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Rajewski P, Pawłowska M, Kozielewicz D, Dybowska D, Olczak A, Cieściński J. Hepatitis C Infection Is Not a Cardiovascular Risk Factor in Young Adults. Biomedicines 2024; 12:2400. [PMID: 39457712 PMCID: PMC11505620 DOI: 10.3390/biomedicines12102400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 10/15/2024] [Accepted: 10/17/2024] [Indexed: 10/28/2024] Open
Abstract
Background: Cardiovascular diseases are one of the leading causes of hospitalization and death in Poland and around the world and are still an ongoing problem for modern medicine. Despite advances in diagnosis and treatment, both conservative and invasive, the prevention of cardiovascular disease directed at reducing risk factors remains a problem. The main classical risk factors for the development of cardiovascular disease in Poland include hypertension, lipid disorders, obesity, diabetes and smoking. A new non-classical risk factor is HCV infection. Most of the studies on the impact of HCV infection on cardiovascular disease involve elderly populations with long-term infections and advanced liver fibrosis. Methods: Hence, we set out to analyze the prevalence of risk factors and cardiovascular disease in a population of young adults under 45 years of age infected with HCV, according to gender, HCV genotype and the duration of infection. The study group consisted of 217 patients of both sexes aged 21 to 45 years (mean age 36 years). Results: No cardiovascular disease was found among the young adults infected with HCV in the study group. The most common risk factor was cigarette smoking, which affected 20.7% of the subjects, followed by hypertension (12%) and diabetes mellitus (5.5%); the prevalence was lower than in the general population. Most of the patients were characterized as overweight, with a mean BMI of 26.39 kg/m2. The mean values of other metabolic parameters-total cholesterol, LDL, HDL, uric acid and glucose-were within the population norm. The mean value of CRP was 1.43, which may indicate a moderate cardiovascular risk. Conclusions: Based on the conducted research, it was found that HCV infection in young individuals was not a risk factor for cardiovascular diseases, and the prevalence of risk factors was similar to that in the general population. The effect of HCV on the increase in C-reactive protein requires further study. The early detection of HCV infection and treatment can be considered as a prevention of cardiovascular disease.
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Affiliation(s)
- Paweł Rajewski
- Department of Internal and Infectious Diseases, Provincial Infectious Disease Hospital, 85-030 Bydgoszcz, Poland;
- Faculty of Health Sciences, University of Health Sciences in Bydgoszcz, 85-067 Bydgoszcz, Poland
| | - Małgorzata Pawłowska
- Department of Infectious Diseases and Hepatology, Faculty of Medicine, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University, 87-100 Torun, Poland; (M.P.); (D.K.); (D.D.); (A.O.)
| | - Dorota Kozielewicz
- Department of Infectious Diseases and Hepatology, Faculty of Medicine, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University, 87-100 Torun, Poland; (M.P.); (D.K.); (D.D.); (A.O.)
| | - Dorota Dybowska
- Department of Infectious Diseases and Hepatology, Faculty of Medicine, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University, 87-100 Torun, Poland; (M.P.); (D.K.); (D.D.); (A.O.)
| | - Anita Olczak
- Department of Infectious Diseases and Hepatology, Faculty of Medicine, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University, 87-100 Torun, Poland; (M.P.); (D.K.); (D.D.); (A.O.)
| | - Jakub Cieściński
- Department of Internal and Infectious Diseases, Provincial Infectious Disease Hospital, 85-030 Bydgoszcz, Poland;
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Lv R, Lu Y, Xiang W, Meng M, Li S. Chronic viral hepatitis C micro-elimination program using telemedicine in Guigang city. J Viral Hepat 2024; 31:208-215. [PMID: 38326936 DOI: 10.1111/jvh.13922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 01/08/2024] [Accepted: 01/13/2024] [Indexed: 02/09/2024]
Abstract
Hepatitis C virus (HCV) represents a formidable menace to human health, necessitating urgent attention. The objective of this study was to assess the efficacy and safety of HCV health management in the city of Guigang which consists of five districts, employing a comprehensive multi-modal approach. The study systematically carried out HCV screening in Guigang city which consists of five districts, such as Gangbei District, Gangnan District, Guiping District, Qintang District, and Pingnan District from 1 January 2016 to 30 December 2022. The target population consisted of individuals residing in these aforementioned districts, falling within the age range of 30-75 years. A multidisciplinary HCV management team was established to deliver anti-HCV screening, diagnosis, and direct-acting antiviral (DAA) therapy. The primary outcome of interest was the achievement of sustained virologic response (SVR). A total of 2489 individuals were included as the target population, with 1694 individuals residing in Gangbei District, 202 in Gangnan District, 111 in Qintang District, 167 in Pingnan District, and 315 in Guiping District. Out of these individuals, 2478 were subjected to anti-HCV screening. The screening rates varied across the districts, ranging from a peak of 99.55% in Guigang City to a nadir of 98.41% in Guiping District. Remarkably, within Guigang City, a noteworthy enhancement was observed in the HCV-RNA diagnosis rate from 23.4% prior to program implementation to a remarkable 100% following 7 years of intervention and management. Furthermore, the diagnosis and treatment coordination rate experienced a substantial improvement, rising from 26.8% before program inception to 80%. Importantly, a total of 1180 individuals affected by hepatitis C were successfully cured, equating to a 100% cure rate. Logistic regression analysis revealed a significant association between serological status and factors such as Aging, bilirubin, and glutamic oxalacetic transaminase. The findings from our investigation unveil a pioneering HCV management model, exemplified by the Guigang model, which has contributed crucially to HCV microclearance efforts and serves as an invaluable reference for future initiatives.
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Affiliation(s)
- Riying Lv
- Department of Infectious Diseases, Guigang City People's Hospital, Guigang, Guangxi, China
| | - Yanmeng Lu
- Department of Infectious Diseases, Guigang City People's Hospital, Guigang, Guangxi, China
| | - Wenyao Xiang
- Department of Infectious Diseases, Guigang City People's Hospital, Guigang, Guangxi, China
| | - Menglan Meng
- Department of Infectious Diseases, Guigang City People's Hospital, Guigang, Guangxi, China
| | - Shixiong Li
- Department of Infectious Diseases, Guigang City People's Hospital, Guigang, Guangxi, China
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Gorgzadeh A, Nazari A, Ali Ehsan Ismaeel A, Safarzadeh D, Hassan JAK, Mohammadzadehsaliani S, Kheradjoo H, Yasamineh P, Yasamineh S. A state-of-the-art review of the recent advances in exosome isolation and detection methods in viral infection. Virol J 2024; 21:34. [PMID: 38291452 PMCID: PMC10829349 DOI: 10.1186/s12985-024-02301-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 01/22/2024] [Indexed: 02/01/2024] Open
Abstract
Proteins, RNA, DNA, lipids, and carbohydrates are only some of the molecular components found in exosomes released by tumor cells. They play an essential role in healthy and diseased cells as messengers of short- and long-distance intercellular communication. However, since exosomes are released by every kind of cell and may be found in blood and other bodily fluids, they may one day serve as biomarkers for a wide range of disorders. In many pathological conditions, including cancer, inflammation, and infection, they play a role. It has been shown that the biogenesis of exosomes is analogous to that of viruses and that the exosomal cargo plays an essential role in the propagation, dissemination, and infection of several viruses. Bidirectional modulation of the immune response is achieved by the ability of exosomes associated with viruses to facilitate immunological escape and stimulate the body's antiviral immune response. Recently, exosomes have received a lot of interest due to their potential therapeutic use as biomarkers for viral infections such as human immunodeficiency virus (HIV), Hepatitis B virus (HBV), Hepatitis C virus (HCV), Epstein-Barr virus (EBV), and SARS-CoV-2. This article discusses the purification procedures and detection techniques for exosomes and examines the research on exosomes as a biomarker of viral infection.
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Affiliation(s)
| | - Ahmad Nazari
- Tehran University of Medical Sciences, Tehran, Iran
| | | | - Diba Safarzadeh
- Vocational School of Health Service, Near East University, Nicosia, Cyprus
| | - Jawad A K Hassan
- National University of Science and Technology, Nasiriyah, Dhi Qar, Iraq
| | | | | | - Pooneh Yasamineh
- Young Researchers and Elite Club, Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | - Saman Yasamineh
- Young Researchers and Elite Club, Tabriz Branch, Islamic Azad University, Tabriz, Iran.
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Bilska-Markowska M, Kaźmierczak M. Horner-Wadsworth-Emmons reaction as an excellent tool in the synthesis of fluoro-containing biologically important compounds. Org Biomol Chem 2023; 21:1095-1120. [PMID: 36632995 DOI: 10.1039/d2ob01969h] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Selective introduction of a double bond motif into a multifunctional organic compound is always a big challenge. The Horner-Wadsworth-Emmons reaction is one of the most reliable, simple, and stereoselective olefination methods, widely used in organic chemistry. To the best of our knowledge, no review article on the application of HWE reaction in the synthesis of fluoroorganic compounds with direct biological interest has been published in recent years. The importance of the HWE reaction should be emphasised due to its simplicity and stereoselectivity. Under mild conditions and in one step, valuable compounds can be obtained. The HWE reaction is primarily a great tool in the synthesis of fluoroolefins that are, among others, peptide bond mimetics. Therefore, it can serve as an indispensable approach to access peptide bioisosteres and, consequently, analogues of numerous enzyme inhibitors. The protocol may be utilized to obtain florinated vinylphosphonate, vinylsulfone or sulfonate derivatives, which exhibit biological activity. In this review article, we would like to summarize the HWE reaction output of the last 12 years (since 2010).
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Affiliation(s)
- Monika Bilska-Markowska
- Faculty of Chemistry, Adam Mickiewicz University in Poznań, Uniwersytetu Poznańskiego 8, 61-614 Poznań, Poland.
| | - Marcin Kaźmierczak
- Faculty of Chemistry, Adam Mickiewicz University in Poznań, Uniwersytetu Poznańskiego 8, 61-614 Poznań, Poland. .,Centre for Advanced Technologies, Adam Mickiewicz University in Poznań, Uniwersytetu Poznańskiego 10, 61-614 Poznań, Poland
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Garcia-Lainez G, El Ouardi M, Moreno A, Lence E, González-Bello C, Miranda MA, Andreu I. Singlet oxygen and radical-mediated mechanisms in the oxidative cellular damage photosensitized by the protease inhibitor simeprevir. Free Radic Biol Med 2023; 194:42-51. [PMID: 36375737 DOI: 10.1016/j.freeradbiomed.2022.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 10/04/2022] [Accepted: 11/06/2022] [Indexed: 11/13/2022]
Abstract
Hepatitis C, a liver inflammation caused by the hepatitis C virus (HCV), is treated with antiviral drugs. In this context, simeprevir (SIM) is an NS3/4A protease inhibitor used in HCV genotypes 1 and 4. It is orally administered and achieves high virological cure rates. Among adverse reactions associated with SIM treatment, photosensitivity reactions have been reported. In the present work, it is clearly shown that SIM is markedly phototoxic, according to the in vitro NRU assay using BALB/c 3T3 mouse fibroblast. This result sheds light on the nature of the photosensitivity reactions induced by SIM in HCV patients, suggesting that porphyrin elevation in patients treated with SIM may not be the only mechanism responsible for SIM-associated photosensitivity. Moreover, lipid photoperoxidation and protein photooxidation assays, using human skin fibroblasts (FSK) and human serum albumin (HSA), respectively, reveal the capability of this drug to promote photodamage to cellular membranes. Also, DNA photo lesions induced by SIM are noticed through comet assay in FSK cells. Photochemical and photobiological studies on the mechanism of SIM-mediated photodamage to biomolecules indicate that the key transient species generated upon SIM irradiation is the triplet excited state. This species is efficiently quenched by oxygen giving rise to singlet oxygen, which is responsible for the oxidation of lipids and DNA (Type II mechanism). In the presence of HSA, the photobehavior is dominated by binding to site 3 of the protein, to give a stable SIM@HSA complex. Inside the complex, quenching of the triplet excited state is less efficient, which results in a longer triplet lifetime and in a decreased singlet oxygen formation. Hence, SIM-mediated photooxidation of the protein is better explained through a radical (Type I) mechanism.
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Affiliation(s)
- Guillermo Garcia-Lainez
- Instituto de Investigación Sanitaria (IIS) La Fe, Hospital Universitari i Politècnic La Fe, Avenida de Fernando Abril Martorell 106, 46026, Valencia, Spain
| | - Meryem El Ouardi
- Departamento de Química-Instituto de Tecnología Química UPV-CSIC. Universitat Politècnica de València, Camino de Vera s/n, 46022, Valencia, Spain; Unidad Mixta de Investigación UPV- IIS La Fe, Hospital Universitari i Politècnic La Fe, Avenida de Fernando Abril Martorell 106, 46026, Valencia, Spain
| | - Alejandro Moreno
- Instituto de Investigación Sanitaria (IIS) La Fe, Hospital Universitari i Politècnic La Fe, Avenida de Fernando Abril Martorell 106, 46026, Valencia, Spain
| | - Emilio Lence
- Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Departamento de Química Orgánica, Universidade de Santiago de Compostela, Jenaro de la Fuente s/n, 15782, Santiago de Compostela, Spain
| | - Concepción González-Bello
- Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Departamento de Química Orgánica, Universidade de Santiago de Compostela, Jenaro de la Fuente s/n, 15782, Santiago de Compostela, Spain
| | - Miguel A Miranda
- Departamento de Química-Instituto de Tecnología Química UPV-CSIC. Universitat Politècnica de València, Camino de Vera s/n, 46022, Valencia, Spain; Unidad Mixta de Investigación UPV- IIS La Fe, Hospital Universitari i Politècnic La Fe, Avenida de Fernando Abril Martorell 106, 46026, Valencia, Spain.
| | - Inmaculada Andreu
- Departamento de Química-Instituto de Tecnología Química UPV-CSIC. Universitat Politècnica de València, Camino de Vera s/n, 46022, Valencia, Spain; Unidad Mixta de Investigación UPV- IIS La Fe, Hospital Universitari i Politècnic La Fe, Avenida de Fernando Abril Martorell 106, 46026, Valencia, Spain.
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HCV Genotype Has No Influence on the Incidence of Diabetes-EpiTer Multicentre Study. J Clin Med 2022; 11:jcm11020379. [PMID: 35054072 PMCID: PMC8780546 DOI: 10.3390/jcm11020379] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 12/30/2021] [Accepted: 01/05/2022] [Indexed: 12/17/2022] Open
Abstract
HCV infection is one of the main reasons for liver cirrhosis and hepatocellular carcinoma. In recent years, one finds more and more extrahepatic manifestations of HCV infection, including its possible influence on the development of diabetes. In the presented work, one finds the frequency analysis of the incidence of diabetes among 2898 HCV infected patients treated in Poland, and the assessment of their relevance to the HCV genotype and the progression of fibrosis. The results indicate that the hepatitis C infection seems to be a risk factor for diabetes in persons with more advanced liver fibrosis, for older people, and for the male gender. Thus, one found no differences regarding the frequency of its incidence depending on HCV genotype, including genotype 3.
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Shabani M, Sadegh Ehdaei B, Fathi F, Dowran R. A mini-review on sofosbuvir and daclatasvir treatment in coronavirus disease 2019. New Microbes New Infect 2021; 42:100895. [PMID: 33976895 PMCID: PMC8103737 DOI: 10.1016/j.nmni.2021.100895] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/01/2021] [Accepted: 05/04/2021] [Indexed: 12/28/2022] Open
Abstract
Sofosbuvir and daclatasvir have been used successfully since 2013 for hepatitis C treatment. It has been shown by different studies that sofosbuvir can inhibit RNA polymerase of other positive-strand RNA viruses including Flaviviridae and Togaviridae. Homology between hepatitis C virus RNA polymerase and severe acute respiratory syndrome coronavirus 2 has also been established. The efficacy of sofosbuvir and daclatasvir as potential choices in treating patients with coronavirus disease 2019 and their recovery can be hypothesized.
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Affiliation(s)
- M. Shabani
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - B. Sadegh Ehdaei
- Microbiology and Immunology Department, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - F. Fathi
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - R. Dowran
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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Anwar MF, Khalid R, Hasanain A, Naeem S, Zarina S, Abidi SH, Ali S. Integrated Cheminformatics-Molecular Docking Approach to Drug Discovery Against Viruses. Infect Disord Drug Targets 2020; 20:150-159. [PMID: 30345931 DOI: 10.2174/1871526518666181019162359] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 08/03/2018] [Accepted: 10/11/2018] [Indexed: 11/22/2022]
Abstract
BACKGROUND In the current study, we present an integrated in silico cheminformaticsmolecular docking approach to screen and test potential therapeutic compounds against viruses. Fluoroquinolones have been shown to inhibit HCV replication by targeting HCV NS3-helicase. Based on this observation, we hypothesized that natural analogs of fluoroquinolones will have similar or superior inhibitory potential while having potentially fewer adverse effects. METHODS To screen for natural analogs of fluoroquinolones, we devised an integrated in silico Cheminformatics-Molecular Docking approach. We used 17 fluoroquinolones as bait reference, to screen large databases of natural analogs. 10399 natural compounds and their derivatives were retrieved from the databases. From these compounds, molecules bearing physicochemical similarities with fluoroquinolones were analyzed using a cheminformatics-docking approach. RESULTS From the 10399 compounds screened using our cheminformatics approach, only 20 compounds were found to share physicochemical similarities with fluoroquinolones, while the remaining 10379 compounds were physiochemically different from fluoroquinolones. Molecular docking analysis showed 32 amino acids in the HCV NS3 active site that were most frequently targeted by fluoroquinolones and their natural analogues, indicating a functional similarity between the two groups of compounds. CONCLUSION This study describes a speedy and inexpensive approach to complement drug discovery and design against viral agents. The in silico analyses we used here can be employed to shortlist promising compounds/putative drugs that can be further tested in wet-lab.
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Affiliation(s)
- Muhammad Faraz Anwar
- National Center for Proteomics, University of Karachi, Karachi, Pakistan.,Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Pakistan
| | - Ramsha Khalid
- Department of Biochemistry, University of Karachi, Karachi, Pakistan
| | | | - Sadaf Naeem
- Department of Biochemistry, University of Karachi, Karachi, Pakistan
| | - Shamshad Zarina
- National Center for Proteomics, University of Karachi, Karachi, Pakistan
| | - Syed Hani Abidi
- Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Pakistan.,Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom
| | - Syed Ali
- Department of Biomedical Sciences, Nazarbayev University School of Medicine, Nazarbayev University, Astana, Kazakhstan
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Jing JS, Wang ZQ, Jiang YK, Zhang XY, Jiang WM. Association of cytokine gene polymorphisms with chronic hepatitis C virus genotype 1b infection in Chinese Han population: An observational study. Medicine (Baltimore) 2020; 99:e22362. [PMID: 32957410 PMCID: PMC7505299 DOI: 10.1097/md.0000000000022362] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Cytokines are extensively involved in the process of hepatitis C virus (HCV) infection and take a crucial part in host immune regulation. We aimed to explore the potential correlation of cytokine single nucleotide polymorphisms (SNPs) with HCV susceptibility and response rate of interferon (IFN)-based antiviral therapy in Chinese Han population.A case-control genetic association study was conducted between 198 patients with chronic HCV genotype 1b infection and 142 healthy controls. Genetic polymorphisms of TNF-α (rs1800629), TGF-β (rs1800469), IL-10 (rs1800896, rs1800871, and rs1800872), IL-6 (rs1800795, rs1800796), IFN-γ (rs2430561), and IL-28B (rs12979860, rs12980275, and rs8099917) were analyzed by MassARRAY SNP technology. Patients were treated with IFNα-2b or pegylated-IFNα-2a plus ribavirin for 48 weeks. Sustained virological response (SVR) was assessed 6 months after the completion of the treatment.The IL-28B rs12979860-CC (odds ratio [OR] = 4.35, 95% confidence interval [CI]: 1.69-11.21, P = .001), rs12980275-AA (OR = 3.41, 95% CI: 1.08-10.76, P = .028), and rs8099917-TT (OR = 3.86, 95% CI: 1.49-10.12, P = .004) were significantly associated with SVR, and IL-10 rs1800871-TT (OR = .50, 95% CI: 0.25-1.00, P = .049) and rs1800872-AA (OR = .50, 95% CI: 0.25-1.00, P = .049) were also significant for SVR. No association was found between the cytokine SNPs and HCV susceptibility. Additionally, multivariate analysis showed that low baseline viral load (OR = 3.63, 95% CI: 1.01-13.02, P = .048), pegylated-IFN (OR = 9.68, 95% CI: 1.14-82.13, P = .037) and rs12979860-CC (OR = 6.08, 95% CI: 2.00-18.46, P = .001) were independent factors for SVR.IL-28 and IL-10 gene polymorphisms played an important role in predicting host response to IFN-based antiviral therapy in HCV genotype 1b infection.
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Affiliation(s)
| | - Zhuo-Qun Wang
- Department of Medical Imaging, Jurong People's Hospital Affiliated to Jiangsu University, Jiangsu
| | - Ying-Kui Jiang
- Department of Infectious Diseases, Huashan Hospital Affiliated to Fudan University, Shanghai, China
| | - Xin-Yun Zhang
- Department of Infectious Diseases, Huashan Hospital Affiliated to Fudan University, Shanghai, China
| | - Wei-Min Jiang
- Department of Infectious Diseases, Huashan Hospital Affiliated to Fudan University, Shanghai, China
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Correlates of subjective hepatitis C knowledge among clinical staff in US drug treatment programs. J Public Health (Oxf) 2020. [DOI: 10.1007/s10389-019-01032-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
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11
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Badierah RA, Uversky VN, Redwan EM. Dancing with Trojan horses: an interplay between the extracellular vesicles and viruses. J Biomol Struct Dyn 2020; 39:3034-3060. [DOI: 10.1080/07391102.2020.1756409] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Raied A. Badierah
- Biological Science Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
- Molecular Diagnostic Laboratory, King Abdulaziz University Hospital, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Vladimir N. Uversky
- Biological Science Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
- Laboratory of New Methods in Biology, Institute for Biological Instrumentation, Russian Academy of Sciences, Federal Research Center ‘Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences’, Pushchino, Moscow Region, Russia
| | - Elrashdy M. Redwan
- Biological Science Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
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12
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Application of an integrated cheminformatics-molecular docking approach for discovery for physicochemically similar analogs of fluoroquinolones as putative HCV inhibitors. Comput Biol Chem 2019; 84:107167. [PMID: 31855781 DOI: 10.1016/j.compbiolchem.2019.107167] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 10/02/2019] [Accepted: 11/16/2019] [Indexed: 01/13/2023]
Abstract
BACKGROUND Hepatitis C Virus (HCV) infection is a major public health concern across the globe. At present, direct-acting antivirals are the treatment of choice. However, the long-term effect of this therapy has yet to be ascertained. Previously, fluoroquinolones have been reported to inhibit HCV replication by targeting NS3 protein. Therefore, it is logical to hypothesize that the natural analogs of fluoroquinolones will exhibit NS3 inhibitory activity with substantially lesser side effects. METHOD In this study, we tested the application of a recently devised integrated in-silico Cheminformatics-Molecular Docking approach to identify physicochemically similar natural analogs of fluoroquinolones from the available databases (Ambinter, Analyticon, Indofines, Specs, and TimTec). Molecular docking and ROC curve analyses were performed, using PatchDock and Graphpad software, respectively, to compare and analyze drug-protein interactions between active natural analogs, Fluoroquinolones, and HCV NS3 protein. RESULT In our analysis, we were able to shortlist 18 active natural analogs, out of 10,399, that shared physicochemical properties with the template drugs (fluoroquinolones). These analogs showed comparable binding efficacy with fluoroquinolones in targeting 32 amino acids in the HCV NS3 active site that are crucial for NS3 activity. Our approach had around 80 % sensitivity and 70 % specificity in identifying physicochemically similar analogs of fluoroquinolones. CONCLUSION Our current data suggest that our approach can be efficiently applied to identify putative HCV drug inhibitors that can be taken for in vitro testing. This approach can be applied to discover physicochemically similar analogs of virtually any drug, thus providing a speedy and inexpensive approach to complement drug discovery and design, which can tremendously economize on time and money spent on the screening of putative drugs.
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Sadeghimehr M, Bertisch B, Schaetti C, Wandeler G, Richard JL, Scheidegger C, Keiser O, Estill J. Modelling the impact of different testing strategies for HCV infection in Switzerland. J Virus Erad 2019. [DOI: 10.1016/s2055-6640(20)30036-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
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Abstract
A prominent role for complement has been identified in the linkage of innate and adaptive immunity. The liver is the main source of complement and hepatocytes are the primary sites for synthesis of complement components in vivo. We have discovered that hepatitis C virus (HCV) impairs C4 and C3 synthesis. Liver damage may diminish capacity of complement synthesis in patients. However, we observed that the changes in measured complement components in chronically HCV infected patients do not correlate with liver fibrosis or rheumatoid factor present in the blood, serum albumin, or alkaline phosphatase levels. Complement component C3 is of critical importance in B cell activation and T cell-dependent antibody responses. C3 activity is required for optimal expansion of CD8+T cells during a systemic viral infection. Deficiencies in complement may predispose patients to infections via ineffective opsonization, and defects in lytic activity via membrane attack complex. Interestingly, C9 is significantly reduced at the mRNA level in chronically HCV infected liver biopsy specimens, while many hepatocyte derived complement components (C6, C8, Factor B, MASP1, and MBL) and unrelated genes remain mostly unaffected. This implies an HCV specific effect, not a global effect from liver disease.
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Affiliation(s)
- Young-Chan Kwon
- Department of Internal Medicine, Saint Louis University, St. Louis, MO, USA
- Department of Molecular Microbiology and Immunology, Saint Louis University, St. Louis, MO, USA
- Institut Pasteur Korea, Daejeon, Republic of Korea
| | - Ranjit Ray
- Department of Internal Medicine, Saint Louis University, St. Louis, MO, USA.
- Department of Molecular Microbiology and Immunology, Saint Louis University, St. Louis, MO, USA.
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15
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Cohen-Bucay A, Francis JM, Gordon CE. Timing of hepatitis C virus infection treatment in kidney transplant candidates. Hemodial Int 2019; 22 Suppl 1:S61-S70. [PMID: 29694723 DOI: 10.1111/hdi.12643] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Hepatitis C virus (HCV) infection is prevalent in patients with kidney disease including transplant candidates and recipients. It is associated with increased morbidity and mortality in end-stage renal disease patients and also increases the risk of allograft rejection and decreases allograft and patient survival post-transplant. Newly developed direct acting antivirals have revolutionized the way HCV is treated. Whether patients are treated before or after kidney transplantation, the cure rates with direct acting antivirals are >90%. Great debate has formed revolving the optimal timing to treat kidney transplant candidates. On the one hand, treatment before transplantation decreases early post-transplant complications related to HCV. On the other, postponing treatment until after transplantation opens the possibility of transplanting a kidney from a HCV positive donor, which is associated with shorter waiting time and improved organ utilization by expanding the organ donor pool. Most patients living in an area where waiting time is reduced by accepting an HCV positive kidney would benefit by the strategy of treatment post-transplantation, but this decision needs to be individualized in a patient-by-patient basis given that there are special circumstances (i.e., severe HCV-related extrahepatic manifestations, availability of live donors, etc.) in which treatment before transplant might be preferred.
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Affiliation(s)
- Abraham Cohen-Bucay
- Renal Section, Boston University Medical Center, Boston, Massachusetts, USA.,Division of Nephrology and Transplant Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Jean M Francis
- Renal Section, Boston University Medical Center, Boston, Massachusetts, USA
| | - Craig E Gordon
- Renal Section, Boston University Medical Center, Boston, Massachusetts, USA
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16
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Schulz TR, Kanhutu K, Sasadeusz J, Watkinson S, Biggs BA. Using telehealth to improve access to hepatitis C treatment in the direct-acting antiviral therapy era. J Telemed Telecare 2018; 26:180-185. [PMID: 30336724 DOI: 10.1177/1357633x18806651] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Introduction One-third of the Australian population lives outside major cities and this group has worse health outcomes. Telehealth is becoming an accepted way to improve patient access to specialist healthcare. Over 200,000 Australian’s have hepatitis C virus (HCV) and new treatments are very effective and well tolerated. We aim to demonstrate that HCV treatment utilising telehealth support for care delivery has cure rates similar to onsite care in clinical trials. We also report length of consultation and calculate reductions in travel and carbon output. Methods Patient demographic, clinical, and treatment outcome data were collected prospectively from hospital software and analysed retrospectively. This was an audit of all patients treated for HCV in one year from a single tertiary hospital that included telehealth in their care delivery. Results Sustained virological response was achieved in 51/52 (98%) patients with completed treatment courses, and 51/58 (88%) of those who had a planned telehealth consultation as part of their management. A median of 634 km of patient travel was saved per telehealth consultation. Discussion We found that a telehealth-supported outreach programme for patients in regional Australia with HCV produced similar outcomes to clinical trials. There was a considerable saving in time and cost for the patients and significant environmental benefit through the reduction in carbon footprint associated with travel to distant specialist health services. We conclude that telehealth facilitated outreach is a feasible and effective way to access HCV treatment and cure in regional Australia.
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Affiliation(s)
- Thomas R Schulz
- Victorian Infectious Diseases Service, The Royal Melbourne Hospital, at The Doherty Institute, Melbourne Australia.,University of Melbourne, Department of Medicine/RMH, at The Doherty Institute, Melbourne, Australia
| | - Kudzai Kanhutu
- Victorian Infectious Diseases Service, The Royal Melbourne Hospital, at The Doherty Institute, Melbourne Australia.,University of Melbourne, Department of Medicine/RMH, at The Doherty Institute, Melbourne, Australia.,Health Informatics Society, Melbourne, Australia
| | - Joseph Sasadeusz
- Victorian Infectious Diseases Service, The Royal Melbourne Hospital, at The Doherty Institute, Melbourne Australia
| | - Sally Watkinson
- Victorian Infectious Diseases Service, The Royal Melbourne Hospital, at The Doherty Institute, Melbourne Australia
| | - Beverley-Ann Biggs
- Victorian Infectious Diseases Service, The Royal Melbourne Hospital, at The Doherty Institute, Melbourne Australia.,University of Melbourne, Department of Medicine/RMH, at The Doherty Institute, Melbourne, Australia
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17
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Zahra M, Azzazy H, Moustafa A. Transcriptional Regulatory Networks in Hepatitis C Virus-induced Hepatocellular Carcinoma. Sci Rep 2018; 8:14234. [PMID: 30250040 PMCID: PMC6155139 DOI: 10.1038/s41598-018-32464-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 09/04/2018] [Indexed: 01/09/2023] Open
Abstract
Understanding the transcriptional regulatory elements that influence the progression of liver disease in the presence of hepatitis C virus (HCV) infection is critical for the development of diagnostic and therapeutic approaches. Systems biology provides a roadmap by which these elements may be integrated. In this study, a previously published dataset of 124 microarray samples was analyzed in order to determine differentially expressed genes across four tissue types/conditions (normal, cirrhosis, cirrhosis HCC, and HCC). Differentially expressed genes were assessed for their functional clustering and those genes were annotated with their potential transcription factors and miRNAs. Transcriptional regulatory networks were constructed for each pairwise comparison between the 4 tissue types/conditions. Based on our analysis, it is predicted that the disruption in the regulation of transcription factors such as AP-1, PPARγ, and NF-κB could contribute to the liver progression from cirrhosis to steatosis and eventually to HCC. Whereas the condition of the liver digresses, the downregulation of miRNAs' (such as miR-27, Let-7, and miR-106a) expression makes the transition of the liver through each pathological stage more apparent. This preliminary data can be used to guide future experimental work. An understanding of the transcriptional regulatory attributes acts as a road map to help design interference strategies in order to target the key regulators of progression of HCV induced HCC.
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Affiliation(s)
- Marwa Zahra
- Biotechnology Graduate Program, American University, New Cairo, 11835, Egypt
| | - Hassan Azzazy
- Biotechnology Graduate Program, American University, New Cairo, 11835, Egypt. .,Department of Chemistry, The American University in Cairo, School of Sciences & Engineering, New Cairo, 11835, Egypt.
| | - Ahmed Moustafa
- Biotechnology Graduate Program, American University, New Cairo, 11835, Egypt.,Department of Biology, The American University in Cairo, New Cairo, 11835, Egypt
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18
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Buchanan-Hughes AM, Buti M, Hanman K, Langford B, Wright M, Eddowes LA. Health state utility values measured using the EuroQol 5-dimensions questionnaire in adults with chronic hepatitis C: a systematic literature review and meta-analysis. Qual Life Res 2018; 28:297-319. [PMID: 30225787 DOI: 10.1007/s11136-018-1992-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/31/2018] [Indexed: 01/27/2023]
Abstract
PURPOSE Chronic hepatitis C infection and its treatment can considerably affect patients' health-related quality-of-life (HRQoL). This study aimed to identify and summarise the current evidence base for health state utility values (HSUVs) in patients with chronic hepatitis C infection, generated using the EuroQol 5-dimensions (EQ-5D) questionnaire. METHODS MEDLINE, Embase, the Cochrane Library and EconLit were searched from database inception through 31 August 2017. Eligible studies reported HSUVs elicited using the EQ-5D questionnaire in adults with chronic hepatitis C infection. Study quality and risk of bias were assessed. RESULTS Of 1480 records identified, 26 studies were included. The most commonly defined health states described different stages of chronic hepatitis C infection and specific liver-related disease states, including METAVIR score, compensated and decompensated cirrhosis, hepatocellular carcinoma and liver transplantation. Patients with higher METAVIR scores tended to have lower EQ-5D scores compared to patients with lower METAVIR scores. Patients that achieved sustained virologic responses tended to have higher EQ-5D scores compared to those that did not. A meta-analysis conducted on three studies confirmed that patients with decompensated cirrhosis have significantly lower HSUVs than patients with compensated cirrhosis [mean difference - 0.11 (95% CI - 0.19 to - 0.04)], implying worse HRQoL. However, there was not sufficient evidence to compare how different treatments for chronic hepatitis C infection affect EQ-5D scores. CONCLUSIONS This study provides a summary of EQ-5D HSUVs for patients with chronic hepatitis C infection, and demonstrates that clinically important disease stages associated with treatment decisions are associated with differences in HRQoL.
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Affiliation(s)
| | - M Buti
- Hospital Universitario Valle Hebron, Barcelona, Spain.,Ciberehd del Instituto Carlos III, Madrid, Spain
| | - K Hanman
- Costello Medical Consulting Ltd, Cambridge, UK
| | - B Langford
- Costello Medical Consulting Ltd, Cambridge, UK
| | - M Wright
- University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - L A Eddowes
- Costello Medical Consulting Ltd, Cambridge, UK
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19
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Preclinical Pharmacokinetics and First-in-Human Pharmacokinetics, Safety, and Tolerability of Velpatasvir, a Pangenotypic Hepatitis C Virus NS5A Inhibitor, in Healthy Subjects. Antimicrob Agents Chemother 2017; 61:AAC.02084-16. [PMID: 28193657 DOI: 10.1128/aac.02084-16] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 02/04/2017] [Indexed: 12/13/2022] Open
Abstract
Preclinical characterization of velpatasvir (VEL; GS-5816), an inhibitor of the hepatitis C virus (HCV) NS5A protein, demonstrated that it has favorable in vitro and in vivo properties, including potent antiviral activity against hepatitis C virus genotype 1 to 6 replicons, good metabolic stability, low systemic clearance, and adequate bioavailability and physicochemical properties, to warrant clinical evaluation. The phase 1 (first-in-human) study evaluated the safety, tolerability, and pharmacokinetics of VEL in healthy human subjects following administration of single and multiple (n = 7) once-daily ascending doses and of VEL in the presence and absence of food. Following administration of single and multiple doses, VEL was safe and well tolerated when administered at up to 450 mg and when administered with food. The pharmacokinetic behavior of VEL observed in humans was generally in agreement with that seen during preclinical characterization. Following administration of multiple doses, VEL trough concentrations were significantly greater than the protein-adjusted half-maximal (50%) effective concentration of VEL against HCV genotype 1 to 6 replicons at all evaluated doses greater than 5 mg. The pharmacokinetics of VEL were not significantly affected by administration with food. Collectively, the results of this study support the further clinical investigation of VEL administered once daily as part of a regimen with other pangenotypic direct-acting antivirals for the treatment of HCV infection.
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20
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Wang HL, Lu X, Yang X, Xu N. Effectiveness and safety of daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: Systematic review and meta-analysis. J Gastroenterol Hepatol 2017; 32:45-52. [PMID: 27597318 DOI: 10.1111/jgh.13587] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Revised: 07/29/2016] [Accepted: 08/24/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Daclatasvir plus asunaprevir (DCV + ASV) has demonstrated potent antiviral activity in patients with hepatitis C virus (HCV) genotype 1b infection. A definite conclusion about efficacy and safety of DCV + ASV in patients with HCV genotype 1b is not available. A meta-analysis was conducted to evaluate outcomes of all-oral treatment with DCV + ASV in terms of sustained virological response at 12 (SVR12 ) and 24 (SVR24 ) weeks and adverse effects after the end of treatment. METHODS PUBMED, MEDLINE, and EMBASE databases were searched in May 2016. The data were analyzed with Review Manager 5.3. RESULTS Nine trials (n = 1690) met entry criteria. SVR12 was achieved by 89.9% of treatment-naïve patients, 84.7% of interferon-ineligible/intolerant patients, and 81.9% of nonresponder patients. Moreover, 89.0% of interferon-ineligible/intolerant patients and 83.1% of nonresponder patients achieved SVR24 . Baseline characteristics, including gender, race, advanced age, non-CC IL28B genotype, and cirrhosis, did not appear to impact SVR rates. However, the rate of SVR12 in all patients with viral load < 8 × 105 was higher than that of all those with viral load ≥ 8 × 105 (151/162 vs 625/753). Moreover, pre-existing nonstructural protein 5A resistance-associated variants (RAVs) were associated with virological failure during DCV + ASV therapy, resulting in the emergence of multiple RAVs. Treatment with DCV + ASV was well tolerated, with low incidences of serious adverse effects, discontinuations, and grade 3 or 4 laboratory abnormalities in all patients. CONCLUSIONS Daclatasvir plus asunaprevir provides a highly effective and well-tolerated treatment option for patients with HCV genotype 1b. However, patients with nonstructural protein 5A RAVs at baseline should be assessed to optimize more potent direct antiviral agent therapies.
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Affiliation(s)
- Hui-Lian Wang
- Department of Genetics and Molecular Biology, Xi'an Jiaotong University School of Medicine, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, China
| | - Xi Lu
- School of Mechanical Engineering, Xi'an Jiaotong University, Xi'an, China
| | - Xudong Yang
- Department of Genetics and Molecular Biology, Xi'an Jiaotong University School of Medicine, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, China
| | - Nan Xu
- 2nd Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an, China
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21
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Sarrazin C, Manns M, Calleja JL, Garcia-Samaniego J, Forns X, Kaste R, Bai X, Wu J, Stern JO. HCVerso3: An Open-Label, Phase IIb Study of Faldaprevir and Deleobuvir with Ribavirin in Hepatitis C Virus Genotype-1b-Infected Patients with Cirrhosis and Moderate Hepatic Impairment. PLoS One 2016; 11:e0168544. [PMID: 28030579 PMCID: PMC5193411 DOI: 10.1371/journal.pone.0168544] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Accepted: 11/25/2016] [Indexed: 12/12/2022] Open
Abstract
This study evaluated the interferon-free, oral combination of deleobuvir (non-nucleoside HCV NS5-RNA-polymerase inhibitor) and faldaprevir (HCV NS3/4A-protease inhibitor) with ribavirin in patients with HCV genotype-1b and moderate (Child-Pugh B [CPB], n = 17) or mild hepatic impairment (Child-Pugh A [CPA], n = 18). Patients received faldaprevir 120 mg and deleobuvir (600 mg [CPA], 400 mg [CPB]) twice-daily with weight-based ribavirin for 24 weeks. Baseline characteristics were similar between groups. Among CPA patients, 13/18 completed treatment; discontinuations were for adverse events (AEs, n = 1), lack of efficacy (n = 3) and withdrawal (n = 1). Among CPB patients, 8/17 completed treatment; discontinuations were for AEs (n = 6), withdrawal (n = 1) and ‘other’ (n = 2). Sustained virologic response at post-treatment Week 12 (SVR12) was achieved by 11 (61%) CPA patients (95% confidence interval: 38.6%–83.6%) and 9 (53%) CPB patients (95% confidence interval: 29.2%–76.7%), including most CPA (11/16) patients with Week 4 HCV RNA <25 IU.mL-1 (target detected or not detected) and most CPB (8/9) patients with Week 4 HCV RNA <25 IU.mL-1 (target not detected); 0/4 CPB patients with Week 4 HCV RNA <25 IU.mL-1 (target detected) achieved SVR12. The most common AEs in both groups were nausea, diarrhoea and vomiting. Serious AEs were observed in 9 (53%) CPB patients and 1 (6%) CPA patient. Plasma trough concentrations of deleobuvir and faldaprevir were not substantially different between the CPA and CPB groups. In conclusion, in this small study the safety and efficacy profiles for 24 weeks of treatment with faldaprevir+deleobuvir+ribavirin in patients with mild or moderate hepatic impairment were consistent with the safety and efficacy profile of this regimen in non-cirrhotic patients. Faldaprevir+deleobuvir+ribavirin resulted in SVR12 in 53–61% of patients: proportions achieving SVR4 but not SVR12 were higher than in non-cirrhotic patients and overall response rates were lower than rates reported with other all-oral regimens in patients with cirrhosis. Trial Registration: ClinicalTrials.gov NCT01830127.
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Affiliation(s)
| | | | - Jose Luis Calleja
- Hospital Universitario Puerta de Hierro, Universidad Autonomy de Madrid. CIBERehd, Madrid, Spain
| | | | - Xavier Forns
- Hospital Clínic, CIBERehd, IDIBAPS, Barcelona, Spain
| | - Renee Kaste
- Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, United States of America
| | - Xiaofei Bai
- Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, United States of America
| | - Jing Wu
- Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, United States of America
| | - Jerry O. Stern
- Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, United States of America
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22
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Mogalian E, German P, Kearney BP, Yang CY, Brainard D, McNally J, Moorehead L, Mathias A. Use of Multiple Probes to Assess Transporter- and Cytochrome P450-Mediated Drug-Drug Interaction Potential of the Pangenotypic HCV NS5A Inhibitor Velpatasvir. Clin Pharmacokinet 2016; 55:605-13. [PMID: 26519191 DOI: 10.1007/s40262-015-0334-7] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND AND OBJECTIVES Velpatasvir (VEL; GS-5816) is a potent, pangenotypic hepatitis C virus (HCV), non-structural protein 5A inhibitor in clinical development for the treatment of chronic HCV infection. In vitro studies indicate that VEL may inhibit several drug transporters and be a substrate for enzyme/drug transport systems in vivo. The purpose of this study was to evaluate the potential of VEL as a perpetrator or victim of metabolic- and transporter-based drug-drug interactions using complementary probe drugs. METHODS This Phase 1 study was a randomized, cross-over, open-label, single- and multiple-dose, five-cohort study. Serial blood samples were collected following oral administration of reference and test treatments. The primary pharmacokinetic parameters of each analyte were compared when administered alone or in combination. The 90% confidence intervals (CI) for the ratio of the geometric least-squares means of the test and reference treatments was calculated for each analyte and parameter of interest. RESULTS This study demonstrated that VEL is a weak (P-gp, OATP) to moderate (breast cancer resistance protein) transport inhibitor. As a victim of interactions, VEL is moderately affected by potent inhibitors and to a greater extent, potent inducers of enzyme/drug transporter systems. CONCLUSIONS The impact of specific transporters and overall contribution of drug transport vs. metabolizing enzymes on the disposition of VEL was characterized through the use of complementary probes, despite the lack of phenotypic specificity, and informs a broad range of drug-drug interaction recommendations.
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Affiliation(s)
- Erik Mogalian
- Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA, 94404, USA.
| | - Polina German
- Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA, 94404, USA
| | - Brian P Kearney
- Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA, 94404, USA
| | - Cheng Yong Yang
- Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA, 94404, USA
| | - Diana Brainard
- Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA, 94404, USA
| | - John McNally
- Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA, 94404, USA
| | - Lisa Moorehead
- Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA, 94404, USA
| | - Anita Mathias
- Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA, 94404, USA
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23
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El-Bendary M, Neamatallah M, Esmat G, Kamel E, Elalfy H, Besheer T, Eldeib D, Eladl AH, El-Setouhy M, El-Gilany AH, El-Waseef A. Associations of human leucocyte antigen class II-DQB1 alleles with hepatitis C virus infection in Egyptian population: a multicentre family-based study. J Viral Hepat 2016; 23:961-970. [PMID: 27599887 DOI: 10.1111/jvh.12573] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 06/07/2016] [Indexed: 12/14/2022]
Abstract
Hepatitis C infection is a global pandemic. HLA-DQB1 alleles are believed to have an effective role in immune response against HCV including susceptibility to or protection from this infection. The aim of this study was to investigate the contribution of HLA-DQB1 alleles in the outcome of HCV genotype-4 infection through a family-based association study. Egyptian families with HCV (324) were recruited for this study (324 index positive for RNA-HCV, 225 positive relatives representing chronic hepatitis C cases and 582 family members negative for HCV-RNA [control], 63 of whom spontaneously cleared the virus. All subjects were genotyped for HLA-DQB1 alleles by sequence-specific primers (SSP-PCR) and sequence-based typing (SBT) methods. The frequency of DQB1*02:01:01 carriage was significantly higher in infected patients when compared to controls and those who spontaneously cleared virus (OR=5.47, P<.0001 and OR= 6.5234, P<.0001, respectively), and the carriage of the DQB1*03:01:01:01 allele was significantly higher in those who cleared and controls when compared to the infected patients (OR=0.2889, P<.0001 and OR=0.3016, P<.0001, respectively). On the other hand, the frequency of DQB1*06:01:01 and QB1*05:01:01:01 alleles was not associated with infection (comparison of infected and cleared patients showed OR of 2.1598 [P<.01]), but it becomes nonsignificant after adjustments with the Bonferroni formula (PC >0.05) and OR= 1.3523, P>.05, respectively. This study shows that clearance of HCV is associated with DQB1*03:01:01:01 allele and chronicity of HCV infection associated with the risk allele: DQB1*02:01:01.
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Affiliation(s)
- M El-Bendary
- Tropical Medicine & Hepatology, Mansoura Faculty of Medicine, Mansoura, Egypt
| | - M Neamatallah
- Medical Biochemistry, Mansoura Faculty of Medicine, Mansoura, Egypt
| | - G Esmat
- Tropical Medicine & Hepatology, Cairo Faculty of Medicine, Cairo, Egypt
| | - E Kamel
- Public Health & Preventive Medicine Department, Mansoura Faculty of Medicine, Mansoura, Egypt
| | - H Elalfy
- Tropical Medicine & Hepatology, Mansoura Faculty of Medicine, Mansoura, Egypt
| | - T Besheer
- Tropical Medicine & Hepatology, Mansoura Faculty of Medicine, Mansoura, Egypt
| | - D Eldeib
- Biochemistry, Faculty of Science, Mansoura University, Mansoura, Egypt
| | - A-H Eladl
- Internal Medicine Department, Alazhar Faculty of Medicine- Assiut University, Assiut, Egypt
| | - M El-Setouhy
- Department of Community, Environmental and Occupational Medicine, Ain Shams Faculty of Medicine, Cairo, Egypt
| | - A-H El-Gilany
- Public Health & Preventive Medicine Department, Mansoura Faculty of Medicine, Mansoura, Egypt
| | - A El-Waseef
- Biochemistry, Faculty of Science, Mansoura University, Mansoura, Egypt
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24
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Sarrazin C, Castelli F, Andreone P, Buti M, Colombo M, Pol S, Calinas F, Puoti M, Olveira A, Shiffman M, Stern JO, Kukolj G, Roehrle M, Aslanyan S, Deng Q, Vinisko R, Mensa FJ, Nelson DR. HCVerso1 and 2: faldaprevir with deleobuvir (BI 207127) and ribavirin for treatment-naïve patients with chronic hepatitis C virus genotype-1b infection. Clin Exp Gastroenterol 2016; 9:351-363. [PMID: 27920566 PMCID: PMC5125810 DOI: 10.2147/ceg.s111116] [Citation(s) in RCA: 3] [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: 01/08/2023] Open
Abstract
The interferon-free combination of once-daily faldaprevir 120 mg, twice-daily deleobuvir 600 mg, and weight-based ribavirin was evaluated in two Phase III studies (HCVerso1, HCVerso2) in hepatitis C virus genotype-1b-infected, treatment-naïve patients, including those ineligible for peginterferon (HCVerso2). Patients without cirrhosis were randomized to 16 weeks (Arm 1; n=208 HCVerso1, n=213 HCVerso2) or 24 weeks (Arm 2; n=211 in both studies) of faldaprevir + deleobuvir + ribavirin. Patients with compensated cirrhosis received open-label faldaprevir + deleobuvir + ribavirin for 24 weeks (Arm 3; n=51, n=72). Primary endpoints were comparisons of adjusted sustained virologic response (SVR) rates with historical rates: 71% (HCVerso1) and 68% (HCVerso2). Adjusted SVR12 rates were significantly greater than historical controls for Arms 1 and 2 in HCVerso2 (76%, 95% confidence interval [CI] 71-81, P=0.002; 81%, 95% CI 76-86, P<0.0001) and Arm 2 in HCVerso1 (81%, 95% CI 77-86, P<0.0001), but not for Arm 1 of HCVerso1 (72%, 95% CI 66-77, P=0.3989). Unadjusted SVR12 rates in Arms 1, 2, and 3 were 71.6%, 82.5%, and 72.5%, respectively, in HCVerso1 and 75.6%, 82.0%, and 73.6%, respectively, in HCVerso2. Virologic breakthrough and relapse occurred in 24-week arms in 8%-9% and 1% of patients, respectively, and in 16-week arms in 7%-8% and 9%-11% of patients, respectively. The most common adverse events were nausea (46%-61%) and vomiting (29%-35%). Adverse events resulted in discontinuation of all medications in 6%-8% of patients. In treatment-naïve patients with hepatitis C virus genotype-1b infection, with or without cirrhosis, faldaprevir + deleobuvir + ribavirin treatment for 24 weeks resulted in adjusted SVR12 rates significantly higher than historical controls. Both studies were registered in ClinicalTrials.gov (NCT01732796, NCT01728324).
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Affiliation(s)
- Christoph Sarrazin
- Department of Internal Medicine 1, JW Goethe University Hospital, Frankfurt, Germany
| | - Francesco Castelli
- Department of Infectious and Tropical Diseases, University of Brescia, Brescia
| | - Pietro Andreone
- Department of Medical and Surgical Sciences, Università di Bologna and Azienda Ospedaliero-Universitaria, Policlinico Sant‘Orsola-Malpighi, Bologna, Italy
| | - Maria Buti
- Department of Internal Medicine, Hospital Universitari Vall d’Hebron and CIBERehd del Instituto Carlos III, Barcelona, Spain
| | - Massimo Colombo
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Stanislas Pol
- University Paris Descartes, Department of Hepatology, Hospital Cochin, APHP and INSERM UMS-20, Institut Pasteur, Paris, France
| | - Filipe Calinas
- Department of Gastroenterology, Centro Hospitalar de Lisboa Central, Lisbon, Portugal
| | - Massimo Puoti
- Department of Infectious Diseases, AO Ospedale Niguarda Cà Granda, Milan, Italy
| | - Antonio Olveira
- Liver Unit, Hospital Universitario La Paz, CIBERehd, Madrid, Spain
| | - Mitchell Shiffman
- Liver Institute of Virginia, Bon Secours Health System, Richmond, VA, USA
| | - Jerry O Stern
- Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA
| | - George Kukolj
- Boehringer Ingelheim Ltd/Ltée, Burlington, ON, Canada
| | - Michael Roehrle
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Stella Aslanyan
- Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA
| | - Qiqi Deng
- Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA
| | - Richard Vinisko
- Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA
| | | | - David R Nelson
- Clinical and Translational Science Institute, University of Florida, Gainesville, FL, USA
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Suppression of Host Innate Immune Response by Hepatitis C Virus via Induction of Autophagic Degradation of TRAF6. J Virol 2016; 90:10928-10935. [PMID: 27681126 DOI: 10.1128/jvi.01365-16] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Accepted: 09/21/2016] [Indexed: 12/15/2022] Open
Abstract
Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) is an important adaptor molecule that mediates the TNFR family and interleukin-1 (IL-1)/Toll-like receptor (TLR) signaling cascades. These pathways are important for the host to control viral infections. In this report, we demonstrated that hepatitis C virus (HCV) depleted TRAF6 from its host cells through a posttranslational mechanism. This depletion was independent of proteasomes, as it was not affected by the proteasome inhibitor MG132, but it was suppressed by bafilomycin A1, which led to the association of TRAF6 with autophagosomes. As bafilomycin A1 is a vacuolar ATPase inhibitor that inhibits autophagic protein degradation, these results suggested that HCV depleted TRAF6 via autophagy. The degradation of TRAF6 was apparently mediated by the p62 sequestosome protein, which is a factor important for selective autophagy, as it could bind to TRAF6 and its silencing stabilized TRAF6. The depletion of TRAF6 suppressed activation of NF-κB and induction of proinflammatory cytokines and enhanced HCV replication. In contrast, the overexpression of TRAF6 suppressed HCV replication. These results revealed a novel mechanism that was used by HCV to disrupt the host innate immune responses for viral replication and persistence. IMPORTANCE HCV can cause severe liver diseases and is one of the most important human pathogens. It establishes chronic infections in the great majority of patients that it infects, indicating that it has evolved sophisticated mechanisms to evade host immunity. TRAF6 is an important signaling molecule that mediates activation of NF-κB and expression of proinflammatory cytokines and interferons. In this study, we found that HCV infection suppressed the host innate immune response through the induction of autophagic degradation of TRAF6. This finding provided important information for further understanding how HCV evades host immunity to establish persistence.
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Kowdley KV, Nelson DR, Lalezari JP, Box T, Gitlin N, Poleynard G, Rabinovitz M, Ravendhran N, Sheikh AM, Siddique A, Bhore R, Noviello S, Rana K. On-treatment HCV RNA as a predictor of sustained virological response in HCV genotype 3-infected patients treated with daclatasvir and sofosbuvir. Liver Int 2016; 36:1611-1618. [PMID: 27188960 DOI: 10.1111/liv.13165] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Accepted: 05/13/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Many currently available direct-acting antiviral (DAA) regimens are less effective against HCV genotype 3 than against other HCV genotypes. The all-oral, pangenotypic DAA combination of daclatasvir (NS5A inhibitor) + sofosbuvir (nucleotide NS5B inhibitor) was studied in genotype 3-infected treatment-naive and -experienced patients (ALLY-3) who achieved rates of sustained virological response at post-treatment Week 12 (SVR12) of 90 and 86% respectively. In this analysis, we assessed whether on-treatment responses to daclatasvir + sofosbuvir in genotype 3-infected patients could predict treatment outcome. METHODS In ALLY-3, treatment-naive and -experienced patients, with or without cirrhosis, were treated with daclatasvir + sofosbuvir for 12 weeks. HCV RNA kinetics and categorical virological responses on treatment were assessed. The proportions of responders and nonresponders by study week, and time to first undetectable HCV RNA, were analysed for utility in predicting treatment outcome. RESULTS Overall, HCV RNA levels declined rapidly during Week 1 of treatment in both treatment-naive and -experienced cohorts. Although patients with cirrhosis had a slower initial virological response as measured by the proportion of patients with HCV RNA below the lower limit of quantification at Week 1, responses converged thereafter. Positive and negative predictive values calculated for on-treatment responses were generally comparable with the overall SVR12 rate and were therefore limited indicators of outcome. SVR12 rates were not impacted by time to first undetectable HCV RNA. CONCLUSIONS On-treatment responses are not useful predictors of ultimate virological response to the daclatasvir + sofosbuvir regimen.
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Affiliation(s)
| | | | | | - Terry Box
- Clinical Research Centers of America, LLC, Murray, UT, USA
| | - Norman Gitlin
- Atlanta Gastroenterology Associates, Atlanta, GA, USA
| | | | | | | | - Aasim M Sheikh
- Gastrointestinal Specialists of Georgia, Marietta, GA, USA
| | | | - Rafia Bhore
- Bristol-Myers Squibb Research and Development, Princeton, NJ, USA
| | | | - Khurram Rana
- Bristol-Myers Squibb Research and Development, Wallingford, CT, USA
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27
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Wei L, Zhang M, Xu M, Chuang WL, Lu W, Xie W, Jia Z, Gong G, Li Y, Bae SH, Yang YF, Xie Q, Lin S, Chen X, Niu J, Jia J, Garimella T, Torbeyns A, McPhee F, Treitel M, Yin PD, Mo L. A phase 3, open-label study of daclatasvir plus asunaprevir in Asian patients with chronic hepatitis C virus genotype 1b infection who are ineligible for or intolerant to interferon alfa therapies with or without ribavirin. J Gastroenterol Hepatol 2016; 31:1860-1867. [PMID: 27003037 DOI: 10.1111/jgh.13379] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Revised: 03/08/2016] [Accepted: 03/11/2016] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIM Daclatasvir plus asunaprevir has demonstrated efficacy and safety in patients with chronic hepatitis C virus genotype 1b infection. This study focused on evaluating daclatasvir plus asunaprevir in interferon (±ribavirin)-ineligible or -intolerant Asian patients with genotype 1b infection from mainland China, Korea, and Taiwan. METHODS Interferon (±ribavirin)-ineligible and -intolerant patients with genotype 1b infection received daclatasvir 60 mg tablets once daily plus asunaprevir 100 mg soft capsules twice daily for 24 weeks. The primary endpoint was sustained virologic response at post-treatment week 24 (SVR24). RESULTS Of the 159 patients treated, 89.3% were Chinese, 65.4% were female, and 73.6% were interferon-intolerant. Cirrhosis was present in 32.7% of patients, and 40.3% had IL28B non-CC genotypes. SVR24 was achieved by 145/159 (91.2%) patients (100% concordance with SVR12) and was similarly high in cirrhotic patients (47/52, 90.4%). SVR24 was higher in patients without baseline NS5A (L31M or Y93H) resistance-associated variants (RAVs) (137/139, 98.6%), including those with cirrhosis (43/44, 97.7%). Prevalence of baseline NS5A RAVs was low (19/159, 11.9%), particularly in mainland China (10/127, 7.9%). One death (0.6%), five serious adverse events (3.1%), and three grade 4 laboratory abnormalities (1.9%) occurred on treatment; none were considered related to study drugs. Two patients (1.3%) discontinued because of adverse events. Treatment was generally well tolerated regardless of cirrhosis status. CONCLUSIONS Daclatasvir plus asunaprevir achieved a SVR24 rate of 91.2%, rising to 98.6% in patients without baseline NS5A RAVs, and was generally well tolerated in interferon (±ribavirin)-ineligible or -intolerant patients with genotype 1b infection from mainland China, Korea, and Taiwan.
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Affiliation(s)
- Lai Wei
- Peking University People's Hospital and Peking University Hepatology Institute, Beijing
| | | | - Min Xu
- Guangzhou No.8 People's Hospital, Guangzhou
| | - Wan-Long Chuang
- Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung
| | - Wei Lu
- Tianjin Second People's Hospital, Tianjin
| | - Wen Xie
- Beijing Ditan Hospital, Capital Medical University, Beijing
| | | | - Guozhong Gong
- The Second Xiangya Hospital of Central South University, Changsha
| | - Yueqi Li
- 302 Military Hospital of China, Beijing
| | - Si Hyun Bae
- Seoul St. Mary Hospital, The Catholic University of Korea, Seoul
| | - Yong-Feng Yang
- The 2nd Hospital of Nanjing, Affiliated to Medical School of South East University, Nanjing
| | - Qing Xie
- Shanghai Ruijin Hospital, Jiaotong University School of Medicine, Guangzhou
| | - Shumei Lin
- The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an
| | - Xinyue Chen
- Beijing Youan Hospital, Capital Medical University, Beijing
| | - Junqi Niu
- First Hospital of Jilin University, Changchun
| | - Jidong Jia
- Beijing Friendship Hospital, Capital Medical University, Beijing
| | | | | | | | | | | | - Ling Mo
- Bristol-Myers Squibb, Shanghai
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Hepatitis C Virus in North Africa: An Emerging Threat. ScientificWorldJournal 2016; 2016:7370524. [PMID: 27610403 PMCID: PMC5004010 DOI: 10.1155/2016/7370524] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 06/21/2016] [Accepted: 07/19/2016] [Indexed: 02/08/2023] Open
Abstract
Hepatitis C virus is a major public health threat associated with serious clinical consequences worldwide. North Africa is a unique region composed of seven countries that vary considerably in the predisposing factors to microbial diseases both historically and at the present time. The dynamics of HCV in the region are not well documented. The data are both limited and controversial in most of the countries in the region. In North Africa, the epidemiology of HCV is disparate and understanding it has been hampered by regional "epidemiological homogeneity" concepts. As the dynamics of HCV vary from country to country, context-specific research is needed. In this review, we assess studies performed in each country in the general populations as well as among blood donors and groups exposed to the HCV infection. The reported prevalence of HCV ranges from 0.6% to 8.4% in the Maghreb countries and is predominated by genotype 1. In the Nile valley region, it ranges from 2.2% to 18.9% and is dominated by genotype 4. In North African countries, HCV seems to be a serious problem that is driven by different vectors even in different geographical locations within the same country. Efforts should be combined at both the national and regional levels to implement efficient preventive and treatment strategies.
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Cosentino S, Zhu C, Bertrand E, Metcalfe J, Janicki S, Cines S. Examination of the metacognitive errors that contribute to anosognosia in Alzheimer's disease. Cortex 2016; 84:101-110. [PMID: 27750070 DOI: 10.1016/j.cortex.2016.08.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Revised: 07/27/2016] [Accepted: 08/05/2016] [Indexed: 11/16/2022]
Abstract
Disordered awareness of memory loss (i.e., anosognosia) is a frequent and clinically relevant symptom of Alzheimer's disease (AD). The metacognitive errors which characterize anosognosia in AD, however, have not been fully articulated. The current study examined metamemory performance as a function of clinically defined awareness groups using different task conditions to examine the extent to which specific metacognitive deficits (i.e., detecting, integrating, or being explicitly aware of errors) contribute to anosognosia in AD (n = 49). In the prospective condition of the metamemory task, analyses examining the association between awareness group, confidence (i.e., FOK) ratings, and memory performance demonstrated an interaction effect F (1, 43) = 5.16, p = .028 with only the aware group (n = 22) providing higher FOK ratings for correct responses compared to incorrect responses (p < .001). The unaware group (n = 27) did not show this dissociation (p = .167), and also made higher FOK ratings for incorrect responses than the aware group (p = .048). There was no main effect of task condition on FOK [F (2, 66) = 1.51, p = .228] with all participants providing comparable FOK ratings for memory performance whether ratings were made prospectively, retrospectively, or in the context of examiner feedback. The overall pattern of performance in the unaware group, whereby individuals did not sufficiently lower confidence ratings in the context of memory errors, and did not benefit from either retrospective assessment or examiner feedback, appears most consistent with a primary anosognosia in which memory failures are not available in explicit awareness.
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Affiliation(s)
- Stephanie Cosentino
- Cognitive Neuroscience Division of the Gertrude H. Sergievsky Center, Columbia University Medical Center, New York, NY, United States; Cognitive Neuroscience Division of the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, United States; Cognitive Neuroscience Division of the Department of Neurology, Columbia University Medical Center, New York, NY, United States.
| | - Carolyn Zhu
- Department of Geriatrics and Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Elodie Bertrand
- Cognitive Neuroscience Division of the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, United States
| | - Janet Metcalfe
- Department of Psychology, Columbia University, New York, NY, United States
| | - Sarah Janicki
- Cognitive Neuroscience Division of the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, United States; Cognitive Neuroscience Division of the Department of Neurology, Columbia University Medical Center, New York, NY, United States
| | - Sarah Cines
- Cognitive Neuroscience Division of the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, United States
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Basnayake SK, Easterbrook PJ. Wide variation in estimates of global prevalence and burden of chronic hepatitis B and C infection cited in published literature. J Viral Hepat 2016; 23:545-59. [PMID: 27028545 DOI: 10.1111/jvh.12519] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 01/14/2016] [Indexed: 12/15/2022]
Abstract
To evaluate the extent of heterogeneity in global estimates of chronic hepatitis B (HBV) and C (HCV) cited in the published literature, we undertook a systematic review of the published literature. We identified articles from 2010 to 2014 that had cited global estimates for at least one of ten indicators [prevalence and numbers infected with HBV, HCV, HIV-HBV or HIV-HCV co-infection, and mortality (number of deaths annually) for HBV and HCV]. Overall, 488 articles were retrieved: 239 articles cited a HBV-related global estimate [prevalence (n = 12), number infected (n = 193) and number of annual deaths (n = 82)]; 280 articles had HCV-related global estimates [prevalence (n = 86), number infected (n = 203) and number of annual deaths (n = 31)]; 31 had estimates on both HBV and HCV; 54 had HIV-HBV co-infection estimates [prevalence (n = 42) and number co-infected (n = 12)]; and 68 had estimates for HIV-HCV co-infection [prevalence (n = 40) and number co-infected (n = 28)]. There was considerable heterogeneity in the estimates cited and also a lack of consistency in the terminology used. Although 40% of 488 articles cited WHO as the source of the estimate, many of these were from outdated or secondary sources. Our findings highlight the importance of clear and consistent communication from WHO and other global health agencies on current consensus estimates of hepatitis B and C burden and prevalence, the need for standardisation in their citation, and for regular updates.
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Affiliation(s)
| | - P J Easterbrook
- Global Hepatitis Programme, HIV Department, World Health Organization, Geneva, Switzerland
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Large scale production of a mammalian cell derived quadrivalent hepatitis C virus like particle vaccine. J Virol Methods 2016; 236:87-92. [PMID: 27373602 DOI: 10.1016/j.jviromet.2016.06.012] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 06/24/2016] [Accepted: 06/27/2016] [Indexed: 12/14/2022]
Abstract
A method for the large-scale production of a quadrivalent mammalian cell derived hepatitis C virus-like particles (HCV VLPs) is described. The HCV core E1 and E2 coding sequences of genotype 1a, 1b, 2a or 3a were co-expressed in Huh7 cell factories using a recombinant adenoviral expression system. The structural proteins self-assembled into VLPs that were purified from Huh7 cell lysates by iodixanol ultracentrifugation and Stirred cell ultrafiltration. Electron microscopy, revealed VLPs of the different genotypes that are morphologically similar. Our results show that it is possible to produce large quantities of individual HCV genotype VLPs with relative ease thus making this approach an alternative for the manufacture of a quadrivalent mammalian cell derived HCV VLP vaccine.
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Kwon YC, Kim H, Meyer K, Di Bisceglie AM, Ray R. Distinct CD55 Isoform Synthesis and Inhibition of Complement-Dependent Cytolysis by Hepatitis C Virus. THE JOURNAL OF IMMUNOLOGY 2016; 197:1127-36. [PMID: 27357152 DOI: 10.4049/jimmunol.1600631] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Accepted: 06/02/2016] [Indexed: 01/31/2023]
Abstract
CD55/DAF, one of the regulators of complement activation, is known to limit excess complement activation on the host cell surface by accelerating the decay of C3 convertase. We reported previously that hepatitis C virus (HCV) infection or virus core protein expression upregulates CD55 expression. CD55 associates with HCV particles, potentially protecting HCV from lysis in circulation. An increase in CD55 on the surface of HCV-infected cells may inhibit complement-mediated cell killing. In this study, we show that Abs against cancer cell surface proteins induce complement-dependent cytolysis or Ab-dependent cell-mediated cytotoxicity of immortalized human hepatocytes in the presence of CD55-blocking Ab. CD55 has a secreted isoform (sCD55) that is generated by alternative splicing. We observed that sCD55 is induced in HCV-infected or HCV replicon-harboring cells, as well as in liver biopsy samples from chronically HCV-infected patients. Conditioned medium from HCV-infected hepatoma cells (Huh7.5 cells) or immortalized human hepatocytes inhibited C3 convertase activity and complement-dependent cytolysis of sheep blood erythrocytes. Chronically HCV-infected patient sera inhibited C3 convertase activity, further implicating HCV-specific impairment of complement function in infected humans. CD55-blocking Ab inhibited erythrocyte lysis by conditioned medium, suggesting that CD55/sCD55 impairs convertase activity. Together, our data show that HCV infection induces sCD55 expression in HCV-infected cell culture-conditioned medium and inhibits C3 convertase activity. This may have implications for modulating complement-mediated immune function in the microenvironment and on HCV-harboring cells.
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Affiliation(s)
- Young-Chan Kwon
- Department of Internal Medicine, Saint Louis University, St. Louis, MO 63104; and
| | - Hangeun Kim
- Department of Internal Medicine, Saint Louis University, St. Louis, MO 63104; and
| | - Keith Meyer
- Department of Internal Medicine, Saint Louis University, St. Louis, MO 63104; and
| | | | - Ranjit Ray
- Department of Internal Medicine, Saint Louis University, St. Louis, MO 63104; and Department of Molecular Microbiology and Immunology, Saint Louis University, St. Louis, MO 63140
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Abstract
INTRODUCTION The direct acting antiviral daclatasvir is an NS5A replication inhibitor active against the entire range of hepatitis C virus genotypes. It is a key step in establishing the goal of an all-oral, ribavirin-free, pan-genotypic regimen against hepatitis C. AREAS COVERED We review current literature including published abstracts and manuscripts. Evidence was obtained through PubMed/Medline search using listed keywords and through review of published abstracts. EXPERT OPINION Daclatasvir introduces a degree of pangenotypic potency currently lacking in other NS5A agents. Emerging literature suggests that daclatasvir in combination with other DAAs will represent a promising option in this difficult to treat populations including posttransplant, genotype 3 and HIV patients.
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Affiliation(s)
- Syed-Mohammed Jafri
- a Division of Gastroenterology , Henry Ford Hospital , Detroit , MI 48202 , USA
| | - Stuart C Gordon
- a Division of Gastroenterology , Henry Ford Hospital , Detroit , MI 48202 , USA
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Ide K, Kawasaki Y, Yamada H, Masaki N. Regional differences in hepatitis C treatment with peginterferon and ribavirin in Japan: a retrospective cohort study. Drug Des Devel Ther 2016; 10:1217-1223. [PMID: 27042013 PMCID: PMC4809336 DOI: 10.2147/dddt.s102458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
PURPOSE The aims of this study were to investigate regional differences in hepatitis C virus (HCV) infection treatment with peginterferon and ribavirin in Japan and to develop and validate statistical models for analysis of regional differences, using generalized linear mixed models. METHODS Individuals with chronic HCV infection were identified from the Japanese Interferon Database (registered from December 2009 to April 2013). The total sustained virologic response rate and the rate in each prefecture were calculated. In the analysis using generalized linear mixed models, the following four models were constructed: 1) prefecture as a fixed effect, 2) prefecture and other confounding variables as fixed effects, 3) prefecture as a random effect, and 4) prefecture as a random effect and other confounding variables as fixed effects. The quality of the model fit was assessed using the Akaike information criterion and the Bayesian information criterion. All statistical analyses were performed using SAS Version 9.4 for Windows. RESULTS From 36 prefectures, 16,349 cases were recorded in the study period. Of these, 4,677 were excluded according to certain criteria. The total sustained virologic response rate was 59.9% (range, 43.9%-71.6%). The statistical model including prefecture as a random effect and other confounding variables as fixed effects showed the best fit based on the Akaike information criterion (13,830.92) and Bayesian information criterion (13,845.17). CONCLUSION Regional differences may exist in HCV infection treatment in Japan. The model including prefecture as a random effect and other confounding variables as fixed effects was appropriate for analysis of such regional differences. Additional studies considering the medical situations of each patient would provide useful information that could contribute to improve and standardize HCV infection treatment.
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Affiliation(s)
- Kazuki Ide
- Department of Drug Evaluation and Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Yohei Kawasaki
- Department of Drug Evaluation and Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Hiroshi Yamada
- Department of Drug Evaluation and Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Naohiko Masaki
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
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Gamal N, Andreone P. Safety and efficacy of once daily ledipasvir/sofosbuvir fixed-dose combination in patients with chronic hepatitis C. Expert Opin Drug Saf 2016; 15:549-557. [PMID: 26899025 DOI: 10.1517/14740338.2016.1157163] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Accepted: 02/18/2016] [Indexed: 12/26/2022]
Abstract
INTRODUCTION During the past couple of years, the regulatory authorities have approved seven new direct-acting antivirals (DAAs) for the treatment of chronic hepatitis C (CHC). In 2014, the US FDA approved the fixed dose combination of ledipasvir (LDV) plus sofosbuvir (SOF) for the treatment of genotype (GT) 1 HCV and the European Commission Granted its marketing authorization to treat patients with GT1 and 4. This regimen showed outstanding rates of virologic response along with a favorable safety profile with a very low rate of both virologic failure and treatment discontinuation. AREAS COVERED In this review, we sought to review the pharmacokinetics, clinical efficacy and safety profile pertaining to LDV/SOF combination in treatment of CHC with special emphasis on phase III clinical trials. EXPERT OPINION In all phase III trials, the 12-week course of this new interferon (IFN)-sparing regimen has delivered high virologic cure rates among patient with GT1 and 4 both treatment-naïve and - experienced Data about its effectiveness in patients under 18 years of age, end-stage renal disease and patients with significant other organ involvement are eagerly awaited.
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Affiliation(s)
- N Gamal
- a Department of Medical and Surgical Sciences , University of Bologna , Bologna , Italy
| | - P Andreone
- a Department of Medical and Surgical Sciences , University of Bologna , Bologna , Italy
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Zhu GQ, Zou ZL, Zheng JN, Chen DZ, Zou TT, Shi KQ, Zheng MH. Systematic Review and Network Meta-Analysis of Randomized Controlled Trials: Comparative Effectiveness and Safety of Direct-Acting Antiviral Agents for Treatment-Naive Hepatitis C Genotype 1. Medicine (Baltimore) 2016; 95:e3004. [PMID: 26945424 PMCID: PMC4782908 DOI: 10.1097/md.0000000000003004] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2015] [Revised: 01/22/2016] [Accepted: 02/11/2016] [Indexed: 12/18/2022] Open
Abstract
All possible direct-acting antiviral agent (DAA) regimens for treatment-naive hepatitis C genotype 1 were evaluated by many randomized controlled trials (RCTs). However, the optimum regimen remains inconclusive. We aim to compare interventions in terms of sustained virological response at 12 (SVR12) and 24 (SVR24) weeks after the end of treatment and adverse effects (AEs) (fatigue, headache, nausea, insomnia). PubMed, Embase, and the Cochrane Library were searched for RCTs until July 31, 2015. We estimated odds ratios (ORs) between treatments on clinical outcomes. Twenty-two eligible RCTs were included. Compared with peginterferon-ribavirin (PR), daclatasvir plus PR (OR 8.90, P < 0.001), faldaprevir plus PR (OR 3.72, P < 0.001), simeprevir plus PR (OR 3.59, P < 0.001), sofosbuvir plus PR (OR 4.69, P < 0.001) yield a significant effect in improving SVR12. Consistently, simeprevir plus PR (OR 3.49, P < 0.001), sofosbuvir plus PR (OR 4.51, P < 0.001), daclatasvir plus PR (OR 4.77, P < 0.001) also improved the rates of SVR24 significantly compared with PR. With respect to AEs, compared with PR, ledipasvir plus sofosbuvir plus PR (OR 2.13, P < 0.001) confer a significant AE in nausea, whereas daclatasvir plus PR (OR 0.20, P < 0.001 and OR 0.18, P < 0.001, respectively) lowered the incidence of fatigue and nausea significantly when compared with ledipasvir plus sofosbuvir plus PR. Daclatasvir plus PR was the most effective in SVR12 and SVR24, but caused an increased AEs profile (headache and insomnia). Combined ledipasvir with sofosbuvir or combination of PR was associated with higher incidence of fatigue and nausea.
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Affiliation(s)
- Gui-Qi Zhu
- From the Department of Infection and Liver Diseases, Liver Research Center, the First Affiliated Hospital of Wenzhou Medical University (G-QZ, J-NZ, D-ZC, T-TZ, K-QS, M-HZ), School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou (G-QZ, J-NZ, T-TZ), Department of Infection Diseases, the First Hospital of Jiaxing, Jiaxing (Z-LZ), Queen Mary Hospital, University of Hong Kong, Hong Kong (D-ZC), and Institute of Hepatology (K-QS, M-HZ), Wenzhou Medical University, Wenzhou, China
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Zeuzem S, Hézode C, Bronowicki JP, Loustaud-Ratti V, Gea F, Buti M, Olveira A, Banyai T, Al-Assi MT, Petersen J, Thabut D, Gadano A, Pruitt R, Makara M, Bourlière M, Pol S, Beumont-Mauviel M, Ouwerkerk-Mahadevan S, Picchio G, Bifano M, McPhee F, Boparai N, Cheung K, Hughes EA, Noviello S. Daclatasvir plus simeprevir with or without ribavirin for the treatment of chronic hepatitis C virus genotype 1 infection. J Hepatol 2016; 64:292-300. [PMID: 26453968 DOI: 10.1016/j.jhep.2015.09.024] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Revised: 09/18/2015] [Accepted: 09/29/2015] [Indexed: 01/05/2023]
Abstract
BACKGROUND & AIMS We evaluated the combination of daclatasvir (pan-genotypic NS5A inhibitor) and simeprevir (NS3/4A protease inhibitor), with or without ribavirin, in hepatitis C virus genotype 1-infected patients. METHODS This phase II, open-label study enrolled treatment-naive patients or prior null responders with genotype 1b (n=147) or 1a (n=21) infection. Genotype 1b-infected patients were randomized 1:1 to receive daclatasvir 30mg plus simeprevir 150mg once daily with or without ribavirin; those who completed the initial 12-week treatment were re-randomized 1:1 to stop treatment or continue treatment through to week 24. Genotype 1a-infected patients received daclatasvir plus simeprevir with ribavirin for 24weeks. The primary endpoint was the proportion of patients with sustained virologic response at posttreatment week 12 (SVR12). RESULTS For genotype 1b, 84.9% (45/53) and 74.5% (38/51) of treatment-naive patients and 69.6% (16/23) and 95.0% (19/20) of prior null responders to peginterferon and ribavirin achieved SVR12 with daclatasvir plus simeprevir alone and with ribavirin, respectively. Treatment duration did not have a well-defined impact on response. For genotype 1a, daclatasvir plus simeprevir with ribavirin provided a 66.7% (8/12) response rate in treatment-naive patients and was not effective in prior null responders. Data suggest that baseline resistance polymorphisms influenced SVR12 rates. Daclatasvir plus simeprevir was well tolerated with or without ribavirin with low incidences of serious adverse events and adverse events leading to discontinuation. CONCLUSIONS Daclatasvir plus simeprevir, with or without ribavirin, was effective with a 12- or 24-week duration in genotype 1b-infected patients and was well tolerated. ClinicalTrials.gov identifier: NCT01628692.
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Affiliation(s)
- Stefan Zeuzem
- Klinikum der Goethe Universität, Frankfurt, Germany.
| | - Christophe Hézode
- Hôpital Henri Mondor, AP-HP, Université Paris-Est, INSERM U955, Créteil, France
| | - Jean-Pierre Bronowicki
- INSERM U954, Centre Hospitalier Universitaire de Nancy, Université de Lorraine, Vandoeuvre les Nancy, France
| | | | | | - Maria Buti
- Hospital Vall Hebron, Barcelona and CIBEREHD del Instituto Carlos III, Spain
| | | | | | | | - Joerg Petersen
- IFI Institut für Interdisziplinäre Medizin, Hamburg, Germany
| | | | - Adrian Gadano
- Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Ronald Pruitt
- Nashville Medical Research Institute, Nashville, TN, USA
| | | | | | - Stanislas Pol
- Université Paris Descartes, AP-HP, Unité d'Hépatologie, Hôpital Cochin, INSERM UMS-20, Institut Pasteur, Paris, France
| | | | | | | | - Marc Bifano
- Bristol-Myers Squibb Research and Development, Princeton, NJ, USA
| | - Fiona McPhee
- Bristol-Myers Squibb Research and Development, Wallingford, CT, USA
| | - Navdeep Boparai
- Bristol-Myers Squibb Research and Development, Princeton, NJ, USA
| | - Kin Cheung
- Bristol-Myers Squibb Research and Development, Wallingford, CT, USA
| | - Eric A Hughes
- Bristol-Myers Squibb Research and Development, Princeton, NJ, USA
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Chronic hepatitis C: treat or wait? A prospective study on reasons for treatment or nontreatment in the era of first-generation protease inhibitors. Eur J Gastroenterol Hepatol 2016; 28:164-72. [PMID: 26560750 DOI: 10.1097/meg.0000000000000506] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS In many countries, current treatment for patients with chronic hepatitis C involves a combination of peginterferon and ribavirin, associated with a protease inhibitor for hepatitis C virus genotype 1. More recent and efficient less toxic antiviral treatments are now available for some patients. Thus, the decision to treat or to wait is challenging. The aims of this study were to: (a) estimate the proportion of treated patients, (b) evaluate the reasons for this decision, and (c) examine the patients' points-of-view in treatment decision. METHODS This was a prospective study conducted at three French referral centers between March and June 2013. Epidemiological and virological data, reasons for treatment or nontreatment, and data on the doctors' and patients' choices were collected. RESULTS A total of 255 patients were analyzed. Only 52.6% of patients with fibrosis of 2 or higher were treated. Treatment uptake was reduced in the following groups: previously treated patients, those with poor tolerance during prior treatment, those with heavy alcohol consumption, and those with hepatocellular carcinoma. Of the cirrhotic patients, 55% were not treated: 51.1% had a contraindication, 22.2% had a previous nonresponse. When treatment was refused by the patient, fear of side effects and professional problems were the most frequently cited reasons (90 and 40%, respectively). CONCLUSION Patients were treated primarily according to consensus guidelines. However, only 45% of cirrhotic patients were treated. In 7.6% of the cases, the patient refused therapy. This study enabled us to measure the importance of patient choice in medical decision-making. Well-informed patients expected not only more efficient but also well-tolerated therapy.
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In Vitro Antiviral Activity and Resistance Profile Characterization of the Hepatitis C Virus NS5A Inhibitor Ledipasvir. Antimicrob Agents Chemother 2016; 60:1847-1853. [PMID: 26824950 DOI: 10.1128/aac.02524-15] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2015] [Accepted: 01/02/2016] [Indexed: 12/25/2022] Open
Abstract
Ledipasvir (LDV; GS-5885), a component of Harvoni (a fixed-dose combination of LDV with sofosbuvir [SOF]), is approved to treat chronic hepatitis C virus (HCV) infection. Here, we report key preclinical antiviral properties of LDV, including in vitro potency, in vitro resistance profile, and activity in combination with other anti-HCV agents. LDV has picomolar antiviral activity against genotype 1a and genotype 1b replicons with 50% effective concentration (EC50) values of 0.031 nM and 0.004 nM, respectively. LDV is also active against HCV genotypes 4a, 4d, 5a, and 6a with EC50 values of 0.11 to 1.1 nM. LDV has relatively less in vitro antiviral activity against genotypes 2a, 2b, 3a, and 6e, with EC50 values of 16 to 530 nM. In vitro resistance selection with LDV identified the single Y93H and Q30E resistance-associated variants (RAVs) in the NS5A gene; these RAVs were also observed in patients after a 3-day monotherapy treatment. In vitro antiviral combination studies indicate that LDV has additive to moderately synergistic antiviral activity when combined with other classes of HCV direct-acting antiviral (DAA) agents, including NS3/4A protease inhibitors and the nucleotide NS5B polymerase inhibitor SOF. Furthermore, LDV is active against known NS3 protease and NS5B polymerase inhibitor RAVs with EC50 values equivalent to those for the wild type.
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40
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von Delft A, Humphreys IS, Brown A, Pfafferott K, Lucas M, Klenerman P, Lauer GM, Cox AL, Gaudieri S, Barnes E. The broad assessment of HCV genotypes 1 and 3 antigenic targets reveals limited cross-reactivity with implications for vaccine design. Gut 2016; 65:112-23. [PMID: 26092843 PMCID: PMC4717358 DOI: 10.1136/gutjnl-2014-308724] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Accepted: 04/20/2015] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Developing a vaccine that is cross-reactive between HCV genotypes requires data on T cell antigenic targets that extends beyond genotype-1. We characterised T cell immune responses against HCV genotype-3, the most common infecting genotype in the UK and Asia, and assessed within genotype and between genotype cross-reactivity. DESIGN T cell targets were identified in 140 subjects with either acute, chronic or spontaneously resolved HCV genotype-3 infection using (1) overlapping peptides and (2) putative human leucocyte antigens (HLA)-class-I wild type and variant epitopes through the prior assessment of polymorphic HCV genomic sites associated with host HLA, in IFNγ-ELISpot assays. CD4+/CD8+ T cell subsets were defined and viral variability at T cell targets was determined through population analysis and viral sequencing. T cell cross-reactivity between genotype-1 and genotype-3 variants was assessed. RESULTS In resolved genotype-3 infection, T cells preferentially targeted non-structural proteins at a high magnitude, whereas in chronic disease T cells were absent or skewed to target structural proteins. Additional responses to wild type but not variant HLA predicted peptides were defined. Major sequence viral variability was observed within genotype-3 and between genotypes 1 and 3 HCV at T cell targets in resolved infection and at dominant epitopes, with limited T cell cross-reactivity between viral variants. Overall 41 CD4/CD8+ genotype-3 T cell targets were identified with minimal overlap with those described for HCV genotype-1. CONCLUSIONS HCV T cell specificity is distinct between genotypes with limited T cell cross-reactivity in resolved and chronic disease. Therefore, viral regions targeted in natural HCV infection may not serve as attractive targets for a vaccine that aims to protect against multiple HCV genotypes.
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Affiliation(s)
| | | | | | | | - Michaela Lucas
- Institute of Immunology and Infectious Diseases, Murdoch University, Perth, Western Australia, Australia,School of Medicine and Pharmacology, Harry Perkins Institute, University of Western Australia, Western Australia, Australia,School of Pathology and Laboratory Medicine, University of Western Australia, Western Australia, Australia
| | | | | | - Andrea L Cox
- John Hopkins University, Baltimore, Maryland, USA
| | - Silvana Gaudieri
- Institute of Immunology and Infectious Diseases, Murdoch University, Perth, Western Australia, Australia,School of Anatomy, Physiology and Human Biology, University of Western Australia, Perth, Western Australia, Australia
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Aliberti A, Cusano AM, Battista E, Causa F, Netti PA. High sensitive and direct fluorescence detection of single viral DNA sequences by integration of double strand probes onto microgels particles. Analyst 2016; 141:1250-6. [DOI: 10.1039/c5an02001h] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
A novel class of probes for fluorescence detection was developed and combined to microgel particles for a high sensitive fluorescence detection of nucleic acids.
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Affiliation(s)
- A. Aliberti
- Center for Advanced Biomaterials for Healthcare@CRIB
- Istituto Italiano di Tecnologia (IIT)
- 80125 Naples
- Italy
| | - A. M. Cusano
- Center for Advanced Biomaterials for Healthcare@CRIB
- Istituto Italiano di Tecnologia (IIT)
- 80125 Naples
- Italy
| | - E. Battista
- Center for Advanced Biomaterials for Healthcare@CRIB
- Istituto Italiano di Tecnologia (IIT)
- 80125 Naples
- Italy
| | - F. Causa
- Center for Advanced Biomaterials for Healthcare@CRIB
- Istituto Italiano di Tecnologia (IIT)
- 80125 Naples
- Italy
- Interdisciplinary Research Centre on Biomaterials (CRIB)
| | - P. A. Netti
- Center for Advanced Biomaterials for Healthcare@CRIB
- Istituto Italiano di Tecnologia (IIT)
- 80125 Naples
- Italy
- Interdisciplinary Research Centre on Biomaterials (CRIB)
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The Dual Role of Exosomes in Hepatitis A and C Virus Transmission and Viral Immune Activation. Viruses 2015; 7:6707-15. [PMID: 26694453 PMCID: PMC4690890 DOI: 10.3390/v7122967] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Revised: 11/30/2015] [Accepted: 12/10/2015] [Indexed: 12/21/2022] Open
Abstract
Exosomes are small nanovesicles of about 100 nm in diameter that act as intercellular messengers because they can shuttle RNA, proteins and lipids between different cells. Many studies have found that exosomes also play various roles in viral pathogenesis. Hepatitis A virus (HAV; a picornavirus) and Hepatitis C virus (HCV; a flavivirus) two single strand plus-sense RNA viruses, in particular, have been found to use exosomes for viral transmission thus evading antibody-mediated immune responses. Paradoxically, both viral exosomes can also be detected by plasmacytoid dendritic cells (pDCs) leading to innate immune activation and type I interferon production. This article will review recent findings regarding these two viruses and outline how exosomes are involved in their transmission and immune sensing.
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43
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Sanford M. Simeprevir: a review of its use in patients with chronic hepatitis C virus infection. Drugs 2015; 75:183-96. [PMID: 25559421 DOI: 10.1007/s40265-014-0341-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Simeprevir (Olysio™; Galexos™; Sovriad®) is an orally-administered NS3/4A protease inhibitor for use in combined drug regimens against chronic hepatitis C virus (HCV) infection. This article reviews studies relevant to the EU simeprevir label. In proof-of-concept studies, simeprevir had potent antiviral activity against all HCV genotypes, except genotype 3. In trials in patients with chronic HCV genotype 1 infection, week-12 sustained virological response (SVR12) rates in treatment-naïve patients and prior relapsers were significantly higher with simeprevir plus peginterferon-α/ribavirin (PR) [79-89 %] than with placebo plus PR (36-62 %). In prior partial/null responders, the SVR12 rate with simeprevir plus PR (54 %) was noninferior to that with telaprevir plus PR (55 %). Simeprevir plus PR was also efficacious in patients with HCV genotype 1/HIV-1 co-infection. In prior null responders without severe liver fibrosis (cohort 1) and treatment-naïve patients with severe liver fibrosis (cohort 2) treated with simeprevir plus sofosbuvir, the SVR12 rate for the two cohorts combined was 92 %. In patients with chronic HCV genotype 4 infection, the SVR12 rates with simeprevir plus PR were 83, 87 and 40 % in treatment-naïve patients, prior relapsers and prior null responders, respectively. Grade 3-4 adverse event, serious adverse event and treatment withdrawal rates with simeprevir plus PR were similar to those with placebo plus PR. Skin rashes with simeprevir were mostly mild or moderate; serious photosensitivity reactions occur, but are rare. Simeprevir is efficacious and generally well tolerated in patients with chronic HCV genotypes 1 and 4 infection. Studies of simeprevir in interferon-free regimens and in other subpopulations with HCV infections will be of interest.
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Affiliation(s)
- Mark Sanford
- Springer, Private Bag 65901, Mairangi Bay, 0754, Auckland, New Zealand,
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44
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Pawlotsky JM, Flisiak R, Sarin SK, Rasenack J, Piratvisuth T, Chuang WL, Peng CY, Foster GR, Shah S, Wedemeyer H, Hézode C, Zhang W, Wong KA, Li B, Avila C, Naoumov NV. Alisporivir plus ribavirin, interferon free or in combination with pegylated interferon, for hepatitis C virus genotype 2 or 3 infection. Hepatology 2015; 62:1013-1023. [PMID: 26118427 DOI: 10.1002/hep.27960] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2015] [Revised: 06/17/2015] [Accepted: 06/24/2015] [Indexed: 12/14/2022]
Abstract
UNLABELLED Alisporivir is a cyclophilin inhibitor with pan-genotypic anti-hepatitis C virus (HCV) activity and a high barrier to viral resistance. The VITAL-1 study assessed alisporivir as interferon (IFN)-free therapy in treatment-naïve patients infected with HCV genotype 2 or 3. Three hundred forty patients without cirrhosis were randomized to: arm 1, alisporivir (ALV) 1,000 mg once-daily (QD); arm 2, ALV 600 mg QD and ribavirin (RBV); arm 3, ALV 800 mg QD and RBV; arm 4, ALV 600 mg QD and pegylated IFN (Peg-IFN); or arm 5, Peg-IFN and RBV. Patients receiving IFN-free ALV regimens who achieved rapid virological response (RVR) continued the same treatment throughout, whereas those with detectable HCV RNA at week 4 received ALV, RBV, and Peg-IFN from weeks 6 to 24. Overall, 300 patients received ALV-based regimens. In arm 1 to arm 4, the intent-to-treat rates of sustained virological response (SVR) 24 weeks after treatment (SVR24) were from 80% to 85%, compared with 58% (n = 23 of 40) with Peg-IFN/RBV. Per-protocol analysis showed higher SVR24 rates in patients who received ALV/RBV, IFN-free after RVR (92%; n = 56 of 61) than with ALV alone after RVR (72%; n = 13 of 18) or with Peg-IFN/RBV (70%; n = 23 of 33). Both RVRs and SVRs to ALV IFN-free regimens were numerically higher in genotype 3- than in genotype 2-infected patients. Viral breakthrough was infrequent (3%; n = 7 of 258). IFN-free ALV treatment showed markedly better safety/tolerability than IFN-containing regimens. CONCLUSIONS ALV plus RBV represents an effective IFN-free option for a proportion of patients with HCV genotype 2 or 3 infections, with high SVR rates for patients with early viral clearance. Further investigations of ALV in IFN-free combination regimens with direct-acting antiviral drugs deserve exploration in future trials.
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Affiliation(s)
- Jean-Michel Pawlotsky
- National Reference Center for Viral Hepatitis B, C and Delta, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France
- INSERM U955, Créteil, France
| | | | - Shiv K Sarin
- Institute of Liver and Biliary Sciences, New Delhi, India
| | - Jens Rasenack
- Klinikum der Albert-Ludwigs-Universität, Freiburg, Germany
| | - Teerha Piratvisuth
- Prince of Songkla University, Songklanagarind Hospital, Hat-Yai, Songkhla, Thailand
| | - Wan-Long Chuang
- Kaohsiung Medical University, Chang-Ho Memorial Hospital, Kaohsiung, Taiwan
| | - Cheng-Yuan Peng
- School of Medicine, China Medical University, Taichung, Taiwan
| | - Graham R Foster
- Bart's and The London School of Medicine, Queen Mary's University of London, London, United Kingdom
| | | | | | - Christophe Hézode
- INSERM U955, Créteil, France
- Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France
| | - Wei Zhang
- Beijing Novartis Pharma Co Ltd, Shanghai, China
| | - Kelly A Wong
- Novartis Institute of Biomedical Research, Emeryville, CA
| | - Bin Li
- Novartis Institute of Biomedical Research, Cambridge, MA
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Wang H, Wang S, Cheng L, Chen L, Wang Y, Qing J, Huang S, Wang Y, Lei X, Wu Y, Ma Z, Zhang L, Tang Y. Discovery of Imidazo[1,2-α][1,8]naphthyridine Derivatives as Potential HCV Entry Inhibitor. ACS Med Chem Lett 2015; 6:977-81. [PMID: 26396683 DOI: 10.1021/acsmedchemlett.5b00159] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Accepted: 07/26/2015] [Indexed: 02/05/2023] Open
Abstract
RO8191 represents a newly discovered small-molecule IFN-like agent that displays potent anti-HCV activity. With it as lead, a series of compounds bearing an imidazo[1,2-α][1,8]naphthyridine core and an amide bond-linked side chain were designed and synthesized. These compounds were evaluated on HCV cell culture system (HCVcc-hRluc-JFH1), and some of them exhibited remarkable anti-HCV activity (EC50 = 0.017-0.159 μM) and low toxicity (CC50 > 25 μM). Moreover, it was revealed that these newly identified anti-HCV agents exert their antiviral effect through a distinct mechanism of action from that of RO8191 by targeting the viral entry process. Thus, our study provides a starting point for the development of potential HCV entry inhibitor.
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Affiliation(s)
- Huan Wang
- Comprehensive
AIDS Research Center, and Department of Pharmacology and Pharmaceutical
Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Shuo Wang
- Comprehensive
AIDS Research Center, and Department of Pharmacology and Pharmaceutical
Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Lili Cheng
- Comprehensive
AIDS Research Center, and Department of Pharmacology and Pharmaceutical
Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Ligong Chen
- Comprehensive
AIDS Research Center, and Department of Pharmacology and Pharmaceutical
Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
- Collaborative
Innovation Center for Biotherapy, State Key Laboratory of Biotherapy
and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China
| | - Yongguang Wang
- Comprehensive
AIDS Research Center, and Department of Pharmacology and Pharmaceutical
Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Jie Qing
- Comprehensive
AIDS Research Center, Collaborative Innovation Center for Diagnosis
and Treatment of Infectious Diseases, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Shengdian Huang
- Comprehensive
AIDS Research Center, and Department of Pharmacology and Pharmaceutical
Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Yuanhao Wang
- Comprehensive
AIDS Research Center, and Department of Pharmacology and Pharmaceutical
Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Xiaoqiang Lei
- Comprehensive
AIDS Research Center, and Department of Pharmacology and Pharmaceutical
Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Yunfei Wu
- Comprehensive
AIDS Research Center, and Department of Pharmacology and Pharmaceutical
Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
- Collaborative
Innovation Center for Biotherapy, State Key Laboratory of Biotherapy
and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China
| | - Zhilong Ma
- Comprehensive
AIDS Research Center, and Department of Pharmacology and Pharmaceutical
Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Linqi Zhang
- Comprehensive
AIDS Research Center, Collaborative Innovation Center for Diagnosis
and Treatment of Infectious Diseases, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Yefeng Tang
- Comprehensive
AIDS Research Center, and Department of Pharmacology and Pharmaceutical
Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
- Collaborative
Innovation Center for Biotherapy, State Key Laboratory of Biotherapy
and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China
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Hézode C, Alric L, Brown A, Hassanein T, Rizzetto M, Buti M, Bourlière M, Thabut D, Molina E, Rustgi V, Samuel D, McPhee F, Liu Z, Yin PD, Hughes E, Treitel M. Randomized controlled trial of the NS5A inhibitor daclatasvir plus pegylated interferon and ribavirin for HCV genotype-4 (COMMAND-4). Antivir Ther 2015; 21:195-205. [PMID: 26313445 DOI: 10.3851/imp2985] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/16/2015] [Indexed: 10/23/2022]
Abstract
BACKGROUND Treatment options for HCV genotype-4 (GT4) are limited. This Phase III study (COMMAND-4; AI444-042) evaluated the efficacy and safety of daclatasvir (DCV), a pan-genotypic HCV NS5A inhibitor, with pegylated interferon-α2a/ribavirin (PEG-IFN/RBV) in treatment-naive patients with HCV GT4 infection. METHODS Patients were randomly assigned (2:1; blinded) to treatment with DCV 60 mg (n=82) or placebo (n=42) once daily plus PEG-IFN 180 µg weekly and RBV 1,000-1,200 mg/day (weight-based) twice daily. DCV-treated patients with undetectable HCV RNA at weeks 4 and 12 (eRVR) received 24 weeks of DCV plus PEG-IFN/RBV; those without eRVR received an additional 24 weeks of PEG-IFN/RBV. All placebo-treated patients received 48 weeks of PEG-IFN/RBV. The primary end point was sustained virological response (SVR) at post-treatment week 12 (SVR12). RESULTS Patients were 75% IL28B non-CC and 11% had cirrhosis. SVR rates (HCV RNA < lower limit of quantitation [LLOQ]) at post-treatment week 12 or later (imputed to include patients missing SVR12 assessments but had SVR after post-treatment week 12) were 82% (67/82) with DCV plus PEG-IFN/RBV versus 43% (18/42) with PEG-IFN/RBV (P<0.0001). In DCV recipients, SVR12 rates were comparable across subgroups. The safety and tolerability profile of DCV plus PEG-IFN/RBV was comparable to that of PEG-IFN/RBV. Discontinuations due to adverse events occurred in 4.9% of patients receiving DCV plus PEG-IFN/RBV and 7.1% of patients receiving PEG-IFN/RBV. CONCLUSIONS In treatment-naive patients with HCV GT4 infection, DCV plus PEG-IFN/RBV achieved higher SVR12 rates than PEG-IFN/RBV alone. These data support DCV-based regimens for treatment of HCV GT4 infection, including all-oral combinations with other direct-acting antivirals (AI444-042; ClinicalTrials.gov NCT01448044).
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Affiliation(s)
- Christophe Hézode
- Hôpital Henri Mondor, AP-HP, Université Paris-Est, INSERM U955, Créteil, France.
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Spelman T, Morris MD, Zang G, Rice T, Page K, Maher L, Lloyd A, Grebely J, Dore GJ, Kim AY, Shoukry NH, Hellard M, Bruneau J. A longitudinal study of hepatitis C virus testing and infection status notification on behaviour change in people who inject drugs. J Epidemiol Community Health 2015; 69:745-52. [PMID: 25814695 PMCID: PMC4515217 DOI: 10.1136/jech-2014-205224] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Accepted: 02/26/2015] [Indexed: 12/20/2022]
Abstract
BACKGROUND Hepatitis C virus (HCV) testing and counselling have the potential to impact individual behaviour and transmission dynamics at the population level. Evidence of the impact of an HCV-positive status notification on injection risk reduction is limited. The objective of our study was to (1) assess drug and alcohol use and injection risk behaviours following notification; (2) to compare behaviour change in people who inject drugs (PWID) who received a positive test result and those who remained negative; and (3) to assess the effect of age on risk behaviour. METHODS Data from the International Collaboration of Incident HIV and HCV Infection in Injecting Cohorts (InC3 Study) were analysed. Participants who were initially HCV seronegative were followed prospectively with periodic HCV blood testing and post-test disclosure and interview-administered questionnaires assessing drug use and injection behaviours. Multivariable generalised estimating equations were used to assess behavioural changes over time. RESULTS Notification of an HCV-positive test was independently associated with a small increase in alcohol use relative to notification of a negative test. No significant differences in postnotification injection drug use, receptive sharing of ancillary injecting equipment and syringe borrowing postnotification were observed between diagnosis groups. Younger PWID receiving a positive HCV test notification demonstrated a significant increase in subsequent alcohol use compared with younger HCV negative. CONCLUSIONS The proportion of PWID reporting alcohol use increased among those receiving an HCV-positive notification, increased the frequency of alcohol use postnotification, while no reduction in injection drug use behaviours was observed between notification groups. These findings underscore the need to develop novel communication strategies during post-test notification to improve their impact on subsequent alcohol use and risk behaviours.
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Affiliation(s)
- T Spelman
- Centre of Population Health, Burnet Institute, Melbourne, Victoria, Australia
| | - M D Morris
- Department of Epidemiology & Biostatistics, University of California San Francisco, San Francisco, California, USA
| | - G Zang
- Centre Hospitalier de l'Université de Montréal Research Center (CRCHUM), Université de Montréal, Montréal, Canada
| | - T Rice
- Department of Epidemiology & Biostatistics, University of California San Francisco, San Francisco, California, USA
| | - K Page
- Department of Epidemiology, Biostatistics and Preventive Medicine, University of New Mexico Health Sciences Center
| | - L Maher
- Kirby Institute, UNSW Australia, Sydney, Australia
| | - A Lloyd
- UNSW Australia, Sydney, Australia
| | - J Grebely
- Kirby Institute, UNSW Australia, Sydney, Australia
| | - G J Dore
- Kirby Institute, UNSW Australia, Sydney, Australia
| | - A Y Kim
- Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - N H Shoukry
- Centre Hospitalier de l'Université de Montréal Research Center (CRCHUM), Université de Montréal, Montréal, Canada
| | - M Hellard
- Centre of Population Health, Burnet Institute, Melbourne, Victoria, Australia
| | - J Bruneau
- Centre Hospitalier de l'Université de Montréal Research Center (CRCHUM), Université de Montréal, Montréal, Canada
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Crespo J, Diago M, Cabezas J, Berenguer M, Broquetas T, Serra MÁ, Morillas R, García-Samaniego J, Calleja JL, Sánchez JJ, Lens S, Soto-Fernández S, Sacristán B, Fernández I, López-Núñez C, Buti M, Romero-Gómez M, Sáez-Royuela F, Fernández C, Jorquera F, Sánchez-Antolín G, Pascasio JM, Cuadrado A, Hernández-Guerra M. High efficacy and safety of triple therapy in HCV genotype 1 and moderate fibrosis: a multicenter study of clinical practice in Spain. Ann Hepatol 2015; 14:477-486. [PMID: 26019034 DOI: 10.1016/s1665-2681(19)31169-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/31/2023]
Abstract
BACKGROUND AND RATIONAL Telaprevir-based therapy (TBT) has been extensively evaluated in clinical trials. So we designed a study to compare the efficacy and safety of TBT between patients with moderate fibrosis and those suffering from advanced fibrosis in clinical practice. A multicenter observational and ambispective study was conducted. It included 582 patients with chronic hepatitis C genotype 1, 214 with fibrosis F2, and 368 with F3/F4 (F3: 148; F4: 220). RESULTS The mean patient age was 55 years, 67% male. Type of prior response was 22% naïve, 57% relapsers, and 21% partial/null responders, 69% had high viral load (> 800,000 IU/mL). HCV genotypes were 1a (19%), 1b (69%), and 1 (12%), respectively. Sixty-five percent were non-CC IL28B genotype. Week-12 sustained virologic response (SVR12) was significantly higher among F2-naïve patients (78%) compared with F3/F4-naïve patients (60%; p = 0.039) and among F2 non-responders (67%) compared with F3/F4 non-responders (42%; p = 0.014). SVR12 among relapsers was remarkably high in both groups (F2:89% vs. F3/F4:78%). Severe anemia and thrombocytopenia were more frequent among patients with F3/F4 than those with F2 (p < 0.01). Overall, 132 patients (22%) discontinued treatment: 58 due to adverse effects, 42 due to the stopping-rule, and 32 due to breakthrough. Premature discontinuation was more frequent among patients with F3/F4 (p = 0.028), especially due to breakthrough (p < 0.001). CONCLUSIONS This multicenter study demonstrates high efficacy and an acceptable safety profile with regard to TBT in F2-patients in clinical practice.
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Affiliation(s)
- Javier Crespo
- Hospital Universitario Marqués de Valdecilla and IDIVAL. Santander. Spain
| | | | - Joaquín Cabezas
- Hospital Universitario Marqués de Valdecilla and IDIVAL. Santander. Spain
| | | | | | | | - Rosa Morillas
- Hospital Universitario Trías y Pujol and CIBERehd. Badalona. Spain
| | | | | | | | - Sabela Lens
- Hospital Clinic, IDIBAPS and CIBERehd. Barcelona. Spain
| | | | | | | | | | - María Buti
- Hospital Universitario del Vall d'Hebrón and CIEBRehd. Barcelona. Spain
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49
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Novel benzidine and diaminofluorene prolinamide derivatives as potent hepatitis C virus NS5A inhibitors. Eur J Med Chem 2015; 101:163-78. [PMID: 26134551 DOI: 10.1016/j.ejmech.2015.06.033] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Revised: 06/14/2015] [Accepted: 06/15/2015] [Indexed: 12/21/2022]
Abstract
Our study describes the discovery of a series of highly potent hepatitis C virus (HCV) NS5A inhibitors based on symmetrical prolinamide derivatives of benzidine and diaminofluorene. Through modification of benzidine, l-proline, and diaminofluorene derivatives, we developed novel inhibitor structures, which allowed us to establish a library of potent HCV NS5A inhibitors. After optimizing the benzidine prolinamide backbone, we identified inhibitors embedding meta-substituted benzidine core structures that exhibited the most potent anti-HCV activities. Furthermore, through a battery of studies including hERG ligand binding assay, CYP450 binding assay, rat plasma stability test, human liver microsomal stability test, and pharmacokinetic studies, the identified compounds 24, 26, 27, 42, and 43 are found to be nontoxic, and are expected to be effective therapeutic anti-HCV agents.
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50
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Tong YQ, Liu B, Liu H, Zheng HY, Gu J, Liu H, Song EJ, Song C, Li Y. Accurate genotyping of hepatitis C virus through nucleotide sequencing and identification of new HCV subtypes in China population. Clin Microbiol Infect 2015; 21:874.e9-874.e21. [PMID: 26055416 DOI: 10.1016/j.cmi.2015.05.034] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Revised: 05/10/2015] [Accepted: 05/26/2015] [Indexed: 12/21/2022]
Abstract
Nucleotide sequencing of the phylogenetically informative region of NS5B remains the gold standard for hepatitis C virus (HCV) genotyping. Here we developed a new methodology for sequencing new NS5B regions to increase the accuracy and sensitivity of HCV genotyping and subtyping. The eight new primers were identified by scanning the full-length NS5B regions from 1127 HCV genomic sequences found in HCV databases. The ability of each pair of primers to amplify HCV subtypes was scored, and the new primers were able to amplify the NS5B region better than the previously used primers, therefore more accurately subtyping HCV strains. Sequencing the DNA amplified by the new primer pairs can specifically and correctly detect the five standard HCV subtypes (1a, 2a, 3b, 6a and 1b). We further examined patient samples and found that the new primers were able to identify HCV subtypes in clinical samples with high sensitivity. This method was able to detect all subtypes of HCV in 567 clinical samples. Importantly, three novel HCV subtypes (1b-2a, 1b-2k and 6d-6k) were identified in the samples, which have not been previous reported in China. In conclusion, sequencing the NS5B region amplified by the new NS5B primers is a more reliable method of HCV genotyping and a more sensitive diagnostic tool than sequencing using the previously described primers, and could identify new HCV subtypes. Our research is useful for clinical diagnosis, guidance of clinical treatment, management of clinical patients, and studies on the epidemiology of HCV.
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Affiliation(s)
- Y-Q Tong
- Department of Clinical Laboratory, China; Clinical Molecular Diagnostic Centre, Renmin Hospital of Wuhan University, Wuhan, China
| | - B Liu
- Department of Pathology, Affiliated Tianyou Hospital of Wuhan University of Science and Technology, Wuhan, China
| | - H Liu
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - H-Y Zheng
- Clinical Molecular Diagnostic Centre, Renmin Hospital of Wuhan University, Wuhan, China
| | - J Gu
- Department of Clinical Laboratory, China
| | - H Liu
- Clinical Molecular Diagnostic Centre, Renmin Hospital of Wuhan University, Wuhan, China
| | - E J Song
- Pennsylvania State University College of Medicine and Hershey Medical Center, Hershey, PA, USA
| | - C Song
- Pennsylvania State University College of Medicine and Hershey Medical Center, Hershey, PA, USA.
| | - Y Li
- Department of Clinical Laboratory, China; Clinical Molecular Diagnostic Centre, Renmin Hospital of Wuhan University, Wuhan, China.
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