 11009, Spain
| | - Manuel Rodriguez-Iglesias
- Microbiología, Hospital Universitario Puerta del Mar, Facultad de Medicina, Universidad de Cádiz, Instituto para la Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), Cádiz 11009, Spain
| | - José-Antonio Girón-González
- Medicina Interna, Hospital Universitario Puerta del Mar, Facultad de Medicina, Universidad de Cádiz, Instituto para la Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), Cádiz 11009, Spain
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Ahumada A, Rayón L, Usón C, Bañares R, Alonso Lopez S. Hepatocellular carcinoma risk after viral response in hepatitis C virus-advanced fibrosis: Who to screen and for how long? World J Gastroenterol 2021; 27:6737-6749. [PMID: 34790004 PMCID: PMC8567476 DOI: 10.3748/wjg.v27.i40.6737] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 06/24/2021] [Accepted: 09/19/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) chronic infection is associated with fibrosis progression, end-stage liver complications and HCC. Not surprisingly, HCV infection is a leading cause of liver-related morbidity and mortality worldwide. After sustained virological response (SVR), the risk of developing hepatocellular carcinoma is not completely eliminated in patients with established cirrhosis or with advanced fibrosis. Therefore, lifelong surveillance is currently recommended. This strategy is likely not universally cost-effective and harmless, considering that not all patients with advanced fibrosis have the same risk of developing HCC. Factors related to the severity of liver disease and its potential to improve after SVR, the molecular and epigenetic changes that occur during infection and other associated comorbidities might account for different risk levels and are likely essential for identifying patients who would benefit from screening programs after SVR. Efforts to develop predictive models and risk calculators, biomarkers and genetic panels and even deep learning models to estimate the individual risk of HCC have been made in the direct-acting antiviral agents era, when thousands of patients with advanced fibrosis and cirrhosis have reached SVR. These tools could help to identify patients with very low HCC risk in whom surveillance might not be justified. In this review, factors affecting the probability of HCC development after SVR, the benefits and risks of surveillance, suggested strategies to estimate individualized HCC risk and the current evidence to recommend lifelong surveillance are discussed.
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Affiliation(s)
- Adriana Ahumada
- Liver Unit, Hospital General Universitario Gregorio Marañón, Madrid 28007, Spain
- Liver Unit, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid 28007, Spain
| | - Laura Rayón
- Liver Unit, Hospital General Universitario Gregorio Marañón, Madrid 28007, Spain
| | - Clara Usón
- Liver Unit, Hospital General Universitario Gregorio Marañón, Madrid 28007, Spain
| | - Rafael Bañares
- Liver Unit, Hospital General Universitario Gregorio Marañón, Madrid 28007, Spain
- Liver Unit, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid 28007, Spain
- Medicine, Universidad Complutense de Madrid, Madrid 28006, Spain
- Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid 28029, Spain
| | - Sonia Alonso Lopez
- Liver Unit, Hospital General Universitario Gregorio Marañón, Madrid 28007, Spain
- Liver Unit, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid 28007, Spain
- Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid 28029, Spain
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Siphepho PY, Liu YT, Shabangu CS, Huang JF, Huang CF, Yeh ML, Yu ML, Wang SC. The Impact of Steatosis on Chronic Hepatitis C Progression and Response to Antiviral Treatments. Biomedicines 2021; 9:1491. [PMID: 34680608 PMCID: PMC8533513 DOI: 10.3390/biomedicines9101491] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 10/12/2021] [Accepted: 10/13/2021] [Indexed: 02/07/2023] Open
Abstract
Metabolic derangement is characteristic in patients with hepatitis C virus (HCV) infection. Aside from established liver injury, various extrahepatic metabolic disorders impact the natural history of the disease, clinical outcomes, and the efficacy of antiviral therapy. The presence of steatosis, recently redefined as metabolic-associated fatty liver disease (MAFLD), is a common feature in HCV-infected patients, induced by host and/or viral factors. Most chronic HCV-infected (CHC) patients have mild steatosis within the periportal region of the liver with an estimated prevalence of 40% to 86%. Indeed, this is higher than the 19% to 50% prevalence observed in patients with other chronic liver diseases such as chronic hepatitis B (CHB). The histological manifestations of HCV infection are frequently observed in genotype 3 (G-3), where relative to other genotypes, the prevalence and severity of steatosis is also increased. Steatosis may independently influence the treatment efficacy of either interferon-based or interferon-free antiviral regimens. This review aimed to provide updated evidence of the prevalence and risk factors behind HCV-associated steatosis, as well as explore the impact of steatosis on HCV-related outcomes.
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Affiliation(s)
- Phumelele Yvonne Siphepho
- Program in Tropical Medicine, Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (P.Y.S.); (M.-L.Y.)
- Center for Cancer Research, Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.S.S.); (J.-F.H.)
| | - Yi-Ting Liu
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Ciniso Sylvester Shabangu
- Center for Cancer Research, Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.S.S.); (J.-F.H.)
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Jee-Fu Huang
- Center for Cancer Research, Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.S.S.); (J.-F.H.)
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-F.H.); (M.-L.Y.)
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Chung-Feng Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-F.H.); (M.-L.Y.)
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-F.H.); (M.-L.Y.)
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Ming-Lung Yu
- Program in Tropical Medicine, Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (P.Y.S.); (M.-L.Y.)
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-F.H.); (M.-L.Y.)
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Shu-Chi Wang
- Center for Cancer Research, Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.S.S.); (J.-F.H.)
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
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Yaraş S, Sezgin O, Üçbilek E, Özdoğan O, Altıntaş E. Significant decrease in liver stiffness detected by two dimensional shear-wave elastography after treatment with direct-acting antiviral agents in patients with chronic Hepatitis C. TURKISH JOURNAL OF GASTROENTEROLOGY 2021; 31:142-147. [PMID: 32141823 DOI: 10.5152/tjg.2020.19418] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND/AIMS Two-dimensional shear-wave (2D-SWE) elastography is one of the noninvasive methods for the evaluation of liver fibrosis. The purpose of this study is to investigate the changes in liver stiffness (LS) by employing 2D-SWE as well as its correlation with noninvasive fibrosis markers in patients with chronic hepatitis C (CHC), who are undergoing direct-acting antiviral (DAA) therapy. MATERIALS AND METHODS The researchers included all the patients with CHC who are scheduled for DAA treatment in this study. 2D-SWE measurements were performed at baseline, end of treatment (EOT), and 12 weeks after the treatment. According to the latest EFSUMB guidelines, elastography measurements were performed during the ultrasonographic evaluation and recorded in kilopascals (unit). The correlation between biochemical and viral responses, and noninvasive fibrosis scores (FIB-4, AST-to-platelet ratio index (APRI)) was also evaluated. RESULTS This study employed 230 patients who underwent treatment with DAAs between September 2016 and September 2017. However, 131 patients were able to complete the study, of which 48 (36.6%) were male and 83 (63.4%) were female. The mean age was 65.0 (±11.18) years. Both EOT and sustained viral response (SVR) had the same rate of 99.2% (130/131). The SWE measurement (mean) values at pretreatment, EOT, and 12 weeks after treatment was 12.92, 10.45, and 9.07 kPa, respectively (p<0.05), whereas the APRI scores were 0.76, 0.39, and 0.30, respectively (p<0.05). Additionally, the FIB-4 scores at pretreatment, EOT, and 12 weeks after treatment were 2.98, 2.43, and 2.03, respectively (p<0.05). The results of liver stiffness measurements (LSM) were similar in all the groups of cirrhotic, noncirrhotic, treatment-experienced, and treatment-naive patients. CONCLUSION DAA treatments in the patients with CHC led to almost a complete SVR and a considerable decrease in LS in a short time.
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Affiliation(s)
- Serkan Yaraş
- Department of Gastroenterology, Mersin University School of Medicine, Mersin, Turkey
| | - Orhan Sezgin
- Department of Gastroenterology, Mersin University School of Medicine, Mersin, Turkey
| | - Enver Üçbilek
- Department of Gastroenterology, Mersin University School of Medicine, Mersin, Turkey
| | - Osman Özdoğan
- Department of Gastroenterology, Mersin University School of Medicine, Mersin, Turkey
| | - Engin Altıntaş
- Department of Gastroenterology, Mersin University School of Medicine, Mersin, Turkey
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11
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Vergara M, Miquel M, Vela E, Cleries M, Pontes C, Prat A, Rué M. Use of healthcare resources and drug expenditure before and after treatment of chronic hepatitis C with direct antiviral agents. J Viral Hepat 2021; 28:728-738. [PMID: 33555102 DOI: 10.1111/jvh.13479] [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: 09/10/2020] [Accepted: 01/23/2021] [Indexed: 12/09/2022]
Abstract
The aim of this study was to analyse the impact of treating chronic hepatitis C (CHC) with direct-acting agents (DAA) on the use of healthcare resources. We included all patients treated with DAA for CHC from January 2015 to December 2017 in Catalonia whose medical records from 12 months before to 24 months after treatment were available. Data were obtained from the Catalan Health Surveillance System. A total of 12,199 patients in Catalonia were treated with DAA for CHC. Of these, 11.3% had no-minimal fibrosis (F0-F1), 24.0% had moderate fibrosis (F2), 50.3% had significant fibrosis or cirrhosis (F3-F4), and 14.4% had decompensated cirrhosis. Use of healthcare resources decreased from the pre-treatment period to the post-treatment period for the following: hospital admissions due to complications of cirrhosis, from 0.19 to 0.12 per month per 100 patients (RR 0.57; 95% CI 0.47-0.68); length of hospital stay, from 12.9 to 12.2 days (RR 0.93; 95% CI 0.91-0.94); outpatient visits, from 65.0 to 49.2 (RR 0.75; 95% CI 0.74-0.75); and number of medication containers per patient per month, from 13.9 to 12.5 (RR 0.837; 95% CI 0.835-0.838). However, the number of invoices for antineoplastic treatment increased after DAA treatment, especially for patients with high morbidity or advanced fibrosis stage. In conclusion, a decrease in health resource use was seen in CHC patients treated with DAA, as measured by length of hospital stay, number of admissions due to cirrhosis complications, outpatient visits and overall drug invoicing. However, use of antineoplastic drugs increased significantly, especially in patients with cirrhosis and high morbidity.
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Affiliation(s)
- Mercedes Vergara
- Unitat d'Hepatologia, Servei d'Aparell Digestiu, Parc Taulí Sabadell Hospital Universitari, Institut d'Investigació i Innovació I3PT, Universitat Autònoma de Barcelona, Sabadell, Barcelona, Spain.,Departament de Medicina, Universitat Autònoma de Barcelona, Sabadell, Barcelona, Spain.,CIBERehd, Instituto Carlos III, Madrid, Spain
| | - Mireia Miquel
- Unitat d'Hepatologia, Servei d'Aparell Digestiu, Parc Taulí Sabadell Hospital Universitari, Institut d'Investigació i Innovació I3PT, Universitat Autònoma de Barcelona, Sabadell, Barcelona, Spain.,Departament de Medicina, Universitat Autònoma de Barcelona, Sabadell, Barcelona, Spain.,CIBERehd, Instituto Carlos III, Madrid, Spain
| | - Emili Vela
- Unitat d'informació i Coneixement, Servei Català de la Salut, Barcelona, Spain
| | - Montserrat Cleries
- Unitat d'informació i Coneixement, Servei Català de la Salut, Barcelona, Spain
| | - Caridad Pontes
- Gerència del Medicament, Àrea Assistencial, Servei Català de la Salut, Barcelona, Spain.,Departament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de Barcelona, Sabadell, Barcelona, Spain
| | - Alba Prat
- Gerència del Medicament, Àrea Assistencial, Servei Català de la Salut, Barcelona, Spain
| | - Montse Rué
- Basic Medical Sciences Department, University of Lleida, Lleida, Spain
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Takakusagi S, Takagi H, Kosone T, Sato K, Kakizaki S, Uraoka T. Prognosis of late elderly patients with chronic hepatitis C after achieving a sustained viral response by direct-acting antivirals. JGH OPEN 2021; 5:122-127. [PMID: 33490621 PMCID: PMC7812467 DOI: 10.1002/jgh3.12459] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 11/07/2020] [Accepted: 11/09/2020] [Indexed: 12/16/2022]
Abstract
Background and Aim We investigated the prognosis of late elderly patients (≥75 years old) after the achievement of a sustained viral response (SVR) by direct‐acting antivirals (DAAs). Methods One hundred and four late elderly patients and 251 young patients (≤74 years old) who had achieved an SVR were included. We compared the cumulative hepatocellular carcinoma (HCC) incidence rates and survival rates after DAA administration. Furthermore, the factors associated with HCC incidence and the causes of death after DAA administration were also investigated. Results The cumulative HCC incidence rates for 1 and 3 years were 2.9% and 11.7% in the late elderly patients and 2.4% and 5.4% in the young patients, respectively. The cumulative survival rates for 1 and 3 years were 100% and 95.6% in the late elderly patients and 100% and 96.4% in the young patients, respectively, with no significant differences in those rates noted (P = 0.133, P = 0.322, respectively). In the late elderly patients, only a history of HCC was a significant factor associated with HCC incidence after DAA administration. Five late elderly patients died after achieving an SVR, and malignant liver tumor was the cause of death in three of those patients. Conclusions The prognosis did not differ markedly between late elderly patients and young patients. The factor most strongly influencing the prognosis of late elderly patients was likely liver disease, including HCC. DAAs should be introduced even in late elderly patients who can be expected to have a relative long‐term survival.
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Affiliation(s)
- Satoshi Takakusagi
- Department of Gastroenterology and Hepatology Kusunoki Hospital Fujioka Japan
| | - Hitoshi Takagi
- Department of Gastroenterology and Hepatology Kusunoki Hospital Fujioka Japan
| | - Takashi Kosone
- Department of Gastroenterology and Hepatology Kusunoki Hospital Fujioka Japan
| | - Ken Sato
- Department of Gastroenterology and Hepatology Gunma University Graduate School of Medicine Maebashi Japan
| | - Satoru Kakizaki
- Department of Gastroenterology and Hepatology Gunma University Graduate School of Medicine Maebashi Japan.,Department of Clinical Research National Hospital Organization Takasaki General Medical Center Takasaki Japan
| | - Toshio Uraoka
- Department of Gastroenterology and Hepatology Gunma University Graduate School of Medicine Maebashi Japan
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BAKIR A, GÜNEY M, ERDAL H, YAVUZ Ö, GÜNAL A, GÜLŞEN M, YAVUZ MT. Assessment of The Performances of Hepatitis C Virus Viral Markers, Age-Platelet Index and Aspartate aminotransferase to Alanine Aminotransferase Ratio Scores, in Predicting Liver Histopathology. TURKISH JOURNAL OF INTERNAL MEDICINE 2020. [DOI: 10.46310/tjim.825814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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Mostafa MA, Kamal O, Yassin A, Nagi MA, Ahmed OA, Ahmed HA. The diagnostic value of normalized ADC using spleen as reference organ in assessment liver fibrosis. THE EGYPTIAN JOURNAL OF RADIOLOGY AND NUCLEAR MEDICINE 2020. [DOI: 10.1186/s43055-020-00212-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
To investigate the value of liver ADC normalization using spleen as a reference organ in liver fibrosis assessment compared to Fibroscan.
A total of 60 participants were included, 30 HCV positive patients and 30 in control group. We calculated mean spleen apparent diffusion coefficient (ADC), liver mean ADC, and normalized liver ADC (defined as the ratio of liver ADC to spleen ADC) which were compared between cirrhotic patients and the control group. Data was analyzed, and ROC was used to evaluate the performance of nADC.
Results
No significant difference between spleen ADC values of patient and control groups or in-between different fibrosis stages. A negative correlation between liver ADC and nADC values with increasing fibrosis stages. We also found that the mean liver ADC and nADC value in patients with hepatic fibrosis were significantly lower than that of control group (1.53 × 10−3 mm2/s vs 1.65 × 10−3 mm2/s). After analysis with ROC, nADC shows higher diagnostic performance compared to liver ADC. nADC area under the curve (AUC) was 0.878 for detection of stage ≥ F2 with sensitivity and specificity of 87% and 80% respectively while ADC AUC was 0.548 with sensitivity and specificity of 62% and 72% respectively (p = 0.021); ≥ F3 AUC of nADC was 0.891 with sensitivity and specificity of 88.7% and 80% respectively while ADC AUC is 0.603 with sensitivity and specificity of 72% and 72% respectively (p = 0.023), and F4 stage nADC AUC was 0.879 for with sensitivity and specificity of 90% and 80% respectively, while ADC AUC was 0.648 with sensitivity and specificity of 80% and 72% respectively (p = 0.054).
Conclusion
Normalized liver ADC using the spleen as reference organs increases the diagnostic performance of MR in evaluation liver fibrosis compared to ADC alone.
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15
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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: 14] [Impact Index Per Article: 2.8] [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.
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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
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16
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The role of diffusion tensor imaging for the assessment of liver fibrosis and inflammation in chronic viral hepatitis: A preliminary study. MARMARA MEDICAL JOURNAL 2020. [DOI: 10.5472/marumj.741724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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17
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Zhou IY, Clavijo Jordan V, Rotile NJ, Akam E, Krishnan S, Arora G, Krishnan H, Slattery H, Warner N, Mercaldo N, Farrar CT, Wellen J, Martinez R, Schlerman F, Tanabe KK, Fuchs BC, Caravan P. Advanced MRI of Liver Fibrosis and Treatment Response in a Rat Model of Nonalcoholic Steatohepatitis. Radiology 2020; 296:67-75. [PMID: 32343209 DOI: 10.1148/radiol.2020192118] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Background Liver biopsy is the reference standard to diagnose nonalcoholic steatohepatitis (NASH) but is invasive with potential complications. Purpose To evaluate molecular MRI with type 1 collagen-specific probe EP-3533 and allysine-targeted fibrogenesis probe Gd-Hyd, MR elastography, and native T1 to characterize fibrosis and to assess treatment response in a rat model of NASH. Materials and Methods MRI was performed prospectively (June-November 2018) in six groups of male Wistar rats (a) age- and (b) weight-matched animals received standard chow (n = 12 per group); (c) received choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD) for 6 weeks or (d) 9 weeks (n = 8 per group); (e) were fed 6 weeks of CDAHFD and switched to standard chow for 3 weeks (n = 12); (f) were fed CDAHFD for 9 weeks with daily treatment of elafibranor beginning at week 6 (n = 14). Differences in imaging measurements and tissue analyses among groups were tested with one-way analysis of variance. The ability of each imaging measurement to stage fibrosis was quantified by using area under the receiver operating characteristic curve (AUC) with quantitative digital pathology (collagen proportionate area [CPA]) as reference standard. Optimal cutoff values for distinguishing advanced fibrosis were used to assess treatment response. Results AUC for distinguishing fibrotic (CPA >4.8%) from nonfibrotic (CPA ≤4.8%) livers was 0.95 (95% confidence interval [CI]: 0.91, 1.00) for EP-3533, followed by native T1, Gd-Hyd, and MR elastography with AUCs of 0.90 (95% CI: 0.83, 0.98), 0.84 (95% CI: 0.74, 0.95), and 0.65 (95% CI: 0.51, 0.79), respectively. AUCs for discriminating advanced fibrosis (CPA >10.3%) were 0.86 (95% CI: 0.76, 0.97), 0.96 (95% CI: 0.90, 1.01), 0.84 (95% CI: 0.70, 0.98), and 0.74 (95% CI: 0.63, 0.86) for EP-3533, Gd-Hyd, MR elastography, and native T1, respectively. Gd-Hyd MRI had the highest accuracy (24 of 26, 92%; 95% CI: 75%, 99%) in identifying responders and nonresponders in the treated groups compared with MR elastography (23 of 26, 88%; 95% CI: 70%, 98%), EP-3533 (20 of 26, 77%; 95% CI: 56%, 91%), and native T1 (14 of 26, 54%; 95% CI: 33%, 73%). Conclusion Collagen-targeted molecular MRI most accurately detected early onset of fibrosis, whereas the fibrogenesis probe Gd-Hyd proved most accurate for detecting treatment response. © RSNA, 2020 Online supplemental material is available for this article.
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Affiliation(s)
- Iris Y Zhou
- From the Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging (I.Y.Z., V.C.J., N.J.R., E.A., H.K., H.S., N.W., C.T.F., P.C.), Division of Surgical Oncology (S.K., G.A., K.K.T., B.C.F.), and Institute for Technology Assessment, Department of Radiology (N.M.), Massachusetts General Hospital and Harvard Medical School, Charlestown, 149 13th St, Boston, MA 02129; and Pfizer, Cambridge, Mass (J.W., R.M., F.S.)
| | - Veronica Clavijo Jordan
- From the Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging (I.Y.Z., V.C.J., N.J.R., E.A., H.K., H.S., N.W., C.T.F., P.C.), Division of Surgical Oncology (S.K., G.A., K.K.T., B.C.F.), and Institute for Technology Assessment, Department of Radiology (N.M.), Massachusetts General Hospital and Harvard Medical School, Charlestown, 149 13th St, Boston, MA 02129; and Pfizer, Cambridge, Mass (J.W., R.M., F.S.)
| | - Nicholas J Rotile
- From the Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging (I.Y.Z., V.C.J., N.J.R., E.A., H.K., H.S., N.W., C.T.F., P.C.), Division of Surgical Oncology (S.K., G.A., K.K.T., B.C.F.), and Institute for Technology Assessment, Department of Radiology (N.M.), Massachusetts General Hospital and Harvard Medical School, Charlestown, 149 13th St, Boston, MA 02129; and Pfizer, Cambridge, Mass (J.W., R.M., F.S.)
| | - Eman Akam
- From the Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging (I.Y.Z., V.C.J., N.J.R., E.A., H.K., H.S., N.W., C.T.F., P.C.), Division of Surgical Oncology (S.K., G.A., K.K.T., B.C.F.), and Institute for Technology Assessment, Department of Radiology (N.M.), Massachusetts General Hospital and Harvard Medical School, Charlestown, 149 13th St, Boston, MA 02129; and Pfizer, Cambridge, Mass (J.W., R.M., F.S.)
| | - Smitha Krishnan
- From the Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging (I.Y.Z., V.C.J., N.J.R., E.A., H.K., H.S., N.W., C.T.F., P.C.), Division of Surgical Oncology (S.K., G.A., K.K.T., B.C.F.), and Institute for Technology Assessment, Department of Radiology (N.M.), Massachusetts General Hospital and Harvard Medical School, Charlestown, 149 13th St, Boston, MA 02129; and Pfizer, Cambridge, Mass (J.W., R.M., F.S.)
| | - Gunisha Arora
- From the Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging (I.Y.Z., V.C.J., N.J.R., E.A., H.K., H.S., N.W., C.T.F., P.C.), Division of Surgical Oncology (S.K., G.A., K.K.T., B.C.F.), and Institute for Technology Assessment, Department of Radiology (N.M.), Massachusetts General Hospital and Harvard Medical School, Charlestown, 149 13th St, Boston, MA 02129; and Pfizer, Cambridge, Mass (J.W., R.M., F.S.)
| | - Hema Krishnan
- From the Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging (I.Y.Z., V.C.J., N.J.R., E.A., H.K., H.S., N.W., C.T.F., P.C.), Division of Surgical Oncology (S.K., G.A., K.K.T., B.C.F.), and Institute for Technology Assessment, Department of Radiology (N.M.), Massachusetts General Hospital and Harvard Medical School, Charlestown, 149 13th St, Boston, MA 02129; and Pfizer, Cambridge, Mass (J.W., R.M., F.S.)
| | - Hannah Slattery
- From the Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging (I.Y.Z., V.C.J., N.J.R., E.A., H.K., H.S., N.W., C.T.F., P.C.), Division of Surgical Oncology (S.K., G.A., K.K.T., B.C.F.), and Institute for Technology Assessment, Department of Radiology (N.M.), Massachusetts General Hospital and Harvard Medical School, Charlestown, 149 13th St, Boston, MA 02129; and Pfizer, Cambridge, Mass (J.W., R.M., F.S.)
| | - Noah Warner
- From the Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging (I.Y.Z., V.C.J., N.J.R., E.A., H.K., H.S., N.W., C.T.F., P.C.), Division of Surgical Oncology (S.K., G.A., K.K.T., B.C.F.), and Institute for Technology Assessment, Department of Radiology (N.M.), Massachusetts General Hospital and Harvard Medical School, Charlestown, 149 13th St, Boston, MA 02129; and Pfizer, Cambridge, Mass (J.W., R.M., F.S.)
| | - Nathaniel Mercaldo
- From the Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging (I.Y.Z., V.C.J., N.J.R., E.A., H.K., H.S., N.W., C.T.F., P.C.), Division of Surgical Oncology (S.K., G.A., K.K.T., B.C.F.), and Institute for Technology Assessment, Department of Radiology (N.M.), Massachusetts General Hospital and Harvard Medical School, Charlestown, 149 13th St, Boston, MA 02129; and Pfizer, Cambridge, Mass (J.W., R.M., F.S.)
| | - Christian T Farrar
- From the Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging (I.Y.Z., V.C.J., N.J.R., E.A., H.K., H.S., N.W., C.T.F., P.C.), Division of Surgical Oncology (S.K., G.A., K.K.T., B.C.F.), and Institute for Technology Assessment, Department of Radiology (N.M.), Massachusetts General Hospital and Harvard Medical School, Charlestown, 149 13th St, Boston, MA 02129; and Pfizer, Cambridge, Mass (J.W., R.M., F.S.)
| | - Jeremy Wellen
- From the Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging (I.Y.Z., V.C.J., N.J.R., E.A., H.K., H.S., N.W., C.T.F., P.C.), Division of Surgical Oncology (S.K., G.A., K.K.T., B.C.F.), and Institute for Technology Assessment, Department of Radiology (N.M.), Massachusetts General Hospital and Harvard Medical School, Charlestown, 149 13th St, Boston, MA 02129; and Pfizer, Cambridge, Mass (J.W., R.M., F.S.)
| | - Robert Martinez
- From the Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging (I.Y.Z., V.C.J., N.J.R., E.A., H.K., H.S., N.W., C.T.F., P.C.), Division of Surgical Oncology (S.K., G.A., K.K.T., B.C.F.), and Institute for Technology Assessment, Department of Radiology (N.M.), Massachusetts General Hospital and Harvard Medical School, Charlestown, 149 13th St, Boston, MA 02129; and Pfizer, Cambridge, Mass (J.W., R.M., F.S.)
| | - Franklin Schlerman
- From the Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging (I.Y.Z., V.C.J., N.J.R., E.A., H.K., H.S., N.W., C.T.F., P.C.), Division of Surgical Oncology (S.K., G.A., K.K.T., B.C.F.), and Institute for Technology Assessment, Department of Radiology (N.M.), Massachusetts General Hospital and Harvard Medical School, Charlestown, 149 13th St, Boston, MA 02129; and Pfizer, Cambridge, Mass (J.W., R.M., F.S.)
| | - Kenneth K Tanabe
- From the Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging (I.Y.Z., V.C.J., N.J.R., E.A., H.K., H.S., N.W., C.T.F., P.C.), Division of Surgical Oncology (S.K., G.A., K.K.T., B.C.F.), and Institute for Technology Assessment, Department of Radiology (N.M.), Massachusetts General Hospital and Harvard Medical School, Charlestown, 149 13th St, Boston, MA 02129; and Pfizer, Cambridge, Mass (J.W., R.M., F.S.)
| | - Bryan C Fuchs
- From the Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging (I.Y.Z., V.C.J., N.J.R., E.A., H.K., H.S., N.W., C.T.F., P.C.), Division of Surgical Oncology (S.K., G.A., K.K.T., B.C.F.), and Institute for Technology Assessment, Department of Radiology (N.M.), Massachusetts General Hospital and Harvard Medical School, Charlestown, 149 13th St, Boston, MA 02129; and Pfizer, Cambridge, Mass (J.W., R.M., F.S.)
| | - Peter Caravan
- From the Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging (I.Y.Z., V.C.J., N.J.R., E.A., H.K., H.S., N.W., C.T.F., P.C.), Division of Surgical Oncology (S.K., G.A., K.K.T., B.C.F.), and Institute for Technology Assessment, Department of Radiology (N.M.), Massachusetts General Hospital and Harvard Medical School, Charlestown, 149 13th St, Boston, MA 02129; and Pfizer, Cambridge, Mass (J.W., R.M., F.S.)
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Safety Profile of a Multi-Antigenic DNA Vaccine Against Hepatitis C Virus. Vaccines (Basel) 2020; 8:vaccines8010053. [PMID: 32013228 PMCID: PMC7158683 DOI: 10.3390/vaccines8010053] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 01/21/2020] [Indexed: 12/17/2022] Open
Abstract
Despite direct acting antivirals (DAAs) curing >95% of individuals infected with hepatitis C (HCV), in order to achieve the World Health Organization HCV Global Elimination Goals by 2030 there are still major challenges that need to be overcome. DAAs alone are unlikely to eliminate HCV in the absence of a vaccine that can limit viral transmission. Consequently, a prophylactic HCV vaccine is necessary to relieve the worldwide burden of HCV disease. DNA vaccines are a promising vaccine platform due to their commercial viability and ability to elicit robust T-cell-mediated immunity (CMI). We have developed a novel cytolytic DNA vaccine that encodes non-structural HCV proteins and a truncated mouse perforin (PRF), which is more immunogenic than the respective canonical DNA vaccine lacking PRF. Initially we assessed the ability of the HCV pNS3-PRF and pNS4/5-PRF DNA vaccines to elicit robust long-term CMI without any adverse side-effects in mice. Interferon-γ (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assay was used to evaluate CMI against NS3, NS4 and NS5B in a dose-dependent manner. This analysis showed a dose-dependent bell-curve of HCV-specific responses in vaccinated animals. We then thoroughly examined the effects associated with reactogenicity of cytolytic DNA vaccination with the multi-antigenic HCV DNA vaccine (pNS3/4/5B). Hematological, biochemical and histological studies were performed in male Sprague Dawley rats with a relative vaccine dose 10–20-fold higher than the proposed dose in Phase I clinical studies. The vaccine was well tolerated, and no toxicity was observed. Thus, the cytolytic multi-antigenic DNA vaccine is safe and elicits broad memory CMI.
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Erman A, Krahn MD, Hansen T, Wong J, Bielecki JM, Feld JJ, Wong WWL, Grootendorst P, Thein HH. Estimation of fibrosis progression rates for chronic hepatitis C: a systematic review and meta-analysis update. BMJ Open 2019; 9:e027491. [PMID: 31719068 PMCID: PMC6858137 DOI: 10.1136/bmjopen-2018-027491] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES Mathematical models are increasingly important in planning for the upcoming chronic hepatitis C (CHC) elimination efforts. Such models require reliable natural history inputs to make accurate predictions on health and economic outcomes. Yet, hepatitis C virus disease progression is known to vary widely in the literature and published inputs are currently outdated. The objectives of this study were to obtain updated estimates of fibrosis progression rates (FPR) in treatment-naïve patients with CHC and to explore sources of heterogeneity. DESIGN A systematic review was conducted using Ovid-MEDLINE, Ovid-EMBASE and PubMed databases (January 1990 to January 2018) to identify observational studies of hepatic fibrosis in treatment-naïve patients with CHC. OUTCOMES Stage-constant FPRs were estimated for each study given the reported fibrosis scores and duration of infection. Stage-specific FPRs (ie, F0→F1; F1→F2; F2→F3; F3→F4) were estimated using Markov maximum likelihood estimation. Estimates were pooled using random-effects meta-analysis and heterogeneity was evaluated by stratification and random-effects meta-regression. RESULTS The review identified 111 studies involving 131 groups of patients (n=42 693). The pooled stage-constant FPR was 0.094 (95% CI 0.088 to 0.100); stage-specific FPRs were F0→F1: 0.107 (95% CI 0.097 to 0.118); F1→F2: 0.082 (95% CI 0.074 to 0.091); F2→F3: 0.117 (95% CI 0.107 to 0.129); F3→F4: 0.116 (95% CI 0.104 to 0.131). Stratified analysis revealed substantial variation in progression by study population. Meta-regression indicated associations between progression and infection age, duration, source, viral genotype and study population. Findings indicate that FPRs display substantial heterogeneity across study populations and pooled values from more homogenous subpopulations should be considered when estimating prognosis. CONCLUSIONS This large meta-analysis presents updated prognostic estimates for CHC derived from newer studies using better diagnostic methods and improves estimates for important patient populations in terms of clinical policy (eg, injection drug users, non-clinical populations, liver clinic patients) and should be a valuable resource for patients, clinicians and clinical policymakers.
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Affiliation(s)
- Aysegul Erman
- Toronto Health Economics and Health Technology Assessment (THETA) Collaborative, University Health Network, University of Toronto, Toronto, Ontario, Canada
- Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
- University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Murray D Krahn
- Toronto Health Economics and Health Technology Assessment (THETA) Collaborative, University Health Network, University of Toronto, Toronto, Ontario, Canada
- Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
- University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Tawnya Hansen
- University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Josephine Wong
- Toronto Health Economics and Health Technology Assessment (THETA) Collaborative, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Joanna M Bielecki
- Toronto Health Economics and Health Technology Assessment (THETA) Collaborative, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Jordan J Feld
- University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - William W L Wong
- Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
- University of Waterloo School of Pharmacy, Waterloo, Ontario, Canada
| | - Paul Grootendorst
- Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
| | - Hla-Hla Thein
- University of Toronto Dalla Lana School of Public Health, Toronto, Ontario, Canada
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20
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Humanized Mouse Models for the Study of Hepatitis C and Host Interactions. Cells 2019; 8:cells8060604. [PMID: 31213010 PMCID: PMC6627916 DOI: 10.3390/cells8060604] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 06/09/2019] [Accepted: 06/13/2019] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C virus (HCV) infection is commonly attributed as a major cause of chronic hepatotropic diseases, such as, steatosis, cirrhosis and hepatocellular carcinoma. As HCV infects only humans and primates, its narrow host tropism hampers in vivo studies of HCV-mammalian host interactions and the development of effective therapeutics and vaccines. In this context, we will focus our discussion on humanized mice in HCV research. Here, these humanized mice are defined as animal models that encompass either only human hepatocytes or both human liver and immune cells. Aspects related to immunopathogenesis, anti-viral interventions, drug testing and perspectives of these models for future HCV research will be discussed.
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Yu J, He JQ, Chen DY, Pan QL, Yang JF, Cao HC, Li LJ. Dynamic changes of key metabolites during liver fibrosis in rats. World J Gastroenterol 2019; 25:941-954. [PMID: 30833800 PMCID: PMC6397726 DOI: 10.3748/wjg.v25.i8.941] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 01/10/2019] [Accepted: 01/28/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Fibrosis is the single most important predictor of significant morbidity and mortality in patients with chronic liver disease. Established non-invasive tests for monitoring fibrosis are lacking, and new biomarkers of liver fibrosis and function are needed.
AIM To depict the process of liver fibrosis and look for novel biomarkers for diagnosis and monitoring fibrosis progression.
METHODS CCl4 was used to establish the rat liver fibrosis model. Liver fibrosis process was measured by liver chemical tests, liver histopathology, and Masson’s trichrome staining. The expression levels of two fibrotic markers including α-smooth muscle actin and transforming growth factor β1 were assessed using immunohistochemistry and real-time polymerase chain reaction. Dynamic changes in metabolic profiles and biomarker concentrations in rat serum during liver fibrosis progression were investigated using ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. The discriminatory capability of potential biomarkers was evaluated by receiver operating characteristic (ROC) curve analysis.
RESULTS To investigate the dynamic changes of metabolites during the process of liver fibrosis, sera from control and fibrosis model rats based on pathological results were analyzed at five different time points. We investigated the association of liver fibrosis with 21 metabolites including hydroxyethyl glycine, L-threonine, indoleacrylic acid, β-muricholic acid (β-MCA), cervonoyl ethanolamide (CEA), phosphatidylcholines, and lysophosphatidylcholines. Two metabolites, CEA and β-MCA, differed significantly in the fibrosis model rats compared to controls (P < 0.05) and showed prognostic value for fibrosis. ROC curve analyses performed to calculate the area under the curve (AUC) revealed that CEA and β-MCA differed significantly in the fibrosis group compared to controls with AUC values exceeding 0.8, and can clearly differentiate early stage from late stage fibrosis or cirrhosis.
CONCLUSION This study identified two novel biomarkers of fibrosis, CEA and β-MCA, which were effective for diagnosing fibrosis in an animal model.
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Affiliation(s)
- Jiong Yu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Jian-Qin He
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - De-Ying Chen
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Qiao-Ling Pan
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Jin-Feng Yang
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Hong-Cui Cao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Lan-Juan Li
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
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Akkaya HE, Erden A, Kuru Öz D, Ünal S, Erden İ. Magnetic resonance elastography: basic principles, technique, and clinical applications in the liver. ACTA ACUST UNITED AC 2019; 24:328-335. [PMID: 30272563 DOI: 10.5152/dir.2018.18186] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Magnetic resonance elastography (MRE) is a constantly advancing technique for assessment of stiffness of tissues with newer technology and sequences. It is being increasingly used for the assessment of liver fibrosis. In this article, we discuss the advantages of MRE over biopsy and noninvasive methods such as US elastography in the assessment of liver fibrosis. Image acquisition and interpretation of liver MRE is also discussed.
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Affiliation(s)
| | - Ayşe Erden
- Department of Radiology, Ankara University School of Medicine, Ankara, Turkey
| | - Diğdem Kuru Öz
- Department of Radiology, Ankara University School of Medicine, Ankara, Turkey
| | - Sena Ünal
- Department of Radiology, Erzurum Local Training and Research Hospital, Erzurum, Turkey
| | - İlhan Erden
- Department of Radiology, Ankara University School of Medicine, Ankara, Turkey
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Pan-Genotypic Hepatitis C Treatment with Glecaprevir and Pibrentasvir for 8 Weeks Resulted in Improved Cardiovascular and Metabolic Outcomes and Stable Renal Function: A Post-Hoc Analysis of Phase 3 Clinical Trials. Infect Dis Ther 2018; 7:473-484. [PMID: 30368684 PMCID: PMC6249176 DOI: 10.1007/s40121-018-0218-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Indexed: 02/06/2023] Open
Abstract
Introduction Chronic hepatitis C (CHC) infection is associated with extrahepatic manifestations (EHMs) which can affect renal, cardiovascular and other comorbidities. The effect of CHC treatment with short-duration regimens on these EHMs is not well defined. Hence, we examined longitudinal estimated glomerular filtration rate (eGFR), triglycerides and glucose values to assess the impact of short-duration CHC therapy on renal, cardiovascular and metabolic diseases, respectively. Methods We conducted analyses of all patients without cirrhosis treated with glecaprevir and pibrentasvir (G/P) for 8 weeks in two phase 3 clinical trials. In addition, one phase 3 trial was carried out to explore the effects of treatment on renal EHMs in patients with advanced renal impairment at baseline. As a sensitivity analysis, we included all CHC patients treated with G/P for 8 or 12 weeks enrolled across five phase 3 trials. Adjusting for baseline demographics and clinical properties via mixed regression models enabled evaluation of changes in EHMs through end of treatment. Results G/P treatment for 8 weeks resulted in statistically significant declines in triglycerides (− 28.6 mg/dl) and glucose (− 11.2 mg/dl), while there was no statistically significant decline in eGFR. Biomarker improvements were greatest among patients with elevated triglycerides and elevated glucose at baseline. Similar effects were observed across all patients treated with G/P for 8 or 12 weeks. Conclusion Short-duration treatment with G/P resulted in stable renal function and improvements in cardiovascular and metabolic EHM markers, especially in patients with severe EHMs at baseline. Funding AbbVie Inc. Electronic supplementary material The online version of this article (10.1007/s40121-018-0218-x) contains supplementary material, which is available to authorized users.
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Impact of Alcohol and Coffee Intake on the Risk of Advanced Liver Fibrosis: A Longitudinal Analysis in HIV-HCV Coinfected Patients (ANRS HEPAVIH CO-13 Cohort). Nutrients 2018; 10:nu10060705. [PMID: 29857547 PMCID: PMC6024311 DOI: 10.3390/nu10060705] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2018] [Revised: 05/26/2018] [Accepted: 05/29/2018] [Indexed: 12/13/2022] Open
Abstract
Background: Coffee intake has been shown to modulate both the effect of ethanol on serum GGT activities in some alcohol consumers and the risk of alcoholic cirrhosis in some patients with chronic diseases. This study aimed to analyze the impact of coffee intake and alcohol consumption on advanced liver fibrosis (ALF) in HIV-HCV co-infected patients. Methods: ANRS CO13-HEPAVIH is a French, nationwide, multicenter cohort of HIV-HCV-co-infected patients. Sociodemographic, behavioral, and clinical data including alcohol and coffee consumption were prospectively collected using annual self-administered questionnaires during five years of follow-up. Mixed logistic regression models were performed, relating coffee intake and alcohol consumption to ALF. Results: 1019 patients were included. At the last available visit, 5.8% reported high-risk alcohol consumption, 27.4% reported high coffee intake and 14.5% had ALF. Compared with patients with low coffee intake and high-risk alcohol consumption, patients with low coffee intake and low-risk alcohol consumption had a lower risk of ALF (aOR (95% CI) 0.24 (0.12–0.50)). In addition, patients with high coffee intake had a lower risk of ALF than the reference group (0.14 (0.03–0.64) in high-risk alcohol drinkers and 0.11 (0.05–0.25) in low-risk alcohol drinkers). Conclusions: High coffee intake was associated with a low risk of liver fibrosis even in HIV-HCV co-infected patients with high-risk alcohol consumption.
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25
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Tornesello ML, Buonaguro L, Izzo F, Buonaguro FM. Molecular alterations in hepatocellular carcinoma associated with hepatitis B and hepatitis C infections. Oncotarget 2018; 7:25087-102. [PMID: 26943571 PMCID: PMC5041890 DOI: 10.18632/oncotarget.7837] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 02/20/2016] [Indexed: 02/07/2023] Open
Abstract
Chronic infections with hepatitis B (HBV) and hepatitis C viruses (HCV) are the leading cause of cirrhosis and hepatocellular carcinoma (HCC) worldwide. Both viruses encode multifunctional regulatory proteins activating several oncogenic pathways, which induce accumulation of multiple genetic alterations in the infected hepatocytes. Gene mutations in HBV- and HCV-induced HCCs frequently impair the TP53, Wnt/b-catenin, RAS/RAF/MAPK kinase and AKT/mTOR pathways, which represent important anti-cancer targets. In this review, we highlight the molecular mechanisms underlying the pathogenesis of primary liver cancer, with particular emphasis on the host genetic variations identified by high-throughput technologies. In addition, we discuss the importance of genetic alterations, such as mutations in the telomerase reverse transcriptase (TERT) promoter, for the diagnosis, prognosis, and tumor stratification for development of more effective treatment approaches.
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Affiliation(s)
- Maria Lina Tornesello
- Molecular Biology and Viral Oncology Unit, Department of Research, Istituto Nazionale Tumori "Fondazione G. Pascale" - IRCCS, Napoli, Italy
| | - Luigi Buonaguro
- Molecular Biology and Viral Oncology Unit, Department of Research, Istituto Nazionale Tumori "Fondazione G. Pascale" - IRCCS, Napoli, Italy
| | - Francesco Izzo
- Hepato-Biliary Surgery Department, Istituto Nazionale Tumori "Fondazione G. Pascale" - IRCCS, Napoli, Italy
| | - Franco M Buonaguro
- Molecular Biology and Viral Oncology Unit, Department of Research, Istituto Nazionale Tumori "Fondazione G. Pascale" - IRCCS, Napoli, Italy
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Abstract
This study was performed to investigate the relationships of hepatitis B (HBV) and hepatitis C virus (HCV) infection to age-related cataract, and to assess whether liver damage mediates the hepatitis-cataract association. This study analyzed data in the Korea National Health and Nutrition Examination Survey 2010-2012 on 10,037 participants aged ≥40 years. We performed mediation analysis to address the contribution of serum markers of liver damage, high aspartate (AST, >49.9 IU/L) and alanine aminotransferase (ALT, >56.1 IU/L), to the relationships of HBV and HCV infection to cataract. Odds ratios (ORs) for nuclear and any cataract with HBV infection were 1.09 [95% confidence interval (95CI) = 1.02-1.16] and 1.07 (95CI = 1.00-1.14), respectively, compared to HBV uninfection; ORs with HCV infection were 1.35 (95CI = 1.18-1.55) and 1.40 (95CI = 1.12-1.76), respectively. High AST completely mediated the HBV infection-any cataract association. The significant relationships of HCV infection with nuclear and any cataract were formed only by their direct effects, not by mediation effects of high AST or ALT. HBV and HCV infection was significantly associated with nuclear and any cataract. High AST significantly mediates the effects of HBV infections on any cataract outcome, but the associations of HCV infection with nuclear and any cataract were not mediated by high AST or ALT.
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27
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McLauchlan J, Innes H, Dillon JF, Foster G, Holtham E, McDonald S, Wilkes B, Hutchinson SJ, Irving WL. Cohort Profile: The Hepatitis C Virus (HCV) Research UK Clinical Database and Biobank. Int J Epidemiol 2017; 46:1391-1391h. [PMID: 28338838 PMCID: PMC5837619 DOI: 10.1093/ije/dyw362] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/07/2016] [Indexed: 12/11/2022] Open
Affiliation(s)
- J McLauchlan
- MRC-University of Glasgow Centre for Virus Research, Glasgow, UK
| | - H Innes
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK
- Blood Borne Viruses and STIs Division, Health Protection Scotland, Glasgow, UK
| | - J F Dillon
- Division of Molecular and Clinical Medicine; University of Dundee, Dundee, UK
| | - G Foster
- Institute of Cell and Molecular Science, Queen Mary University of London, London, UK
| | - E Holtham
- National Institute for Health Research (NIHR) Digestive Diseases Biomedical Research Unit at Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - S McDonald
- MRC-University of Glasgow Centre for Virus Research, Glasgow, UK
| | - B Wilkes
- National Institute for Health Research (NIHR) Digestive Diseases Biomedical Research Unit at Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - S J Hutchinson
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK
- Blood Borne Viruses and STIs Division, Health Protection Scotland, Glasgow, UK
| | - W L Irving
- National Institute for Health Research (NIHR) Digestive Diseases Biomedical Research Unit at Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
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Hermetet C, Dubois F, Gaudy-Graffin C, Bacq Y, Royer B, Gaborit C, D’Alteroche L, Desenclos JC, Roingeard P, Grammatico-Guillon L. Continuum of hepatitis C care in France: A 20-year cohort study. PLoS One 2017; 12:e0183232. [PMID: 28850623 PMCID: PMC5574535 DOI: 10.1371/journal.pone.0183232] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 08/01/2017] [Indexed: 12/17/2022] Open
Abstract
Background Hepatitis C virus (HCV)-infected patients require a specific continuum of care (CoC) from HCV screening to treatment. We assessed CoC of HCV-infected patients in a longitudinal study. Methods We established a cohort of subjects undergoing HCV screening (high alanine aminotransferase levels or risk factors) during preventive consultations at a French regional medical center from 1993 to 2013. Patients were considered to be HCV-infected if HCV RNA was detected in their serum. CoC was assessed as described by Viner et al. (Hepatology 2015): Stage 1, HCV screening; Stage 2, HCV RNA testing; Stage 3, continuing care; Stage 4, antiviral treatment. Cox multivariate analysis was performed to identify factors favoring CoC, defined as at least one course of antiviral treatment. Results In total, 12,993 HCV tests were performed and 478 outpatients were found to be HCV-seropositive. We included 417 seropositive patients, after excluding false positives and patients lost to follow-up. The baseline characteristics of the patients were: sex ratio (M/F) 1.4; mean age 38.5 years; intravenous drug use (IDU) in 55%; and 28% in unstable social situations, estimated by the EPICES deprivation score. Antiviral treatment was initiated for 179 (42.9%) of the 379 (90.9%) patients attending specialist consultations. CoC was associated with screening after 1997 (HR 2.0, 95%CI 1.4–2.9), age > 45 years (HR 1.5, 95%CI 1.02–2.3), patient acceptance of care (HR 9.3, 95%CI 5.4–16.10), specialist motivation for treatment (HR 10.9, 95%CI 7.4–16.0), and absence of cancer (HR 6.7, 95%CI 1.6–27.9). Other comorbid conditions, such as depression and IDU, were not associated with CoC. Conclusions Our 20-year cohort study reveals the real-life continuum of care for HCV-infected patients in France. The number of patients involved in HCV care after positive testing was substantial due to the organization of healthcare in France. An improved CoC along with new direct-acting antivirals should help to decrease chronic HCV infection.
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Affiliation(s)
- Coralie Hermetet
- SIMEES, CHRU de Tours, Laboratoire de Santé Publique, Université François Rabelais, Tours, France
| | - Frederic Dubois
- INSERM U966, Université François Rabelais et CHRU de Tours, Tours, France
- Service de Bactériologie-Virologie-Hygiène, CHRU de Tours, Tours, France
- UC-IRSA, Département 37, La Riche, France
| | - Catherine Gaudy-Graffin
- INSERM U966, Université François Rabelais et CHRU de Tours, Tours, France
- Service de Bactériologie-Virologie-Hygiène, CHRU de Tours, Tours, France
| | - Yannick Bacq
- Service de d'Hépato-gastro-entérologie, CHRU de Tours, Tours, France
| | | | - Christophe Gaborit
- SIMEES, CHRU de Tours, Laboratoire de Santé Publique, Université François Rabelais, Tours, France
| | - Louis D’Alteroche
- Service de d'Hépato-gastro-entérologie, CHRU de Tours, Tours, France
| | | | - Philippe Roingeard
- INSERM U966, Université François Rabelais et CHRU de Tours, Tours, France
- Laboratoire de Biologie Cellulaire, CHRU de Tours, Tours, France
| | - Leslie Grammatico-Guillon
- SIMEES, CHRU de Tours, Laboratoire de Santé Publique, Université François Rabelais, Tours, France
- INSERM U966, Université François Rabelais et CHRU de Tours, Tours, France
- * E-mail:
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Tan CH, Venkatesh SK. Magnetic Resonance Elastography and Other Magnetic Resonance Imaging Techniques in Chronic Liver Disease: Current Status and Future Directions. Gut Liver 2017; 10:672-86. [PMID: 27563019 PMCID: PMC5003189 DOI: 10.5009/gnl15492] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Revised: 11/29/2015] [Accepted: 12/15/2015] [Indexed: 12/13/2022] Open
Abstract
Recent advances in the noninvasive imaging of chronic liver disease have led to improvements in diagnosis, particularly with magnetic resonance imaging (MRI). A comprehensive evaluation of the liver may be performed with the quantification of the degree of hepatic steatosis, liver iron concentration, and liver fibrosis. In addition, MRI of the liver may be used to identify complications of cirrhosis, including portal hypertension, ascites, and the development of hepatocellular carcinoma. In this review article, we discuss the state of the art techniques in liver MRI, namely, magnetic resonance elastography, hepatobiliary phase MRI, and liver fat and iron quantification MRI. The use of these advanced techniques in the management of chronic liver diseases, including non-alcoholic fatty liver disease, will be elaborated.
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Affiliation(s)
- Cher Heng Tan
- Department of Diagnostic Radiology, Tan Tock Seng Hospital, Singapore
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López-Rodríguez R, Hernández-Bartolomé Á, Borque MJ, Rodríguez-Muñoz Y, Martín-Vílchez S, García-Buey L, González-Moreno L, Real-Martínez Y, Muñoz de Rueda P, Salmerón J, Vidal-Castiñeira JR, López-Larrea C, Rodrigo L, Moreno-Otero R, Sanz-Cameno P. Interferon-related genetic markers of necroinflammatory activity in chronic hepatitis C. PLoS One 2017; 12:e0180927. [PMID: 28704535 PMCID: PMC5507534 DOI: 10.1371/journal.pone.0180927] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Accepted: 06/23/2017] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION Chronic hepatitis C (CHC) is a major cause of liver disease worldwide which often leads to progressive liver inflammation, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). CHC displays heterogeneous progression depending on a broad set of factors, some of them intrinsic to each individual such as the patient's genetic profile. This study aims to evaluate the contribution of certain genetic variants of crucial interferon alpha and lambda signaling pathways to the hepatic necroinflammatory activity (NIA) grade of CHC patients. METHODS NIA was evaluated in 119 CHC patients by METAVIR scale and classified as low (NIA = 0-2, n = 80) or high grade (NIA = 3, n = 39). In a candidate gene approach, 64 SNPs located in 30 different genes related to interferon pathways (IL-28B, IFNAR1-2, JAK-STAT and OAS1-3, among others) were genotyped using the Illumina GoldenGate® Genotyping Assay. Statistical association was determined by logistic regression and expressed as OR and 95% CI. Those SNPs significantly associated were further adjusted by other covariates. RESULTS Seven SNPs located in IL-28B (rs12979860), JAK1 (rs11576173 and rs1497056), TYK2 (rs280519), OAS1 (rs2057778), SOCS1 (rs33932899) and RNASEL (rs3738579) genes were significantly related to severe NIA grade (p<0.05). Regarding to clinical variables, elevated NIA was notably associated with aspartate aminotransferase (AST) serum levels >40 IU/L (p<0.05) but not with other clinical factors. Multivariate logistic regression analysis of these factors reflected that AST (>40 IU/L), TYK2 rs280519 (G allele) and RNASEL rs3738579 (G allele) were factors independently associated with elevated NIA (p<0.05). AST concentration showed a moderate AUC value (AUC = 0.63), similar to TYK2 (rs280519) and RNASEL (rs3738579) SNPs (AUC = 0.61, both) in the ROC_AUC analysis. Interestingly, the model including all significant variables reached a considerable predictive value (AUC = 0.74). CONCLUSION The identified genetic variants in interferon signaling pathways may constitute useful prognostic markers of CHC progression. Further validation in larger cohorts of patients is needed.
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Affiliation(s)
- Rosario López-Rodríguez
- Liver Unit, Gastroenterology Service, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain
| | - Ángel Hernández-Bartolomé
- Liver Unit, Gastroenterology Service, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain
| | - María Jesús Borque
- Molecular Biology Unit, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain
| | - Yolanda Rodríguez-Muñoz
- Liver Unit, Gastroenterology Service, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain
| | - Samuel Martín-Vílchez
- Liver Unit, Gastroenterology Service, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain
| | - Luisa García-Buey
- Liver Unit, Gastroenterology Service, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain
- CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Leticia González-Moreno
- Liver Unit, Gastroenterology Service, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain
| | - Yolanda Real-Martínez
- Liver Unit, Gastroenterology Service, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain
| | - Paloma Muñoz de Rueda
- CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Gastroenterology Unit, Hospital Universitario San Cecilio, Granada, Spain
| | - Javier Salmerón
- CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Gastroenterology Unit, Hospital Universitario San Cecilio, Granada, Spain
| | | | - Carlos López-Larrea
- Inmunology Service, Hospital, Universitario Central de Asturias, Oviedo, Spain
| | - Luis Rodrigo
- Digestive Service, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Ricardo Moreno-Otero
- Liver Unit, Gastroenterology Service, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain
- CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Paloma Sanz-Cameno
- Liver Unit, Gastroenterology Service, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain
- CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
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Martinez SS, Campa A, Li Y, Fleetwood C, Stewart T, Ramamoorthy V, Baum MK. Low Plasma Zinc Is Associated with Higher Mitochondrial Oxidative Stress and Faster Liver Fibrosis Development in the Miami Adult Studies in HIV Cohort. J Nutr 2017; 147:556-562. [PMID: 28228506 PMCID: PMC5368586 DOI: 10.3945/jn.116.243832] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 12/02/2016] [Accepted: 01/31/2017] [Indexed: 12/23/2022] Open
Abstract
Background: Oxidative stress and reduced antioxidants may be a trigger for liver fibrogenesis. Reducing oxidative stress through higher antioxidant concentration may be a potential antifibrotic target.Objective: We aimed to investigate longitudinally whether plasma zinc, an antioxidant, is related to mitochondrial oxidative stress and the progression of liver fibrosis in the Miami Adult Studies in HIV (MASH) cohort.Methods: A prospective observational cohort study was conducted in 487 predominantly African American HIV-monoinfected and HIV/hepatitis C virus (HCV)-coinfected adults with a mean ± SD age of 47.08 ± 7.67 y from the MASH cohort and followed for a median of 34 mo. Blood was collected for plasma zinc and measures were used to calculate the fibrosis-4 (FIB-4) score (aspartate amino transferase, alanine aminotransferase, and platelets). Plasma zinc deficiency was defined as <0.75 mg/L. Total DNA was extracted from peripheral blood mononuclear cells and mitochondrial DNA (mtDNA) 8-hydroxyguanosine (8-oxo-dG) was determined. Adjusted mixed models were used to assess the relations between zinc, stage of liver disease, and oxidative stress over time and compared between HIV and HIV/HCV groups.Results: Zinc concentrations (β: -0.368, SE = 0.172; P = 0.033) and deficiency were associated with lower FIB-4 scores over time (β: 0.381, SE = 0.118; P = 0.001). Compared with those who were not zinc deficient, zinc-deficient participants had an increased risk of having more-progressed liver disease (OR: 1.91; 95% CI: 1.15, 3.16; P = 0.012). Higher mtDNA 8-oxo-dG was associated with zinc deficiency (β: 0.049, SE = 0.024; P = 0.044) and higher FIB-4 scores over time (β: 0.597, SE = 0.168, P < 0.001).Conclusions: Lower plasma zinc concentrations were associated with liver fibrosis progression and mitochondrial oxidative stress in the HIV and HIV/HCV groups. Zinc may play a role in the impact of liver disease outcomes.
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Affiliation(s)
- Sabrina S Martinez
- Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL
| | - Adriana Campa
- Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL
| | - Yinghui Li
- Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL
| | | | - Tiffanie Stewart
- Center for Nanoscience and Technology, University of Notre Dame, Notre Dame, IN; and
| | | | - Marianna K Baum
- Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL;
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Abdulla MA, Murad EA, Aljenaidi HA, Aljowder DR, Aljeeran OI, Farid E, Al Qamish JR. Interrelationship of hepatitis C virus genotypes with patient characteristics in Bahrain. Hepat Med 2017; 9:7-11. [PMID: 28280398 PMCID: PMC5338997 DOI: 10.2147/hmer.s124274] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Aim Hepatitis C virus (HCV) shows genotype-based variation in prevalence across geographical regions. This study was conducted to understand the clinical interrelationship of HCV genotypes with patient characteristics. Methods Medical records of 122 patients positive for HCV RNA test collected during 2013 and 2014 were included for analysis. Only adults were included in the study. HCV RNA extraction and genotyping was done as part of the routine diagnostic requirements. The association of continuous and categorical variables with genotypes was analyzed through analysis of variance and chi-square tests, respectively. Results Of the 122 patients selected, 103 were Bahrainis, 18 non-Bahrainis, and 1 was unregistered. Genotype 1 was the predominant (53%) one, followed by types 3 (23%) and 4 (20%). Classical symptoms, clinical signs, liver function test, and ultrasonographic results were recorded. Cirrhosis and ascites showed significant variation across genotypes. Although alanine transaminase, total bilirubin, and albumin levels were increased, gamma-glutamyltransferase and alkaline phosphatase levels were normal. About 12% of the subjects were alcohol users, 4% were positive for HIV infection and 2.4% were positive for hepatitis B virus infection. The circulating HCV RNA load was at medium-level in the study cohort and showed significant association with the HCV genotypes and subtypes. Patients with genotype 1a had 6 times more load than patients with type 4 (P<0.05). Conclusion This study reconfirmed the incidence and distribution of different genotypes in Bahrain population, and delineated the relationship of HCV RNA viral load with the severity of liver disease in our cohort.
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Affiliation(s)
| | | | | | | | | | - Eman Farid
- Department of Pathology, Salmaniya Medical Complex
| | - Jehad R Al Qamish
- Department of Internal Medicine, Ibn Al Nafees Hospital, Manama, Bahrain
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Xu Z, Lin JZ, Lin GL, Wei FF, Liu J, Zhao ZX, Zhang Y, Ke WM, Zhang XH. Hepatitis C virus load in parenchyma cells correlates with hepatic injury in infected patients. Exp Ther Med 2016; 13:155-159. [PMID: 28123484 PMCID: PMC5245088 DOI: 10.3892/etm.2016.3915] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Accepted: 06/02/2016] [Indexed: 12/14/2022] Open
Abstract
The association between serum hepatitis C virus (HCV) load and hepatic injury in HCV-infected patients has been extensively investigated. The present study aimed to investigate the association between HCV load in hepatic parenchyma cells and hepatic injury in HCV-infected patients. A total of 56 HCV-infected patients were included in the present retrospective study. The serum HCV mRNA was determined using quantitative polymerase chain reaction, while the hepatic parenchyma cell volume and HCV mRNA in hepatic parenchyma cells were also determined. Hepatic injury was evaluated on the basis of the severity of inflammation and fibrosis. The results demonstrated that there were evident differences in the mean serum HCV RNA levels and the HCV load/parenchyma cell volume among the various grades of hepatic inflammation (G1-G4) when groups with the least and most inflammation were compared (G1 vs. G4; P<0.05). Significant differences in the HCV load existed between groups divided according to the fibrosis grade; in addition, differences existed between fibrosis grades S1 and S2, and S2 and S4 when comparing serum HCV RNA levels (P<0.05). Similarly, differences existed between every two fibrosis stages (S0 vs. S4, S2 vs. S3, and S2 vs. S4; P<0.05) when viral loads and parenchyma cell volumes were compared (F=2.860, P<0.05). Furthermore, the fibrosis staging was correlated with the viral load/parenchyma cell volume (F=2.670, P<0.05). In conclusion, hepatic fibrosis grade was found to be associated with HCV load in parenchyma cells. The results of the present study demonstrated that the viral load in parenchyma cells is a more appropriate index compared with the serum viral load for evaluating HCV replication in hepatocytes, and may function as an important factor in HCV-infected hepatic injury evaluation.
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Affiliation(s)
- Zhen Xu
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Ji-Zong Lin
- Department of General Surgery, Lingnan Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510530, P.R. China
| | - Guo-Li Lin
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Fang-Fang Wei
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Jing Liu
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Zhi-Xin Zhao
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Ying Zhang
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Wei-Ming Ke
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Xiao-Hong Zhang
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510630, P.R. China
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Miotto N, Mendes LC, Zanaga LP, Goncales ESL, Lazarini MSK, Pedro MN, Goncales FL, Stucchi RSB, Vigani AG. Predictors of early treatment discontinuation and severe anemia in a Brazilian cohort of hepatitis C patients treated with first-generation protease inhibitors. Braz J Med Biol Res 2016; 49:S0100-879X2016000700702. [PMID: 27356107 PMCID: PMC4926529 DOI: 10.1590/1414-431x20165300] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 03/24/2016] [Indexed: 12/14/2022] Open
Abstract
The aim of this study was to determine risk factors for adverse events (AE)-related treatment discontinuation and severe anemia among patients with chronic hepatitis C virus (HCV) genotype 1 infection, treated with first-generation protease inhibitor (PI)-based therapy. We included all patients who initiated treatment with PI-based therapy at a Brazilian university hospital between November 2013 and December 2014. We prospectively collected data from medical records using standardized questionnaires and used Epi Info 6.0 for analysis. Severe anemia was defined as hemoglobin ≤8.5 mg/dL. We included 203 patients: 132 treated with telaprevir (TVR) and 71 treated with boceprevir (BOC). AE-related treatment discontinuation rate was 19.2% and anemia was the main reason (38.5%). Risk factors for treatment discontinuation were higher comorbidity index (OR=1.85, CI=1.05-3.25) for BOC, and higher bilirubin count (OR=1.02, CI=1.01-1.04) and lower BMI (OR=0.98, CI=0.96-0.99) for TVR. Severe anemia occurred in 35 (17.2%) patients. Risk factors for this outcome were lower estimated glomerular filtration rate (eGFR; OR=0.95, CI=0.91-0.98) for patients treated with TVR, and higher comorbidity index (OR=2.21, CI=1.04-4.67) and ribavirin dosage (OR=0.84, CI=0.72-0.99) for those treated with BOC. Fifty-five (57.3%) patients treated with TVR and 15 (27.3%) patients treated with BOC achieved sustained virological response (SVR). Among patients who received TVR and interrupted treatment due to AE (n=19), only 26.3% (n=5) achieved SVR (P=0.003). Higher number of comorbidities, lower eGFR and advanced liver disease are associated with severe anemia and early treatment cessation, which may compromise SVR achievement.
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Affiliation(s)
- N Miotto
- Divisão de Moléstias Infecciosas, Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil
| | - L C Mendes
- Divisão de Moléstias Infecciosas, Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil
| | - L P Zanaga
- Divisão de Moléstias Infecciosas, Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil
| | - E S L Goncales
- Divisão de Moléstias Infecciosas, Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil
| | - M S K Lazarini
- Divisão de Moléstias Infecciosas, Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil
| | - M N Pedro
- Divisão de Moléstias Infecciosas, Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil
| | - F L Goncales
- Divisão de Moléstias Infecciosas, Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil
| | - R S B Stucchi
- Divisão de Moléstias Infecciosas, Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil
| | - A G Vigani
- Divisão de Moléstias Infecciosas, Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil
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Heo JY, Kim SU, Kim BK, Park JY, Kim DY, Ahn SH, Park YN, Ahn SS, Han KH, Kim HS. Use of Wisteria Floribunda Agglutinin-Positive Human Mac-2 Binding Protein in Assessing Risk of Hepatocellular Carcinoma Due to Hepatitis B Virus. Medicine (Baltimore) 2016; 95:e3328. [PMID: 27057911 PMCID: PMC4998827 DOI: 10.1097/md.0000000000003328] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Revised: 03/15/2016] [Accepted: 03/18/2016] [Indexed: 02/07/2023] Open
Abstract
Wisteria floribunda agglutinin-positive human Mac-2 binding protein (WFA-M2BP) is a serologic marker corresponding with degree of hepatic fibrosis. We evaluated its accuracy in assessing hepatic fibrosis and in predicting the risk of developing hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB).In a 5-year period (2009-2013), a total of 95 CHB patients with available serum WFA-M2BP assay and transient elastography assessment [to assess liver stiffness (LS)] who had undergone liver biopsy were recruited for retrospective analysis.Areas under the receiver operating characteristic curve for predicting fibrosis stages via serum WFA-M2BP level were as follows: ≥F2, 0.688; ≥F3, 0.694; and F4, 0.704 (all P < 0.05). During the follow-up period (median, 45 months), HCC developed in 7 patients (7.4%). In patients with HCC, age, use of antiviral therapy, test parameters (HBV DNA, WFA-M2BP, and LS determinations), and histologic stage of fibrosis were all significantly greater than in those free of HCC, whereas platelet count was significantly lower (all P < 0.05). On multivariate analysis, WFA-M2BP was found independently predictive of emergent HCC [hazard ratio (HR) = 2.375; P = 0.036], although LS and histologic stage of fibrosis were not (P > 0.05). Risk of developing HCC was significantly greater in patients with high WFA-M2BP levels (≥1.8) (adjusted HR = 11.5; P = 0.025). Cumulative incidence rates of HCC were also significantly higher in patients with high (vs. low) levels of WFA-M2BP (log-rank test, P = 0.016).WFA-M2BP determination significantly reflected degree/extent of hepatic fibrosis and independently predicted the risk of developing HCC in patients with CHB.
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Affiliation(s)
- Ja Yoon Heo
- From the Department of Internal Medicine (JYH, SUK, BKK, JYP, DYK, SHA, SSA, K-HH); Institute of Gastroenterology (SUK, BKK, JYP, DYK, SHA, K-HH); Department of Laboratory Medicine (H-SK); and Department of Pathology (YNP), Yonsei University College of Medicine, Seoul, South Korea
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The Effect of rhCygb on CCl4-Induced Hepatic Fibrogenesis in Rat. Sci Rep 2016; 6:23508. [PMID: 27006085 PMCID: PMC4804332 DOI: 10.1038/srep23508] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Accepted: 03/08/2016] [Indexed: 12/22/2022] Open
Abstract
This study aims to investigate whether the use of recombinant human cytoglobin (rhCygb) impact on hepatic fibrogenesis caused by CCl4. SD (n = 150) rats were randomly divided into three groups of normal, CCl4 model and rhCygb groups. After model establishment, rats in rhCygb groups were administered daily with rhCygb (2 mg/kg, s.c.). Histological lesions were staged according to metavir. Serum parameters including ALT, AST, HA, LN, Col III and Col IV were determined. The liver proteins were separated by 2-DE and identified. As a result, the stage of hepatic damage and liver fibrosis in rhCygb groups were significantly milder than that in CCl4 model groups. Meanwhile, rhCygb dramatically reversed serum levels of ALT and AST, and also markedly decreased the liver fibrosis markers levels of LN, HA, Col III and Col IV. In 2-DE, 33 proteins among three groups with the same changing tendency in normal and rhCygb treated groups compared with CCl4 model group were identified. GO analysis showed that several identified proteins involved in oxidative stress pathway. The study provides new insights and data for administration of rhCygb reversing CCl4-induced liver fibrosis suggesting that rhCygb might be used in the treatment of liver fibrosis.
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Hajarizadeh B, Lamoury FM, Feld JJ, Amin J, Keoshkerian E, Matthews GV, Hellard M, Dore GJ, Lloyd AR, Grebely J, Applegate TL. Alanine aminotransferase, HCV RNA levels and pro-inflammatory and pro-fibrogenic cytokines/chemokines during acute hepatitis C virus infection. Virol J 2016; 13:32. [PMID: 26911712 PMCID: PMC4765111 DOI: 10.1186/s12985-016-0482-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Accepted: 02/02/2016] [Indexed: 12/12/2022] Open
Abstract
Background This study assessed the association of alanine-aminotransferase (ALT) and hepatitis C virus (HCV) RNA levels with pro-inflammatory and pro-fibrogenic cytokines and chemokines during acute HCV infection to provide further insight into the potential HCV immunopathogenesis. Methods Participants in the ATAHC study, a prospective study of recent HCV infection, with detectable HCV RNA at the time of HCV detection were included. Plasma levels of 27 cytokines and chemokines were measured and their correlation with ALT and HCV RNA levels were assessed. Log10 transformed cytokines and ALT values were used in the analysis. Results Among 117 individuals, the plasma levels of interferon-gamma inducible protein-10 (IP-10) and macrophage inflammatory protein-1beta (MIP-1β) were positively correlated with ALT levels (IP-10: r = 0.42, P < 0.001; MIP-1β: r = 0.29, P = 0.001) and HCV RNA levels (IP-10: rs = 0.44, P < 0.001; MIP-1β: rs = 0.43, P < 0.001). Using linear regression, after adjusting for sex, age, infection duration, symptomatic infection, HIV co-infection, interferon-lambda rs12979860 genotype, HCV genotype, and assay run, higher ALT levels (β = 0.20; 95 % CI: 0.07, 0.32; P = 0.002) and HCV RNA levels >400,000 IU/mL (vs. <8,500 IU/mL; β = 0.16; 95 % CI: 0.03, 0.28; P = 0.014) were independently associated with higher IP-10 levels. HCV RNA levels >400,000 IU/mL (vs. <8,500 IU/mL; β = 0.16; 95 % CI: 0.01, 0.31; P = 0.036) were associated with higher MIP-1β levels. Conclusions During acute HCV infection, high ALT and HCV RNA levels were associated with increased IP-10 levels, while high HCV RNA levels were also associated with increased MIP-1β levels. These data suggest that IP-10 and MIP-1β may have a role in HCV immuno-pathogenesis starting early in acute HCV infection. Electronic supplementary material The online version of this article (doi:10.1186/s12985-016-0482-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Behzad Hajarizadeh
- The Kirby Institute, UNSW Australia, Wallace Wurth Building, Sydney, 2052, Australia.
| | - François Mj Lamoury
- The Kirby Institute, UNSW Australia, Wallace Wurth Building, Sydney, 2052, Australia.
| | - Jordan J Feld
- Toronto Centre for Liver Disease, McLaughlin-Rotman Centre for Global Health, University of Toronto, Toronto, Canada.
| | - Janaki Amin
- The Kirby Institute, UNSW Australia, Wallace Wurth Building, Sydney, 2052, Australia.
| | - Elizabeth Keoshkerian
- Inflammation and Infection Research Centre, School of Medical Sciences, UNSW Australia, Sydney, Australia.
| | - Gail V Matthews
- The Kirby Institute, UNSW Australia, Wallace Wurth Building, Sydney, 2052, Australia. .,HIV/Immunology/Infectious Diseases Clinical Services Unit, St Vincent's Hospital, Sydney, Australia.
| | | | - Gregory J Dore
- The Kirby Institute, UNSW Australia, Wallace Wurth Building, Sydney, 2052, Australia. .,HIV/Immunology/Infectious Diseases Clinical Services Unit, St Vincent's Hospital, Sydney, Australia.
| | - Andrew R Lloyd
- Inflammation and Infection Research Centre, School of Medical Sciences, UNSW Australia, Sydney, Australia.
| | - Jason Grebely
- The Kirby Institute, UNSW Australia, Wallace Wurth Building, Sydney, 2052, Australia.
| | - Tanya L Applegate
- The Kirby Institute, UNSW Australia, Wallace Wurth Building, Sydney, 2052, Australia.
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Abstract
Hepatitis C infection is a common cause of cirrhosis and indication for liver transplantation in the United States. The incidence of chronic hepatitis C has been declining, but rates of cirrhosis and hepatocellular carcinoma are projected to increase. The outcome of chronic hepatitis C is variable. It is estimated that 20% to 25% will develop cirrhosis over a 25-year to 30-year period. The rate of disease progression is influenced by many host, viral, and environmental factors. Few can be modified.
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Abstract
Hepatitis C virus (HCV) infection is a common liver disease worldwide with a high rate of chronicity (75–80%) in infected individuals. The chronic form of HCV leads to steatosis, cirrhosis and hepatocellualr carcinoma. Steatosis is prevalent in HCV patients (55%) due to a combination of viral factors (effect of viral proteins on some of the intracellular pathways) and host factors (overweight, insulin resistance, diabetes mellitus, and alcohol consumption). The response rates to treatment of chronic HCV with pegylated interferon (PEG-IFN) and (in the case of genotype-1 HCV, the most common infecting genotype in the USA) ribavirin (RBV) is low, with a sustained viral response rate ≤ 40%. Adding direct-acting antiviral agents—recently approved by the FDA—to the standard protocol has increased the response rate; however HCV-related end-stage liver disease is still the primary indication for liver transplantation in the USA. The focus of this article is on the interrelation between HCV, steatosis and metabolic syndrome.
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Affiliation(s)
- Jamak Modaresi Esfeh
- Department of Gastroenterology and Hepatology, The Cleveland Clinic, Cleveland, OH, USA
| | - Kianoush Ansari-Gilani
- Department of Radiology, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH, USA
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Furuta A, Tsubuki M, Endoh M, Miyamoto T, Tanaka J, Salam KA, Akimitsu N, Tani H, Yamashita A, Moriishi K, Nakakoshi M, Sekiguchi Y, Tsuneda S, Noda N. Identification of Hydroxyanthraquinones as Novel Inhibitors of Hepatitis C Virus NS3 Helicase. Int J Mol Sci 2015; 16:18439-53. [PMID: 26262613 PMCID: PMC4581254 DOI: 10.3390/ijms160818439] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 07/14/2015] [Accepted: 07/31/2015] [Indexed: 01/27/2023] Open
Abstract
Hepatitis C virus (HCV) is an important etiological agent of severe liver diseases, including cirrhosis and hepatocellular carcinoma. The HCV genome encodes nonstructural protein 3 (NS3) helicase, which is a potential anti-HCV drug target because its enzymatic activity is essential for viral replication. Some anthracyclines are known to be NS3 helicase inhibitors and have a hydroxyanthraquinone moiety in their structures; mitoxantrone, a hydroxyanthraquinone analogue, is also known to inhibit NS3 helicase. Therefore, we hypothesized that the hydroxyanthraquinone moiety alone could also inhibit NS3 helicase. Here, we performed a structure-activity relationship study on a series of hydroxyanthraquinones by using a fluorescence-based helicase assay. Hydroxyanthraquinones inhibited NS3 helicase with IC50 values in the micromolar range. The inhibitory activity varied depending on the number and position of the phenolic hydroxyl groups, and among different hydroxyanthraquinones examined, 1,4,5,8-tetrahydroxyanthraquinone strongly inhibited NS3 helicase with an IC50 value of 6 µM. Furthermore, hypericin and sennidin A, which both have two hydroxyanthraquinone-like moieties, were found to exert even stronger inhibition with IC50 values of 3 and 0.8 µM, respectively. These results indicate that the hydroxyanthraquinone moiety can inhibit NS3 helicase and suggest that several key chemical structures are important for the inhibition.
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Affiliation(s)
- Atsushi Furuta
- Department of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan.
- Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan.
| | - Masayoshi Tsubuki
- Institute of Medical Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
| | - Miduki Endoh
- Institute of Medical Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
| | - Tatsuki Miyamoto
- Department of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan.
- Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan.
| | - Junichi Tanaka
- Department of Chemistry, Biology and Marine Science, University of the Ryukyus, Nishihara, Okinawa 903-0213, Japan.
| | - Kazi Abdus Salam
- Radioisotope Center, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
| | - Nobuyoshi Akimitsu
- Radioisotope Center, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
| | - Hidenori Tani
- Environmental Measurement Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 16-1 Onogawa, Tsukuba, Ibaraki 305-8569, Japan.
| | - Atsuya Yamashita
- Department of Microbiology, Division of Medicine, Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi 409-3898, Japan.
| | - Kohji Moriishi
- Department of Microbiology, Division of Medicine, Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi 409-3898, Japan.
| | - Masamichi Nakakoshi
- Department of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi-shi, Chiba 274-8510, Japan.
| | - Yuji Sekiguchi
- Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan.
| | - Satoshi Tsuneda
- Department of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan.
| | - Naohiro Noda
- Department of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan.
- Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan.
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Estrabaud E, Appourchaux K, Bièche I, Carrat F, Lapalus M, Lada O, Martinot-Peignoux M, Boyer N, Marcellin P, Vidaud M, Asselah T. IFI35, mir-99a and HCV genotype to predict sustained virological response to pegylated-interferon plus ribavirin in chronic hepatitis C. PLoS One 2015; 10:e0121395. [PMID: 25844942 PMCID: PMC4386819 DOI: 10.1371/journal.pone.0121395] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Accepted: 01/31/2015] [Indexed: 12/20/2022] Open
Abstract
Although, the treatment of chronic hepatitis C (CHC) greatly improved with the use of direct antiviral agents, pegylated-interferon (PEG-IFN) plus ribavirin remains an option for many patients, worldwide. The intra-hepatic level of expression of interferon stimulated genes (ISGs) and the rs12979860 CC genotype located within IFNL3 have been associated with sustained virological response (SVR), in patients with CHC. The aim of the study was to identify micro-RNAs associated with SVR and to build an accurate signature to predict SVR. Pre-treatment liver biopsies from 111 patients, treated with PEG-IFN plus ribavirin, were studied. Fifty-seven patients had SVR, 36 non-response (NR) and 18 relapse (RR). The expression of 851 human miRNAs and 30 selected mRNAs, including ISGs, was assessed by RT-qPCR. In the first group of patients (screen), 20 miRNAs out of the 851 studied were deregulated between NRs and SVRs. From the 4 miRNAs validated (mir-23a, mir-181a*, mir-217 and mir-99a), in the second group of patients (validation), 3 (mir-23a, mir-181a* and mir-99a) were down-regulated in NRs as compared to SVRs. The ISGs, studied, were accumulated in SVRs and IFNL3 rs12979860 CT/TT carriers compared respectively to NRs and CC carriers. Combining, clinical data together with the expression of selected genes and micro-RNAs, we identified a signature (IFI35, mir-99a and HCV genotype) to predict SVR (AUC:0.876) with a positive predictive value of 86.54% with high sensibility (80%) and specificity (80.4%). This signature may help to characterize patients with low chance to respond to PEG-IFN/ribavirin and to elucidate mechanisms of NR.
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Affiliation(s)
- Emilie Estrabaud
- INSERM, UMR1149, Team «Viral hepatitis », Centre de Recherche sur l’inflammation, BP 416, Paris, France
- Université Denis Diderot Paris 7, site Bichat, BP 416, Paris, France
- Service d’Hépatologie, PMAD Hôpital Beaujon, 100 Bd du Général Leclerc, Clichy la Garenne, Clichy, France
- Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France
- * E-mail:
| | - Kevin Appourchaux
- INSERM, UMR1149, Team «Viral hepatitis », Centre de Recherche sur l’inflammation, BP 416, Paris, France
- Université Denis Diderot Paris 7, site Bichat, BP 416, Paris, France
- Service d’Hépatologie, PMAD Hôpital Beaujon, 100 Bd du Général Leclerc, Clichy la Garenne, Clichy, France
- Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France
| | - Ivan Bièche
- UMR745 INSERM, Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France
| | - Fabrice Carrat
- Unité de santé publique, Hôpital Saint-Antoine, Assistance Publique Hôpitaux de Paris and UMR-S 707, UPMC Université Paris 06 & INSERM, Paris, France
| | - Martine Lapalus
- INSERM, UMR1149, Team «Viral hepatitis », Centre de Recherche sur l’inflammation, BP 416, Paris, France
- Université Denis Diderot Paris 7, site Bichat, BP 416, Paris, France
- Service d’Hépatologie, PMAD Hôpital Beaujon, 100 Bd du Général Leclerc, Clichy la Garenne, Clichy, France
- Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France
| | - Olivier Lada
- INSERM, UMR1149, Team «Viral hepatitis », Centre de Recherche sur l’inflammation, BP 416, Paris, France
- Université Denis Diderot Paris 7, site Bichat, BP 416, Paris, France
- Service d’Hépatologie, PMAD Hôpital Beaujon, 100 Bd du Général Leclerc, Clichy la Garenne, Clichy, France
- Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France
| | - Michelle Martinot-Peignoux
- INSERM, UMR1149, Team «Viral hepatitis », Centre de Recherche sur l’inflammation, BP 416, Paris, France
- Université Denis Diderot Paris 7, site Bichat, BP 416, Paris, France
- Service d’Hépatologie, PMAD Hôpital Beaujon, 100 Bd du Général Leclerc, Clichy la Garenne, Clichy, France
- Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France
| | - Nathalie Boyer
- INSERM, UMR1149, Team «Viral hepatitis », Centre de Recherche sur l’inflammation, BP 416, Paris, France
- Université Denis Diderot Paris 7, site Bichat, BP 416, Paris, France
- Service d’Hépatologie, PMAD Hôpital Beaujon, 100 Bd du Général Leclerc, Clichy la Garenne, Clichy, France
- Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France
| | - Patrick Marcellin
- INSERM, UMR1149, Team «Viral hepatitis », Centre de Recherche sur l’inflammation, BP 416, Paris, France
- Université Denis Diderot Paris 7, site Bichat, BP 416, Paris, France
- Service d’Hépatologie, PMAD Hôpital Beaujon, 100 Bd du Général Leclerc, Clichy la Garenne, Clichy, France
- Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France
| | - Michel Vidaud
- UMR745 INSERM, Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France
| | - Tarik Asselah
- INSERM, UMR1149, Team «Viral hepatitis », Centre de Recherche sur l’inflammation, BP 416, Paris, France
- Université Denis Diderot Paris 7, site Bichat, BP 416, Paris, France
- Service d’Hépatologie, PMAD Hôpital Beaujon, 100 Bd du Général Leclerc, Clichy la Garenne, Clichy, France
- Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France
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Abstract
Alcoholic liver disease (ALD) is characterized by hepatocyte damage, inflammatory cell activation and increased intestinal permeability leading to the clinical manifestations of alcoholic hepatitis. Selected members of the family of microRNAs are affected by alcohol, resulting in an abnormal miRNA profile in the liver and circulation in ALD. Increasing evidence suggests that mRNAs that regulate inflammation, lipid metabolism and promote cancer are affected by excessive alcohol administration in mouse models of ALD. This communication highlights recent findings in miRNA expression and functions as they relate to the pathogenesis of ALD. The cell-specific distribution of miRNAs, as well as the significance of circulating extracellular miRNAs, is discussed as potential biomarkers. Finally, the prospects of miRNA-based therapies are evaluated in ALD.
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Affiliation(s)
- Gyongyi Szabo
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts
| | - Abhishek Satishchandran
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts
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Abstract
Alcoholic liver disease (ALD) is characterized by hepatocyte damage, inflammatory cell activation and increased intestinal permeability leading to the clinical manifestations of alcoholic hepatitis. Selected members of the family of microRNAs are affected by alcohol, resulting in an abnormal miRNA profile in the liver and circulation in ALD. Increasing evidence suggests that mRNAs that regulate inflammation, lipid metabolism and promote cancer are affected by excessive alcohol administration in mouse models of ALD. This communication highlights recent findings in miRNA expression and functions as they relate to the pathogenesis of ALD. The cell-specific distribution of miRNAs, as well as the significance of circulating extracellular miRNAs, is discussed as potential biomarkers. Finally, the prospects of miRNA-based therapies are evaluated in ALD.
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Affiliation(s)
- Gyongyi Szabo
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts
| | - Abhishek Satishchandran
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts
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Zou X, Chi X, Pan Y, Du D, Sun H, Matsuda A, Li W, Kuno A, Zhang X, Narimatsu H, Niu J, Zhang Y. LecT-Hepa facilitates estimating treatment outcome during interferon therapy in chronic hepatitis C patients. Clin Proteomics 2014; 11:44. [PMID: 25593566 PMCID: PMC4276098 DOI: 10.1186/1559-0275-11-44] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Accepted: 11/25/2014] [Indexed: 02/07/2023] Open
Abstract
Background A combination treatment of interferon and ribavirin is the standard and the commonly used treatment for chronic hepatitis C (CHC). Developing noninvasive tests like serum indicators that can predict treatment outcome at an early stage of therapy is beneficial for individualized treatment and management of CHC. A glyco-indicator based on the glyco-alteration of serum α1-acid glycoprotein, LecT-Hepa, was discovered by glycomics technologies as a robust indicator of liver fibrosis. Here, we investigated the clinical utility of LecT-Hepa for evaluation of treatment outcome. Results Firstly, ninety-seven patients with CHC were used for comparison of LecT-Hepa in serum and plasma. We found no significant difference in the concentrations of LecT-Hepa in serum and plasma. And then, 213 serum specimens from 45 patients who received 48 weeks of treatment with interferon and ribavirin were followed up for 96 weeks, and were used for evaluation of the role of LecT-Hepa. We found that LecT-Hepa might reflect the change in fibrosis regression during the treatment process. Moreover, the change of LecT-Hepa at the first 12 weeks of treatment could already predict the antiviral treatment response, which was more superior to FIB-4 index and aspartate aminotransferase-to-platelet ratio index (APRI) in this study. Conclusions These results provide a new perspective that serum glycoprotein could be used as a joint diagnosis indicator for estimation treatment outcome of viral hepatitis at earlier stage of therapy. Electronic supplementary material The online version of this article (doi:10.1186/1559-0275-11-44) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xia Zou
- Ministry of Education Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dong Chuan Road, Minhang Shanghai, 200240 China.,SCSB (China) - AIST (Japan) Joint Medical Glycomics Laboratory, 800 Dong Chuan Road, Minhang Shanghai, 200240 China.,Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197, Ruijin Er Road, Shanghai, 200025 China
| | - Xiumei Chi
- Department of Hepatology, First Hospital, Jilin University, Changchun, 130021 China
| | - Yu Pan
- Department of Hepatology, First Hospital, Jilin University, Changchun, 130021 China
| | - Dongning Du
- Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Umezono, Tsukuba, Ibaraki, 305-8568 Japan.,SCSB (China) - AIST (Japan) Joint Medical Glycomics Laboratory, 800 Dong Chuan Road, Minhang Shanghai, 200240 China
| | - Haibo Sun
- Department of Hepatology, First Hospital, Jilin University, Changchun, 130021 China
| | - Atsushi Matsuda
- Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Umezono, Tsukuba, Ibaraki, 305-8568 Japan.,SCSB (China) - AIST (Japan) Joint Medical Glycomics Laboratory, 800 Dong Chuan Road, Minhang Shanghai, 200240 China
| | - Wei Li
- Ministry of Education Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dong Chuan Road, Minhang Shanghai, 200240 China.,SCSB (China) - AIST (Japan) Joint Medical Glycomics Laboratory, 800 Dong Chuan Road, Minhang Shanghai, 200240 China
| | - Atsushi Kuno
- Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Umezono, Tsukuba, Ibaraki, 305-8568 Japan.,SCSB (China) - AIST (Japan) Joint Medical Glycomics Laboratory, 800 Dong Chuan Road, Minhang Shanghai, 200240 China
| | - Xinxin Zhang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197, Ruijin Er Road, Shanghai, 200025 China
| | - Hisashi Narimatsu
- Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Umezono, Tsukuba, Ibaraki, 305-8568 Japan.,SCSB (China) - AIST (Japan) Joint Medical Glycomics Laboratory, 800 Dong Chuan Road, Minhang Shanghai, 200240 China
| | - Junqi Niu
- Department of Hepatology, First Hospital, Jilin University, Changchun, 130021 China
| | - Yan Zhang
- Ministry of Education Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dong Chuan Road, Minhang Shanghai, 200240 China.,SCSB (China) - AIST (Japan) Joint Medical Glycomics Laboratory, 800 Dong Chuan Road, Minhang Shanghai, 200240 China
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Impact of treatment against hepatitis C virus on overall survival of naive patients with advanced liver disease. Antimicrob Agents Chemother 2014; 59:803-10. [PMID: 25403673 DOI: 10.1128/aac.04027-14] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
The beneficial effect of achieving a sustained virological response (SVR) after antiviral treatment against hepatitis C virus is well established. However, it remains unclear whether unsuccessful treatment (non-SVR) also improves patient survival, especially in patients with advanced liver fibrosis. We retrospectively evaluated the incidence of death or liver transplantation in the 427 naive patients with a Child-Pugh score of A and advanced fibrosis newly admitted to the Hospital Beaujon between 2000 and 2010. Patients were followed for a median time of 5.5 years. The baseline characteristics of untreated (n=102) and treated (n=325) patients were largely similar, and there was no evidence of a bias of indication. Treated patients received a combination of interferon and ribavirin and had an SVR rate of 32%. The incidence of death or liver transplantation per 100 person-years was 1.00, 3.20, and 5.44 in SVR, non-SVR, and untreated patients, respectively. After adjusting for baseline characteristics, the risk of death or liver transplantation was significantly lower in SVR than in non-SVR patients and in non-SVR than in untreated patients (hazard ratios, 0.35 and 0.51, respectively; P=0.019 and 0.038, respectively). The effect of treatment in non-SVR patients was higher in patients who had a virological or a biochemical response than in those who did not have a virological or a biochemical response. The risk of death or liver transplantation was significantly lower in treated than in untreated patients. Moreover, there was a gradient of mortality between patients with SVRs, virological or biochemical responders, and untreated patients, suggesting that treatment, even in the absence of viral eradication, has a beneficial effect on survival.
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46
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Christiansen KM, Mössner BK, Hansen JF, Jarnbjer EF, Pedersen C, Christensen PB. Liver stiffness measurement among patients with chronic hepatitis B and C: results from a 5-year prospective study. PLoS One 2014; 9:e111912. [PMID: 25369038 PMCID: PMC4219798 DOI: 10.1371/journal.pone.0111912] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2014] [Accepted: 08/27/2014] [Indexed: 02/07/2023] Open
Abstract
Liver stiffness measurement (LSM) is widely used to evaluate liver fibrosis, but longitudinal studies are rare. The current study was aimed to monitor LSM during follow-up, and to evaluate the association of LSM data with mortality and liver-related outcomes. We included all patients with chronic viral hepatitis and valid LSM using Fibroscan. Information about liver biopsy, antiviral treatment, and clinical outcome was obtained from medical records and national registers. The study included 845 patients: 597 (71%) with hepatitis C virus (HCV), 235 (28%) with hepatitis B virus (HBV) and 13 (2%) with dual infection. The initial LSM distribution (<7/7-9.9/10-16.9/≥ 17 kPa) was 58%/16%/14%/12%. Among patients with initial LSM values of 7-9.9 kPa, 60% of HCV patients and 83% of HBV patients showed LSM values of <7 kPa at the latest follow-up. Progression rates (defined as >20% and >2 kPa increase, with one measure >7 kPa) were 3.4/100 person years (PY) for HCV and 1.5/100 PY for HBV infected patients. Patients with LSM values of ≥ 17 kPa had the same liver-related complication incidence as patients with biopsy-proven cirrhosis (11.1 versus 12.1/100 PY). Thirteen liver-related deaths occurred among HCV patients (0.6/100 PY), but none among HBV patients. Among patients who died of liver-related causes, all but one had baseline LSM values of ≥ 17 kPa. Overall, patients with LSM values <17 kPa were not associated with adverse outcomes. In contrast, LSM values ≥ 17 kPa were associated with significant risk of liver-related problems. The results of the current study suggest that clinical decisions should not be taken based on a single LSM measurement.
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Affiliation(s)
| | - Belinda K. Mössner
- Department of Infectious Diseases, Odense University Hospital, Odense, Denmark
| | - Janne F. Hansen
- Department of Infectious Diseases, Odense University Hospital, Odense, Denmark
| | - Erik F. Jarnbjer
- Department of Infectious Diseases, Odense University Hospital, Odense, Denmark
| | - Court Pedersen
- Department of Infectious Diseases, Odense University Hospital, Odense, Denmark
| | - Peer B. Christensen
- Department of Infectious Diseases, Odense University Hospital, Odense, Denmark
- * E-mail:
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Kakati B, Seetharam A. Hepatitis C Recurrence after Orthotopic Liver Transplantation: Mechanisms and Management. J Clin Transl Hepatol 2014; 2:189-96. [PMID: 26355427 PMCID: PMC4521242 DOI: 10.14218/jcth.2014.00016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Revised: 06/06/2014] [Accepted: 07/07/2014] [Indexed: 12/04/2022] Open
Abstract
Chronic Hepatitis C (HCV) infection is the leading indication for orthotopic liver transplantation and recurrence is nearly universal. Chronic HCV infection is frequently established through evasion of the innate immune system. Priming of adaptive immune responses modulate the severity and rate of fibrosis progression. Those with demonstrable viremia entering the transplant period uniformly suffer recurrence post-transplant. Progression to cirrhosis is accelerated post-transplant secondary to systemic immunosuppression. In addition, a number of factors, including donor, host, and viral characteristics, influence severity and rate of fibrosis progression. Interferon-based therapy, the previous standard of care, in those with advanced cirrhosis or post-transplant has been limited by a number of issues. These include a relative lack of efficacy and poor tolerability with higher incidence of infection and anemia. Recently, approval of direct acting antivirals have ushered in a new era in HCV therapeutics and have applicability in these special populations. Their use immediately prior to or post-transplant is expected to improve both morbidity and mortality.
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Affiliation(s)
- Bobby Kakati
- Banner Transplant and Advanced Liver Disease Center, Phoenix, AZ, USA
| | - Anil Seetharam
- Banner Transplant and Advanced Liver Disease Center, Phoenix, AZ, USA
- University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA
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Estrabaud E, Lapalus M, Broët P, Appourchaux K, Muynck SD, Lada O, Martinot-Peignoux M, Bièche I, Valla D, Bedossa P, Marcellin P, Vidaud M, Asselah T. Reduction of microRNA 122 expression in IFNL3 CT/TT carriers and during progression of fibrosis in patients with chronic hepatitis C. J Virol 2014; 88:6394-402. [PMID: 24672032 PMCID: PMC4093870 DOI: 10.1128/jvi.00016-14] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Accepted: 03/19/2014] [Indexed: 02/06/2023] Open
Abstract
UNLABELLED The microRNA miR-122 is highly expressed in the liver and stimulates hepatitis C virus (HCV) replication in vitro. IFNL3 (lambda-3 interferon gene) polymorphisms and the expression of miR-122 have been associated with sustained virological response (SVR) to treatment with pegylated interferon plus ribavirin in patients with chronic hepatitis C (CHC). We investigated, in vivo, the relationship between miR-122 expression, IFNL3 polymorphism, fibrosis, and response to PEG-IFN plus ribavirin. Pretreatment liver biopsy specimens and serum samples from 133 patients with CHC were included. Sixty-six patients achieved SVR, and 64 failed to respond to the treatment (43 nonresponders [NR] and 21 relapsers [RR]). All stages of fibrosis were represented, with 39, 50, 23, and 19 patients, respectively, having Metavir scores of F1, F2, F3, and F4. miR-122 expression was assessed by real-time quantitative PCR (RT-qPCR) and IFNL3 rs12979860 by direct sequencing. Hepatic miR-122 expression was higher in patients with the IFNL3 CC genotype than in those with the IFNL3 CT or TT genotype, in all patients (P = 0.025), and in NRs plus RRs (P = 0.013). Increased hepatic miR-122 was more strongly associated with complete early virological response (cEVR) (P = 0.003) than with SVR (P = 0.016). In multivariate analysis, increased hepatic miR-122 was only associated with the IFNL3 CC genotype. miR-122 was decreased in patients with advanced fibrosis (Metavir scores of F3 and F4) compared to its levels in patients with mild and moderate fibrosis (F1 and F2) (P = 0.01). Serum and hepatic expression of miR-122 were not associated. The association between miR-122 and IFNL3 was stronger than the association between miR-122 and response to treatment. miR-122 may play a role in the early viral decline that is dependent on IFNL3 and the innate immune response. IMPORTANCE miR-122 plays a crucial role during HCV infection. Moreover, it was reported that miR-122 binding within the HCV genome stimulates its replication. Moreover, miR-122 is highly expressed within hepatocytes, where it regulates many cellular pathways. A reduction of miR-122 expression has been suggested to be associated with responsiveness to IFN-based therapy in patients with chronic hepatitis C. Several independent genome-wide association studies reported a strong association between IFNL3 polymorphism and responsiveness to IFN-based therapy. We report here a strong association between the expression of miR-122 and IFNL3 polymorphism that is independent of the response to the treatment. Our data suggest that modification of miR-122 expression may play an important role in the molecular mechanism associated with IFNL3 polymorphism. Moreover, we report a reduction of miR-122 at more advanced stages of fibrosis in patients with chronic hepatitis C.
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Affiliation(s)
- Emilie Estrabaud
- INSERM, UMR1149, Team Physiopathology and Treatment of Viral Hepatitis, Centre de Recherche sur l'Inflammation, BP 416, Paris, France
- Université Denis Diderot Paris 7, site Bichat, BP 416, Paris, France
- Service d'Hépatologie, PMAD Hôpital Beaujon, Clichy la Garenne, France
- Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France
| | - Martine Lapalus
- INSERM, UMR1149, Team Physiopathology and Treatment of Viral Hepatitis, Centre de Recherche sur l'Inflammation, BP 416, Paris, France
- Université Denis Diderot Paris 7, site Bichat, BP 416, Paris, France
- Service d'Hépatologie, PMAD Hôpital Beaujon, Clichy la Garenne, France
- Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France
| | - Philippe Broët
- University Paris-Sud Inserm UMR669, Villejuif, and AP-HP, Groupe Hospitalier Antoine-Béclère, Bicêtre, Paul-Brousse, Villejuif, France
| | - Kevin Appourchaux
- INSERM, UMR1149, Team Physiopathology and Treatment of Viral Hepatitis, Centre de Recherche sur l'Inflammation, BP 416, Paris, France
- Université Denis Diderot Paris 7, site Bichat, BP 416, Paris, France
- Service d'Hépatologie, PMAD Hôpital Beaujon, Clichy la Garenne, France
- Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France
| | - Simon De Muynck
- INSERM, UMR1149, Team Physiopathology and Treatment of Viral Hepatitis, Centre de Recherche sur l'Inflammation, BP 416, Paris, France
- Université Denis Diderot Paris 7, site Bichat, BP 416, Paris, France
- Service d'Hépatologie, PMAD Hôpital Beaujon, Clichy la Garenne, France
- Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France
| | - Olivier Lada
- INSERM, UMR1149, Team Physiopathology and Treatment of Viral Hepatitis, Centre de Recherche sur l'Inflammation, BP 416, Paris, France
- Université Denis Diderot Paris 7, site Bichat, BP 416, Paris, France
- Service d'Hépatologie, PMAD Hôpital Beaujon, Clichy la Garenne, France
- Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France
| | - Michelle Martinot-Peignoux
- INSERM, UMR1149, Team Physiopathology and Treatment of Viral Hepatitis, Centre de Recherche sur l'Inflammation, BP 416, Paris, France
- Université Denis Diderot Paris 7, site Bichat, BP 416, Paris, France
- Service d'Hépatologie, PMAD Hôpital Beaujon, Clichy la Garenne, France
- Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France
| | - Ivan Bièche
- UMR745 INSERM, Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France
| | - Dominique Valla
- Service d'Hépatologie, PMAD Hôpital Beaujon, Clichy la Garenne, France
| | - Pierre Bedossa
- Service d'Anatomie Pathologique, Hôpital Beaujon, Clichy, France
| | - Patrick Marcellin
- INSERM, UMR1149, Team Physiopathology and Treatment of Viral Hepatitis, Centre de Recherche sur l'Inflammation, BP 416, Paris, France
- Université Denis Diderot Paris 7, site Bichat, BP 416, Paris, France
- Service d'Hépatologie, PMAD Hôpital Beaujon, Clichy la Garenne, France
- Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France
| | - Michel Vidaud
- UMR745 INSERM, Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France
| | - Tarik Asselah
- INSERM, UMR1149, Team Physiopathology and Treatment of Viral Hepatitis, Centre de Recherche sur l'Inflammation, BP 416, Paris, France
- Université Denis Diderot Paris 7, site Bichat, BP 416, Paris, France
- Service d'Hépatologie, PMAD Hôpital Beaujon, Clichy la Garenne, France
- Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France
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Abstract
INTRODUCTION Hepatitis C virus (HCV) therapy continues to evolve rapidly. ABT-450 is a novel potent inhibitor of the non-structural 3/4A protease that has been studied in combination with several agents, allowing shorter duration of therapy and interferon-free/ribavirin-free all-oral regimens. Preliminary data from studies evaluating these new regimens are impressive with sustained virological response (SVR) rates of 88 - 100% after 12 weeks of therapy in patients with previously untreated HCV genotype 1 infection. SVR rates in treatment-experienced patients are also encouraging. AREAS COVERED Efficacy and tolerability of antiviral regimens containing ABT-450 boosted with ritonavir (ABT-450/r). Results from published studies and abstracts from recent meetings are presented. EXPERT OPINION Newer direct-acting antiviral agents such as ABT-450 promise effective and durable suppression of HCV with interferon/ribavirin-free all-oral regimens. This agent also allows for shorter duration of treatment and has tolerable side effects. Results of clinical trials including a broader spectrum of individuals with HCV infection are eagerly awaited.
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Affiliation(s)
- Andres F Carrion
- University of Miami, Miller School of Medicine, Division of Gastroenterology , 1120 NW 14th Street, Suite 310E, Miami, FL 33136 , USA +1 305 243 8644 ; +1 305 243 3762 ;
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50
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Dolan PT, Zhang C, Khadka S, Arumugaswami V, Vangeloff AD, Heaton NS, Sahasrabudhe S, Randall G, Sun R, LaCount DJ. Identification and comparative analysis of hepatitis C virus-host cell protein interactions. MOLECULAR BIOSYSTEMS 2013; 9:3199-209. [PMID: 24136289 DOI: 10.1039/c3mb70343f] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Hepatitis C virus (HCV) alters the global behavior of the host cell to create an environment conducive to its own replication, but much remains unknown about how HCV proteins elicit these changes. Thus, a better understanding of the interface between the virus and host cell is required. Here we report the results of a large-scale yeast two-hybrid screen to identify protein-protein interactions between HCV genotype 2a (strain JFH1) and cellular factors. Our study identified 112 unique interactions between 7 HCV and 94 human proteins, over 40% of which have been linked to HCV infection by other studies. These interactions develop a more complete picture of HCV infection, providing insight into HCV manipulation of pathways, such as lipid and cholesterol metabolism, that were previously linked to HCV infection and implicating novel targets within microtubule-organizing centers, the complement system and cell cycle regulatory machinery. In an effort to understand the relationship between HCV and related viruses, we compared the HCV 2a interactome to those of other HCV genotypes and to the related dengue virus. Greater overlap was observed between HCV and dengue virus targets than between HCV genotypes, demonstrating the value of parallel screening approaches when comparing virus-host cell interactomes. Using siRNAs to inhibit expression of cellular proteins, we found that five of the ten shared targets tested (CUL7, PCM1, RILPL2, RNASET2, and TCF7L2) were required for replication of both HCV and dengue virus. These shared interactions provide insight into common features of the viral life cycles of the family Flaviviridae.
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Affiliation(s)
- Patrick T Dolan
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, RHPH 514, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA.
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