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Arefinia N, Askarpour H, Ghoreshi ZAS, Mashayekhi-Sardoo H, Ali-Hassanzadeh M. The global prevalence of co-occurrence of Sjögren syndrome and Hepatitis C virus infection: A systematic review and meta-analysis. Virus Res 2025; 357:199585. [PMID: 40374124 PMCID: PMC12148365 DOI: 10.1016/j.virusres.2025.199585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 05/10/2025] [Accepted: 05/12/2025] [Indexed: 05/17/2025]
Abstract
Sjögren syndrome (SS) is one of the lesser-known autoimmune diseases, with its mechanisms and pathogenesis not yet fully understood. However, recent studies indicate that infectious diseases, such as Hepatitis C virus (HCV) infection, may serve as risk factors for the development of SS. Accordingly, this study aimed to estimate the global co-occurrence rate of chronic HCV infection and SS. In this systematic review and meta-analysis, a comprehensive search for relevant studies was conducted in PubMed, Scopus, ISI Web of Science, and Google Scholar databases up to June 2024. Data from eligible studies were meticulously extracted and statistically analyzed using Comprehensive Meta-Analysis Software. The pooled prevalence of co-occurrence of HCV and SS was calculated using incidence rates with 95 % confidence intervals (CIs), and the association of chronic HCV infection with the development of SS was assessed via odds ratios (ORs) with 95 % CIs. Analysis of the articles retrieved from the databases showed 24 studies were considered eligible. The pooled estimate for the co-occurrence of HCV and SS was approximately 16.6 % (95 % CI: 8.8-28.9). Moreover, the results indicated that chronic HCV infection significantly increased the risk of developing SS (OR: 2.76; 95 % CI: 1.35-5.63). This study's findings revealed that HCV infection may play a role in the pathogenesis of and susceptibility to SS. Therefore, chronic HCV infection may trigger the onset of SS. However, further studies are required to confirm these results.
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Affiliation(s)
- Nasir Arefinia
- Bio Environmental Health Hazards Research Center, Jiroft University of Medical Sciences, Jiroft, Iran; School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran; Student Research Committee, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Hedyeh Askarpour
- Student Research Committee, Jiroft University of Medical Sciences, Jiroft, Iran; Clinical Research Development Center of Imam Khomeini Hospital, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Zohreh-Al-Sadat Ghoreshi
- Bio Environmental Health Hazards Research Center, Jiroft University of Medical Sciences, Jiroft, Iran; School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran; Student Research Committee, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Habibeh Mashayekhi-Sardoo
- Bio Environmental Health Hazards Research Center, Jiroft University of Medical Sciences, Jiroft, Iran; Student Research Committee, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Mohammad Ali-Hassanzadeh
- Bio Environmental Health Hazards Research Center, Jiroft University of Medical Sciences, Jiroft, Iran; School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran; Department of Immunology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran.
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Pereira CM, Shimizu JF, Cassani NM, Santos IA, Bittar C, Oliveira Cintra AC, Sampaio SV, Harris M, Rahal P, Gomes Jardim AC. Bothropstoxins I and II as potent phospholipase A2 molecules from Bothrops jararacussu to impair Hepatitis C virus infection. Biochimie 2025:S0300-9084(25)00081-1. [PMID: 40288437 DOI: 10.1016/j.biochi.2025.04.006] [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: 06/25/2024] [Revised: 03/26/2025] [Accepted: 04/18/2025] [Indexed: 04/29/2025]
Abstract
Hepatitis C is a hepatological disorder induced by the Hepacivirus hominis (Hepatitis C virus, HCV), with approximately 170 million individuals estimated to be presently affected globally. The current treatment for infected patients primarily relies on direct-acting antivirals (DAAs). However, this treatment is marked by its high cost, numerous side effects, and documented instances of antiviral resistance. These challenges underscore the imperative for developing novel therapeutic strategies. In this framework, naturally occurring compounds have exhibited considerable medical significance attributable to their biological functionalities. Compounds extracted from snake venoms have evidenced antiviral efficacy against a variety of viral pathogens including Orthoflavivirus denguei (DENV), Orthoflavivirus flavi (YFV), Orthoflavivirus zikaense (ZIKV), and HCV. Here, the activity of 10 proteins isolated from snakes' venom of Bothrops genus were evaluated against HCV replicative cycle. The full-length JFH-1 HCV system was used to infect the Huh-7.5 cell. Cell viability was measured simultaneously through MTT assay. Eight compounds inhibited up to 99% of HCV infection, being the most potent inhibitory rates observed in BthTX-I and BthTX-II, with an SI of 13.5 and 1736, respectively, being able to block 84.7% and 96% of HCV infectivity, in the same order. BthTX-II also demonstrated a protective effect in cells treated prior to HCV infection of approximately 86.7%. Molecular docking calculations suggest interactions between the two proteins with HCV E1-E2 glycoprotein complex. BthTX-II exhibited stronger interactions, indicated by 22 hydrophobic interactions. In conclusion, these compounds were shown to inhibit HCV infectivity by either acting on the virus particles or protecting the cells against infection.
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Affiliation(s)
- Carina Machado Pereira
- Genomics Study Laboratory, São Paulo State University, IBILCE, S. José do Rio Preto, SP, Brazil
| | - Jacqueline Farinha Shimizu
- Genomics Study Laboratory, São Paulo State University, IBILCE, S. José do Rio Preto, SP, Brazil; Laboratory of Antiviral Research, Institute of Biomedical Science, ICBIM, Federal University of Uberlândia, Uberlândia, MG, Brazil
| | - Natasha Marques Cassani
- Laboratory of Antiviral Research, Institute of Biomedical Science, ICBIM, Federal University of Uberlândia, Uberlândia, MG, Brazil
| | - Igor Andrade Santos
- Laboratory of Antiviral Research, Institute of Biomedical Science, ICBIM, Federal University of Uberlândia, Uberlândia, MG, Brazil
| | - Cintia Bittar
- Genomics Study Laboratory, São Paulo State University, IBILCE, S. José do Rio Preto, SP, Brazil
| | | | - Suely Vilela Sampaio
- Laboratory of Toxinology, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, SP, Brazil
| | - Mark Harris
- School of Molecular and Cellular Biology, Faculty of Biological Sciences and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom
| | - Paula Rahal
- Genomics Study Laboratory, São Paulo State University, IBILCE, S. José do Rio Preto, SP, Brazil
| | - Ana Carolina Gomes Jardim
- Genomics Study Laboratory, São Paulo State University, IBILCE, S. José do Rio Preto, SP, Brazil; Laboratory of Antiviral Research, Institute of Biomedical Science, ICBIM, Federal University of Uberlândia, Uberlândia, MG, Brazil.
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3
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Piracha ZZ, Saeed U, Uppal R, Uppal MR, Khan AA, Abdullah M, Mari K, Basra A, Gilani SS, Tariq MN, Ozsahin DU, Uzun B, Ozsahin I. Prevalence and clinical profile of hepatitis C virus infections in multitransfused thalassemic patients in the capital twin cities of Pakistan. BRAZ J BIOL 2025; 84:e284453. [PMID: 39879500 DOI: 10.1590/1519-6984.284453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 08/12/2024] [Indexed: 01/31/2025] Open
Abstract
Hepatitis C virus (HCV) presents a significant global health concern, affecting 3.3% of the world's population. The primary mode of HCV transmission is through blood and blood products. Patients with beta thalassemia, who rely on lifelong blood transfusions, are particularly vulnerable to HCV infections. This study aimed to assess the prevalence of hepatitis C virus infections among multitransfused thalassemic patients in the twin cities of Pakistan's capital. The clinical research, involving the enrollment of 262 multitransfused beta thalassemic patients residing in the capital twin cities of Pakistan. The investigation encompassed the evaluation of hepatitis C virus presence, alanine aminotransferase (ALT) levels, serum creatinine, hepatomegaly, splenomegaly, and the occurrence of splenectomy. The overall prevalence of Hepatitis C virus infections was notably high at 55.73%. This was particularly pronounced among patients aged 20 years and older, with a 100% infection rate. In HCV-positive thalassemic patients, the average ALT level was observed to be 98 U/L, while average creatinine values stood at 0.39 mg/dL. Additionally, hepatomegaly was prevalent in 82.20% of HCV-positive thalassemic patients, featuring an average liver size increase of 4.33 cm. Splenomegaly was evident in 67.12% of HCV-positive thalassemic patients, with an average spleen size augmentation of 4.46 cm. Splenectomy was identified in 15.75% of cases. The incidence of HCV infections in the thalassemic population of Pakistan is alarmingly high. Furthermore, the risk of contracting HCV infections escalates with the advancing age of thalassemic patients. Elevated ALT levels and hepatomegaly were pervasive among the majority of HCV-positive thalassemic patients. Consequently, there is a compelling need for rigorous screening of blood products prior to transfusion to mitigate the future burden of HCV in Pakistan.
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Affiliation(s)
- Z Z Piracha
- Al-Mizan Islamic International Medical College Trust (IIMCT) Complex, Riphah International University, Faculty of Rehabilitation and Allied Health Sciences, Rawalpindi, Pakistan
- International Center of Medical Sciences Research - ICMSR, Islamabad, Pakistan
- International Center of Medical Sciences Research - ICMSR, Austin, TX, USA
- International Center of Medical Sciences Research - ICMSR, Essex, United Kingdom
| | - U Saeed
- Operational Research Center in Healthcare, Near East University, Mersin, Turkey
- Islamabad Diagnostic Center - IDC, Islamabad, Pakistan
| | - R Uppal
- Islamabad Diagnostic Center - IDC, Islamabad, Pakistan
| | - M R Uppal
- Islamabad Diagnostic Center - IDC, Islamabad, Pakistan
| | - A Ahmad Khan
- Islamabad Diagnostic Center - IDC, Islamabad, Pakistan
| | - M Abdullah
- Akhtar Saeed Medical and Dental College, Lahore, Pakistan
| | - K Mari
- Ziauddin Medical College, Karachi, Pakistan
| | - A Basra
- Akhtar Saeed Medical and Dental College, Lahore, Pakistan
| | - S S Gilani
- Akhtar Saeed Medical and Dental College, Lahore, Pakistan
| | - M N Tariq
- Akhtar Saeed Medical and Dental College, Lahore, Pakistan
| | - D U Ozsahin
- Operational Research Center in Healthcare, Near East University, Mersin, Turkey
- University of Sharjah, College of Health Sciences, Medical Diagnostic Imaging Department, Sharjah, United Arab Emirates
- University of Sharjah, Research Institute for Medical and Health Sciences, Sharjah, United Arab Emirates
| | - B Uzun
- Operational Research Center in Healthcare, Near East University, Mersin, Turkey
| | - I Ozsahin
- Operational Research Center in Healthcare, Near East University, Mersin, Turkey
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Bui TI, Brown AP, Brown M, Lawless S, Roemmich B, Anderson NW, Farnsworth CW. Comparison of a dual antibody and antigen HCV immunoassay to standard of care algorithmic testing. J Clin Microbiol 2024; 62:e0083224. [PMID: 39283072 PMCID: PMC11481485 DOI: 10.1128/jcm.00832-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 08/15/2024] [Indexed: 10/17/2024] Open
Abstract
The Centers for Disease Control and Prevention (CDC) guidelines for hepatitis C virus (HCV) testing, although effective, may miss crucial diagnostic opportunities. The goal of this study was to assess the utility of an antibody (Ab) and antigen (Ag) combination immunoassay as an alternative to traditional HCV screening. Remnant specimens from 1,341 patients with concurrent third-generation serologic (Roche anti-HCV-II) and nucleic acid amplification testing (NAAT) were assessed using the HCV Duo Ab/Ag immunoassay (Roche). Patient demographics, risk factors, and standard of care (SOC) laboratory results from the medical records were recorded. Overall, 99.0% (197/199) of the HCV Duo Ab+/Ag+specimens accurately identified active infections as confirmed by NAAT, and 99.9% (670/671) Ab-/Ag- samples corresponded to those without HCV infections. Individually, the HCV Duo Ab component demonstrated a 95.6% positive percent agreement (PPA) (95% CI = 93.8-96.9) and 99.1% negative percent agreement (NPA) (98.8-99.6) compared with SOC anti-HCV II Ab assay. The HCV Duo Ag had a 73.5% PPA (67.9-78.4) and 99.8% NPA (99.3-100) with NAAT. Among RNA+ specimens, 73.4% (197/267) were HCV Duo Ag+, and 265/267 (99.3%) were successfully detected on the HCV Duo Ab component. Notably, 5/7 (71.4%) Ab-/RNA +specimens were detected by HCV Duo, which would have been missed by traditional algorithmic testing. Fourth generation HCV Duo Ab/Ag assay demonstrated comparable performance to SOC testing and shortens the diagnostic window but does not eliminate the need for NAAT in all patients. Ab/Ag testing identified several Ab-/RNA+ cases, a subgroup often undiagnosed by current algorithmic testing, demonstrating promise for improved diagnostic efficiency and accuracy in HCV detection.IMPORTANCEThis study highlights the potential of a combined hepatitis C virus (HCV) Duo antibody (Ab) and antigen (Ag) immunoassay to improve early detection of HCV infections. Traditional Ab-only screening methods recommended by the Centers for Disease Control and Prevention may miss early-stage infections. The HCV Duo assay showed high accuracy, detecting nearly all active infections confirmed by nucleic acid amplification testing. Dual detection of HCV Ab and Ag shortens the diagnostic window, enabling intervention and treatment in a single visit, which is crucial for improving patient outcomes and reducing HCV transmission, especially in areas with limited access to confirmatory molecular testing.
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Affiliation(s)
- Tina I. Bui
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, Saint Louis, Missouri, USA
| | - Abigail P. Brown
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, Saint Louis, Missouri, USA
| | - Meghan Brown
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, Saint Louis, Missouri, USA
| | - Sydney Lawless
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, Saint Louis, Missouri, USA
| | - Brittany Roemmich
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, Saint Louis, Missouri, USA
| | - Neil W. Anderson
- Department of Pathology, University Hospitals Health System, Cleveland, Ohio, USA
| | - Christopher W. Farnsworth
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, Saint Louis, Missouri, USA
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Quirino A, Marascio N, Branda F, Ciccozzi A, Romano C, Locci C, Azzena I, Pascale N, Pavia G, Matera G, Casu M, Sanna D, Giovanetti M, Ceccarelli G, Alaimo di Loro P, Ciccozzi M, Scarpa F, Maruotti A. Viral Hepatitis: Host Immune Interaction, Pathogenesis and New Therapeutic Strategies. Pathogens 2024; 13:766. [PMID: 39338957 PMCID: PMC11435051 DOI: 10.3390/pathogens13090766] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 08/30/2024] [Accepted: 09/02/2024] [Indexed: 09/30/2024] Open
Abstract
Viral hepatitis is a major cause of liver illness worldwide. Despite advances in the understanding of these infections, the pathogenesis of hepatitis remains a complex process driven by intricate interactions between hepatitis viruses and host cells at the molecular level. This paper will examine in detail the dynamics of these host-pathogen interactions, highlighting the key mechanisms that regulate virus entry into the hepatocyte, their replication, evasion of immune responses, and induction of hepatocellular damage. The unique strategies employed by different hepatitis viruses, such as hepatitis B, C, D, and E viruses, to exploit metabolic and cell signaling pathways to their advantage will be discussed. At the same time, the innate and adaptive immune responses put in place by the host to counter viral infection will be analyzed. Special attention will be paid to genetic, epigenetic, and environmental factors that modulate individual susceptibility to different forms of viral hepatitis. In addition, this work will highlight the latest findings on the mechanisms of viral persistence leading to the chronic hepatitis state and the potential implications for the development of new therapeutic strategies. Fully understanding the complex host-pathogen interactions in viral hepatitis is crucial to identifying new therapeutic targets, developing more effective approaches for treatment, and shedding light on the mechanisms underlying progression to more advanced stages of liver damage.
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Affiliation(s)
- Angela Quirino
- Unit of Clinical Microbiology, Department of Health Sciences, “Magna Græcia” University of Catanzaro “Renato Dulbecco” Teaching Hospital, 88100 Catanzaro, Italy; (A.Q.); (N.M.); (G.P.); (G.M.)
| | - Nadia Marascio
- Unit of Clinical Microbiology, Department of Health Sciences, “Magna Græcia” University of Catanzaro “Renato Dulbecco” Teaching Hospital, 88100 Catanzaro, Italy; (A.Q.); (N.M.); (G.P.); (G.M.)
| | - Francesco Branda
- Unit of Medical Statistics and Molecular Epidemiology, Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (C.R.); (M.C.)
| | - Alessandra Ciccozzi
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (A.C.); (C.L.); (D.S.); (F.S.)
| | - Chiara Romano
- Unit of Medical Statistics and Molecular Epidemiology, Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (C.R.); (M.C.)
| | - Chiara Locci
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (A.C.); (C.L.); (D.S.); (F.S.)
- Department of Veterinary Medicine, University of Sassari, 07100 Sassari, Italy; (I.A.); (N.P.); (M.C.)
| | - Ilenia Azzena
- Department of Veterinary Medicine, University of Sassari, 07100 Sassari, Italy; (I.A.); (N.P.); (M.C.)
| | - Noemi Pascale
- Department of Veterinary Medicine, University of Sassari, 07100 Sassari, Italy; (I.A.); (N.P.); (M.C.)
- Department of Chemical Physical Mathematical and Natural Sciences, University of Sassari, 07100 Sassari, Italy
| | - Grazia Pavia
- Unit of Clinical Microbiology, Department of Health Sciences, “Magna Græcia” University of Catanzaro “Renato Dulbecco” Teaching Hospital, 88100 Catanzaro, Italy; (A.Q.); (N.M.); (G.P.); (G.M.)
| | - Giovanni Matera
- Unit of Clinical Microbiology, Department of Health Sciences, “Magna Græcia” University of Catanzaro “Renato Dulbecco” Teaching Hospital, 88100 Catanzaro, Italy; (A.Q.); (N.M.); (G.P.); (G.M.)
| | - Marco Casu
- Department of Veterinary Medicine, University of Sassari, 07100 Sassari, Italy; (I.A.); (N.P.); (M.C.)
| | - Daria Sanna
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (A.C.); (C.L.); (D.S.); (F.S.)
| | - Marta Giovanetti
- Department of Sciences and Technologies for Sustainable Development and One Health, Università Campus Bio-Medico di Roma, 00128 Rome, Italy;
- Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte 30190-002, MG, Brazil
- Climate Amplified Diseases and Epidemics (CLIMADE), Brasilia 70070-130, GO, Brazil
| | - Giancarlo Ceccarelli
- Department of Public Health and Infectious Diseases, University Hospital Policlinico Umberto I, Sapienza University of Rome, 00161 Rome, Italy;
| | | | - Massimo Ciccozzi
- Unit of Medical Statistics and Molecular Epidemiology, Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (C.R.); (M.C.)
| | - Fabio Scarpa
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (A.C.); (C.L.); (D.S.); (F.S.)
| | - Antonello Maruotti
- Department GEPLI, Libera Università Maria Ss Assunta, 00193 Rome, Italy;
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Odeny TA, Fink V, Muchengeti M, Gopal S. Cancer in People with HIV. Infect Dis Clin North Am 2024; 38:531-557. [PMID: 39111924 PMCID: PMC11529824 DOI: 10.1016/j.idc.2024.06.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2024]
Abstract
We review the intersection of human immunodeficiency virus (HIV) and cancer globally, including the complex interplay of oncogenic infections, chronic inflammation, and behavioral and other factors in increasing cancer risk among people with HIV (PWH). We discuss current cancer screening, prevention, and treatment recommendations for PWH. Specific interventions include vaccination, behavioral risk reduction, timely HIV diagnosis and treatment, screening for specific cancer sites, and multifaceted treatment considerations unique to PWH including supportive care and drug interactions. Finally, the potential of novel therapies and the need for inclusive cancer clinical trials are highlighted. Collaborative multidisciplinary efforts are critical for continued progress against cancer among PWH.
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Affiliation(s)
- Thomas A Odeny
- Division of Oncology, Department of Medicine, Washington University School of Medicine, 660 S. Euclid Ave., CB 8056, St. Louis, MO 63110-1093, USA
| | - Valeria Fink
- Research Department, Fundación Huésped, Av. Forest 345 (C1427CEA) Buenos Aires, Argentina
| | - Mazvita Muchengeti
- School of Public Health, University of the Witwatersrand, Johannesburg, South Africa; South African DSI-NRF Centre of Excellence in Epidemiological Modelling and Analysis (SACEMA), Stellenbosch University, South Africa
| | - Satish Gopal
- Center for Global Health, National Cancer Institute, 9609 Medical Center Drive, Rockville MD 20850, USA.
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Tok D. Analysis of articles on hepatitis C by scientific mapping: 1989-2022. World J Clin Cases 2024; 12:4301-4316. [PMID: 39015889 PMCID: PMC11235547 DOI: 10.12998/wjcc.v12.i20.4301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 05/01/2024] [Accepted: 05/24/2024] [Indexed: 06/30/2024] Open
Abstract
BACKGROUND Hepatitis C virus (HCV) poses a significant quandary about public health. It is challenging to study the literature in a particular discipline comprehensively today. One solution is bibliometric analysis, which is often used to track the attributes and evolutionary trajectories of scientific outputs. AIM To examine the 35-year scientific evolution of articles focused on HCV. METHODS This study examined the 35-year scientific evolution of articles focused on HCV. Our study utilized the Web of Science database. The study encompassed a total of 11930 articles. RESULTS Regarding the cumulative count of articles, the leading countries are the United States, Japan, and Italy. Rice CM is the author with the highest recorded H-index and G-index values. The journal with the highest recorded H-index and G-index values is the Journal of Virology. The Journal of Viral Hepatitis contributed 10.94% of the articles, whereas the Journal of Virology published 9.68%. According to the strategic diagram, the keywords most frequently used in 2020-2022 are HCV, epidemiology, and sofosbuvir. CONCLUSION This study provides valuable information about 40 years of academic knowledge on HCV.
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Affiliation(s)
- Duran Tok
- Department of Infectious Diseases, Liv Hospital, Ankara 06100, Türkiye
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Basyte-Bacevice V, Kupcinskas L. Viral Hepatitis C: From Unraveling the Nature of Disease to Cure and Global Elimination. Dig Dis 2024; 42:486-495. [PMID: 38718765 DOI: 10.1159/000539210] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 04/23/2024] [Indexed: 06/13/2024]
Abstract
BACKGROUND The discovery of the hepatitis C virus (HCV) and direct-acting antiviral (DAA) drugs is one of the major milestones in the last 3 decades of medicine. These discoveries encouraged the World Health Organization (WHO) to set an ambitious goal to eliminate HCV by 2030, meaning "a 90% reduction in new cases of chronic HCV, a 65% reduction in HCV deaths, and treatment of 80% of eligible people with HCV infections." SUMMARY This review summarizes the key achievements from the discovery of HCV to the development of effective treatment and global elimination strategies. A better understanding of HCV structure, enzymes, and lifecycle led to the introduction of new drug targets and the discovery of DAA. Massive public health interventions are required, such as screening, access to care, treatment, and post-care follow-up, to make the most of DAA's potential. Screening must be supported by fast, accessible, sensitive, specific HCV diagnostic tests and noninvasive methods to determine the stage of liver disease. Linkage to care and treatment access are critical components of a comprehensive HCV elimination program, and decentralization plays a key role in ensuring their effectiveness. KEY MESSAGES Effective and simple screening strategies, rapid diagnostic tools, linkage to health care, and accessible treatment are key elements to achieving the WHO's goal. Incorporating treatment as prevention strategies into elimination programs together with preventive education and harm reduction interventions can have a profound and lasting impact on reducing both the incidence and prevalence of HCV. However, WHO's goal can be challenging to implement because of the need for high financial resources and strong political commitment.
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Affiliation(s)
| | - Limas Kupcinskas
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
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Herron ICT, Laws TR, Nelson M. Marmosets as models of infectious diseases. Front Cell Infect Microbiol 2024; 14:1340017. [PMID: 38465237 PMCID: PMC10921895 DOI: 10.3389/fcimb.2024.1340017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 01/29/2024] [Indexed: 03/12/2024] Open
Abstract
Animal models of infectious disease often serve a crucial purpose in obtaining licensure of therapeutics and medical countermeasures, particularly in situations where human trials are not feasible, i.e., for those diseases that occur infrequently in the human population. The common marmoset (Callithrix jacchus), a Neotropical new-world (platyrrhines) non-human primate, has gained increasing attention as an animal model for a number of diseases given its small size, availability and evolutionary proximity to humans. This review aims to (i) discuss the pros and cons of the common marmoset as an animal model by providing a brief snapshot of how marmosets are currently utilized in biomedical research, (ii) summarize and evaluate relevant aspects of the marmoset immune system to the study of infectious diseases, (iii) provide a historical backdrop, outlining the significance of infectious diseases and the importance of developing reliable animal models to test novel therapeutics, and (iv) provide a summary of infectious diseases for which a marmoset model exists, followed by an in-depth discussion of the marmoset models of two studied bacterial infectious diseases (tularemia and melioidosis) and one viral infectious disease (viral hepatitis C).
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Affiliation(s)
- Ian C. T. Herron
- CBR Division, Defence Science and Technology Laboratory (Dstl), Salisbury, United Kingdom
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Dong J, Ismail N, Fitts E, Walker DH. Molecular testing in emerging infectious diseases. DIAGNOSTIC MOLECULAR PATHOLOGY 2024:175-198. [DOI: 10.1016/b978-0-12-822824-1.00011-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Irfan A, Faisal S, Ahmad S, Saif MJ, Zahoor AF, Khan SG, Javid J, Al-Hussain SA, Muhammed MT, Zaki MEA. An Exploration of the Inhibitory Mechanism of Rationally Screened Benzofuran-1,3,4-Oxadiazoles and-1,2,4-Triazoles as Inhibitors of NS5B RdRp Hepatitis C Virus through Pharmacoinformatic Approaches. Biomedicines 2023; 11:3085. [PMID: 38002085 PMCID: PMC10669698 DOI: 10.3390/biomedicines11113085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 11/02/2023] [Accepted: 11/03/2023] [Indexed: 11/26/2023] Open
Abstract
Benzofuran, 1,3,4-oxadiazole, and 1,2,4-triazole are privileged heterocyclic moieties that display the most promising and wide spectrum of biological activities against a wide variety of diseases. In the current study, benzofuran-1,3,4-oxadiazole BF1-BF7 and benzofuran-1,2,4-triazole compounds BF8-BF15 were tested against HCV NS5B RNA-dependent RNA polymerase (RdRp) utilizing structure-based screening via a computer-aided drug design (CADD) approach. A molecular docking approach was applied to evaluate the binding potential of benzofuran-appended 1,3,4-oxadiazole and 1,2,4-triazole BF1-BF15 molecules. Benzofuran-1,3,4-oxadiazole scaffolds BF1-BF7 showed lesser binding affinities (-12.63 to -14.04 Kcal/mol) than benzofuran-1,2,4-triazole scaffolds BF8-BF15 (-14.11 to -16.09 Kcal/mol) against the HCV NS5B enzyme. Molecular docking studies revealed the excellent binding affinity scores exhibited by benzofuran-1,2,4-triazole structural motifs BF-9 (-16.09 Kcal/mol), BF-12 (-15.75 Kcal/mol), and BF-13 (-15.82 Kcal/mol), respectively, which were comparatively better than benzofuran-based HCV NS5B inhibitors' standard reference drug Nesbuvir (-15.42 Kcal/mol). A molecular dynamics simulation assay was also conducted to obtain valuable insights about the enzyme-compounds interaction profile and structural stability, which indicated the strong intermolecular energies of the BF-9+NS5B complex and the BF-12+NS5B complex as per the MM-PBSA method, while the BF-12+NS5B complex was the most stable system as per the MM-GBSA calculation. The drug-likeness and ADMET studies of all the benzofuran-1,2,4-triazole derivatives BF8-BF15 revealed that these compounds possessed good medicinal chemistry profiles in agreement with all the evaluated parameters for being drugs. The molecular docking affinity scores, MM-PBSA/MM-GBSA and MD-simulation stability analysis, drug-likeness profiling, and ADMET study assessment indicated that N-4-fluorophenyl-S-linked benzofuran-1,2,4-triazole BF-12 could be a future promising anti-HCV NS5B RdRp inhibitor therapeutic drug candidate that has a structural agreement with the Nesbuvir standard reference drug.
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Affiliation(s)
- Ali Irfan
- Department of Chemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan; (A.I.); (A.F.Z.)
| | - Shah Faisal
- Department of Chemistry, Islamia College University Peshawar, Peshawar 25120, Pakistan
| | - Sajjad Ahmad
- Department of Health and Biological Sciences, Abasyn University Peshawar, Peshawar 25000, Pakistan
- Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Beirut P.O. Box 36, Lebanon
- Department of Natural Sciences, Lebanese American University, Beirut P.O. Box 36, Lebanon
| | - Muhammad Jawwad Saif
- Department of Applied Chemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan
| | - Ameer Fawad Zahoor
- Department of Chemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan; (A.I.); (A.F.Z.)
| | - Samreen Gul Khan
- Department of Chemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan; (A.I.); (A.F.Z.)
| | - Jamila Javid
- Department of Chemistry, University of Sialkot, Sialkot 51040, Pakistan
| | - Sami A. Al-Hussain
- Department of Chemistry, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 13623, Saudi Arabia
| | - Muhammed Tilahun Muhammed
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Suleyman Demirel University, Isparta 32260, Turkey
| | - Magdi E. A. Zaki
- Department of Chemistry, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 13623, Saudi Arabia
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12
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Saaed FMA, Ongerth JE. Prevalence of Hepatitis B and Hepatitis C in Migrants from Sub-Saharan Africa Before Onward Dispersal Toward Europe. J Immigr Minor Health 2023; 25:882-888. [PMID: 36640255 PMCID: PMC10310585 DOI: 10.1007/s10903-022-01448-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/27/2022] [Indexed: 01/15/2023]
Abstract
Viral hepatitis is a global health care challenge due to its worldwide distribution, chronic persistence, complications, and high prevalence with unchecked conditions in areas like sub-Saharan Africa. A high proportion of asymptomatic infections allows serious complications and poses infection risk to destination populations. This study aimed to determine the prevalence of both HBV and HCV among 3248 migrants from different parts of sub-Saharan Africa newly arrived at Kufra, Libya, a remote agricultural North African city. All these migrants were required by the Libyan authorities to undergo a complete medical check-up for different purposes such as joining new jobs, and obtaining licenses for trade and commerce. UAT sera from 3248 migrants, aged 18-53 years, attending the Al Kufra city hospital from January 01 to December 31, 2019, were screened for HBsAg and anti-HCV antibody by rapid tests and positive samples were further tested by ELISA method. The results showed that 761/3248 (23.4%) of the migrants were positive for HBV and 1014/3248 (31.2%) were positive for HCV. Migrants from sub-Saharan Africa carry high rates of HBV and HCV infection. This suggests the importance of increased attention to actions to deal with findings among positive migrants, and for awareness about risks of transmission to the local population. Study results indicate the value of routine migrant monitoring, the need for awareness in destination country health authorities, and the potential for impact on migrant destination populations.
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Affiliation(s)
- Frhat M A Saaed
- Department of Zoology, College of Arts and Sciences, Benghazi University, Al Kufra, Libya
| | - Jerry E Ongerth
- Environmental Engineering, University of Wollongong, Wollongong, NSW, 2522, Australia.
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13
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Brzdęk M, Dobrowolska K, Flisiak R, Zarębska-Michaluk D. Genotype 4 hepatitis C virus-a review of a diverse genotype. Adv Med Sci 2023; 68:54-59. [PMID: 36640687 DOI: 10.1016/j.advms.2022.12.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 12/02/2022] [Accepted: 12/21/2022] [Indexed: 01/15/2023]
Abstract
PURPOSE Hepatitis C virus (HCV) infection remains a major health problem and one of the leading causes of chronic liver disease worldwide. The purpose of this paper was to summarize knowledge about the epidemiology of HCV genotype (GT) 4 infection, similarities and differences with other genotypes, specific problems associated with this genotype, and treatment regimens used to treat GT4-infected patients. METHODS We performed an accurate search for literature using the PubMed database to select high-quality reviews and original articles concerning this topic. RESULTS GT4 with a global prevalence of 8% takes third place, closing the global HCV podium in terms of frequency. However, there are regions where GT4 infections are dominant, such as sub-Saharan and North Africa, and the Middle East. The disease course and complications are generally similar to those of chronic hepatitis C caused by other genotypes, although the faster progression of fibrosis was demonstrated in patients with coexisting schistosomiasis. In the era of interferon-based therapy, GT4-infected patients were described as difficult to treat due to suboptimal response. A breakthrough in the treatment of HCV-infected patients, including those with GT4 infection, was the introduction of direct-acting antiviral drugs. CONCLUSIONS The availability of safe and effective therapy has created a real opportunity for HCV eradication in line with the goal set by the World Health Organization. An example of a country where this is happening is Egypt, where GT4 accounts for more than 90% of HCV infections. There, broad access to therapy has been effectively supported by population-based screening.
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Affiliation(s)
- Michał Brzdęk
- Collegium Medicum, Jan Kochanowski University, Kielce, Poland.
| | | | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Bialystok, Poland
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14
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Santiago-Rodriguez TM, Hollister EB. Unraveling the viral dark matter through viral metagenomics. Front Immunol 2022; 13:1005107. [PMID: 36189246 PMCID: PMC9523745 DOI: 10.3389/fimmu.2022.1005107] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 08/31/2022] [Indexed: 11/13/2022] Open
Abstract
Viruses are part of the microbiome and have essential roles in immunology, evolution, biogeochemical cycles, health, and disease progression. Viruses influence a wide variety of systems and processes, and the continued discovery of novel viruses is anticipated to reveal new mechanisms influencing the biology of diverse environments. While the identity and roles of viruses continue to be discovered and understood through viral metagenomics, most of the sequences in virome datasets cannot be attributed to known viruses or may be only distantly related to species already described in public sequence databases, at best. Such viruses are known as the viral dark matter. Ongoing discoveries from the viral dark matter have provided insights into novel viruses from a variety of environments, as well as their potential in immunological processes, virus evolution, health, disease, therapeutics, and surveillance. Increased understanding of the viral dark matter will continue with a combination of cultivation, microscopy, sequencing, and bioinformatic efforts, which are discussed in the present review.
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The Quality Management Ecosystem in Cell Therapy in Catalonia (Spain): An Opportunity for Integrating Standards and Streamlining Quality Compliance. Cells 2022; 11:cells11132112. [PMID: 35805196 PMCID: PMC9265754 DOI: 10.3390/cells11132112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/25/2022] [Accepted: 07/02/2022] [Indexed: 12/04/2022] Open
Abstract
Cell therapies are required to meet with compulsory regulations that co-exist with other optional standards and guidelines that together compose a complex quality management system. Indeed, reliable insights on the mechanisms of action and safety of novel cell-based therapies require adherence to solid quality management structures in all steps of the value chain, from early research and tissue procurement to clinical trials and biovigilance, thus guaranteeing reproducibility and solid foundations for better science and improved clinical practice. Herein we present the concept of the quality ecosystem as a tool to understand and assist all stakeholders involved in developing and structuring the integration of standards as novel developments are taking place. We conclude that the various quality management initiatives can all be thought about under the umbrella of an ecosystem.
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16
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Hanif FM, Majid Z, Luck NH, Tasneem AA, Laeeq SM, Mubarak M. Revolution in the diagnosis and management of hepatitis C virus infection in current era. World J Hepatol 2022; 14:647-669. [PMID: 35646260 PMCID: PMC9099099 DOI: 10.4254/wjh.v14.i4.647] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 02/05/2022] [Accepted: 04/02/2022] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection is a major global public health problem, particularly in developing part of the world. Significant advances have been made in the early diagnosis and treatment of the disease. Its management has been particularly revolutionized during the past two decades. In this review, we summarize the major advances in the diagnostic and management armamentarium for chronic HCV infection. The focus of the present review is on the newer directly acting anti-viral agents, which have revolutionized the management of chronic HCV infection. Management of uncomplicated chronic HCV infection and of specific complications and special at-risk populations of patients will be covered in detail. Despite the advent and approval of highly effective and well tolerable oral agents, still many challenges remain, particularly the affordability, the equitable distribution and access to later drugs. The World Health Organization aims to eliminate viral hepatitis including HCV by 2030 since its poses a major public health threat. There is an urgent need to ensure uniform and early access to diagnostic and therapeutic facilities throughout the world if the later goal has to be realized.
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Affiliation(s)
- Farina M Hanif
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation , Karachi 74200, Sindh, Pakistan
| | - Zain Majid
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation , Karachi 74200, Sindh, Pakistan
| | - Nasir Hassan Luck
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation , Karachi 74200, Sindh, Pakistan
| | - Abbas Ali Tasneem
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation , Karachi 74200, Sindh, Pakistan
| | - Syed Muddasir Laeeq
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation , Karachi 74200, Sindh, Pakistan
| | - Muhammed Mubarak
- Department of Histopathology, Sindh Institute of Urology and Transplantation , Karachi 74200, Sindh, Pakistan.
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17
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Tréguier Y, Bull-Maurer A, Roingeard P. Apolipoprotein E, a Crucial Cellular Protein in the Lifecycle of Hepatitis Viruses. Int J Mol Sci 2022; 23:ijms23073676. [PMID: 35409035 PMCID: PMC8998859 DOI: 10.3390/ijms23073676] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 03/19/2022] [Accepted: 03/25/2022] [Indexed: 02/01/2023] Open
Abstract
Apolipoprotein E (ApoE) is a multifunctional protein expressed in several tissues, including those of the liver. This lipoprotein component is responsible for maintaining lipid content homeostasis at the plasma and tissue levels by transporting lipids between the liver and peripheral tissues. The ability of ApoE to interact with host-cell surface receptors and its involvement in several cellular pathways raised questions about the hijacking of ApoE by hepatotropic viruses. Hepatitis C virus (HCV) was the first hepatitis virus reported to be dependent on ApoE for the completion of its lifecycle, with ApoE being part of the viral particle, mediating its entry into host cells and contributing to viral morphogenesis. Recent studies of the hepatitis B virus (HBV) lifecycle have revealed that this virus and its subviral envelope particles also incorporate ApoE. ApoE favors HBV entry and is crucial for the morphogenesis of infectious particles, through its interaction with HBV envelope glycoproteins. This review summarizes the data highlighting the crucial role of ApoE in the lifecycles of HBV and HCV and discusses its potential role in the lifecycle of other hepatotropic viruses.
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Affiliation(s)
- Yannick Tréguier
- INSERM U1259 MAVIVH, Université de Tours et CHU de Tours, 37032 Tours, France; (Y.T.); (A.B.-M.)
| | - Anne Bull-Maurer
- INSERM U1259 MAVIVH, Université de Tours et CHU de Tours, 37032 Tours, France; (Y.T.); (A.B.-M.)
| | - Philippe Roingeard
- INSERM U1259 MAVIVH, Université de Tours et CHU de Tours, 37032 Tours, France; (Y.T.); (A.B.-M.)
- Plateforme IBiSA des Microscopies, Université de Tours et CHU de Tours, 37032 Tours, France
- Correspondence: ; Tel.: +33-0247-366-232
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18
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Wang H, Zhang Y, Zhou J, Li M, Chen Y, Liu Y, Liu H, Ding P, Liang C, Zhu X, Zhang Y, Xin C, Zhang G, Wang A. Rapid Visual Detection of Hepatitis C Virus Using Reverse Transcription Recombinase-Aided Amplification–Lateral Flow Dipstick. Front Cell Infect Microbiol 2022; 12:816238. [PMID: 35252031 PMCID: PMC8892114 DOI: 10.3389/fcimb.2022.816238] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 01/17/2022] [Indexed: 12/16/2022] Open
Abstract
Hepatitis C virus (HCV) infection is a global public health threat. Reaching the World Health Organization’s objective for eliminating viral hepatitis by 2030 will require a precise disease diagnosis. While immunoassays and qPCR play a significant role in detecting HCV, rapid and accurate point-of-care testing is important for pathogen identification. This study establishes a reverse transcription recombinase-aided amplification–lateral flow dipstick (RT-RAA-LFD) assay to detect HCV. The intact workflow was completed within 30 min, and the detection limit for synthesized C/E1 plasmid gene-containing plasmid was 10 copies/μl. In addition, the test showed good specificity, with no cross-reactivity observed for hepatitis A virus, hepatitis B virus, HIV, syphilis, and human papillomavirus virus. Using extracted RNAs from 46 anti-HCV antibody-positive samples, RT-RAA-LFD showed 100% positive and negative concordance rates with qPCR. In summary, the RT-RAA-LFD assay established in this study is suitable for the rapid clinical detection of HCV at the community level and in remote areas.
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Affiliation(s)
- Haili Wang
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Yuhang Zhang
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, China
| | - Jingming Zhou
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Ming Li
- Henan Key Laboratory of Population Defects Prevention, National Health Commission Key Laboratory of Birth Defects Prevention, Henan Institute of Reproduction Health Science and Technology, Zhengzhou, China
| | - Yumei Chen
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Yankai Liu
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Hongliang Liu
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Peiyang Ding
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Chao Liang
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Xifang Zhu
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Ying Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Cheng Xin
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Gaiping Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, China
- *Correspondence: Gaiping Zhang, ; Aiping Wang,
| | - Aiping Wang
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
- *Correspondence: Gaiping Zhang, ; Aiping Wang,
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19
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van Zyl GU. New Technological Developments in Identification and Monitoring of New and Emerging Infections. ENCYCLOPEDIA OF INFECTION AND IMMUNITY 2022. [PMCID: PMC8291697 DOI: 10.1016/b978-0-12-818731-9.00094-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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20
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Wang Y, Cheng G, Lau G. Achieving WHO target of HCV control in Hong Kong: challenges and strategies. Glob Health Med 2021; 3:276-282. [PMID: 34782869 DOI: 10.35772/ghm.2021.01075] [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: 06/18/2021] [Revised: 07/26/2021] [Accepted: 08/03/2021] [Indexed: 11/08/2022]
Abstract
With the introduction of effective directly acting antiviral agents (DAAs) therapy, control and elimination of hepatitis C virus (HCV) infection is becoming a feasible goal. In Hong Kong, HCV prevalence in general population is 0.3%-0.5% over the past decades. However, like other high-income areas/countries, high prevalence of HCV infection has been found in several population groups, such as people who inject drugs (PWID), patients undergoing dialysis, and human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/ AIDS) patients. Based on the epidemiological study using data retrieved from the Hong Kong HCV Registry from January 2005 to March 2017, the estimated territory-wide diagnosis rate and treatment rate of HCV infection were only 50.9% and 12.4%, respectively. Although these rates was comparable to many developed countries/areas, the performances remained substantially below 90% and 80%, the 2030 targets proposed by World Health Organization (WHO). In recognition of the challenges, the Hong Kong Government set up the Steering Committee on Prevention and Control of Viral Hepatitis (SCVH) which formulated the Hong Kong Viral Hepatitis Action Plan 2020-2024. The Action Plan adopts four key strategies, as described in the WHO framework for global action, namely, awareness, surveillance, prevention and treatment. With the effective implementation of the Action Plan, especially in targeted screening of high-risk populations and more generalized use of the highly efficacious DAAs for all diagnosed HCV subjects, the goals of reducing HCV transmission and HCV-related morbidity and mortality can be achieved in Hong Kong by 2030.
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Affiliation(s)
- Yudong Wang
- Humanity and Health Clinical Trial Center, Humanity & Health Medical Group, Hong Kong SAR, China
| | - Gregory Cheng
- Humanity and Health Clinical Trial Center, Humanity & Health Medical Group, Hong Kong SAR, China.,Faculty of Health Science, University of Macau, Macau SAR, China
| | - George Lau
- Humanity and Health Clinical Trial Center, Humanity & Health Medical Group, Hong Kong SAR, China.,The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
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21
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Koike K. The Way to Decoding Pathogenesis and Conquering of National Afflictions, Viral Hepatitis and Liver Cancer. JMA J 2021; 4:332-338. [PMID: 34796287 PMCID: PMC8580653 DOI: 10.31662/jmaj.2021-0099] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 06/02/2021] [Indexed: 12/28/2022] Open
Abstract
Viral hepatitis and liver cancer are worldwide health problems, and they have been called national afflictions in Japan. We have been studying the mechanism of hepatocarcinogenesis, chiefly using experimental animal models, starting from clinical observations of patients. Observations of the early development of liver cancer in young patients with chronic hepatitis B with minimal hepatic inflammation and fibrosis, as well as the frequent development of hepatic steatosis in patients with chronic hepatitis C, prompted us to study direct roles of hepatitis viruses B and C in such liver pathogenesis. In addition, our establishment of a new paradigm, “hepatitis C as a metabolic disease,” further led us to elucidating the mechanism of nonviral, metabolism-associated liver cancer. Most hepatologists may appreciate a conquest in the war against viral hepatitis and associated liver cancer. However, even if we conquer the external enemies, hepatitis viruses B and C, an intrinsic enemy, metabolism-associated liver disease, would be waiting for us as an alternative cause of liver cancer. Confrontation of liver cancer has never ended.
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Affiliation(s)
- Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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22
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Eames JR, Tran B. Hepatitis C. PHYSICIAN ASSISTANT CLINICS 2021. [DOI: 10.1016/j.cpha.2021.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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23
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Zhao R, Wang M, Cao J, Shen J, Zhou X, Wang D, Cao J. Flavivirus: From Structure to Therapeutics Development. Life (Basel) 2021; 11:life11070615. [PMID: 34202239 PMCID: PMC8303334 DOI: 10.3390/life11070615] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/16/2021] [Accepted: 06/22/2021] [Indexed: 12/25/2022] Open
Abstract
Flaviviruses are still a hidden threat to global human safety, as we are reminded by recent reports of dengue virus infections in Singapore and African-lineage-like Zika virus infections in Brazil. Therapeutic drugs or vaccines for flavivirus infections are in urgent need but are not well developed. The Flaviviridae family comprises a large group of enveloped viruses with a single-strand RNA genome of positive polarity. The genome of flavivirus encodes ten proteins, and each of them plays a different and important role in viral infection. In this review, we briefly summarized the major information of flavivirus and further introduced some strategies for the design and development of vaccines and anti-flavivirus compound drugs based on the structure of the viral proteins. There is no doubt that in the past few years, studies of antiviral drugs have achieved solid progress based on better understanding of the flavivirus biology. However, currently, there are no fully effective antiviral drugs or vaccines for most flaviviruses. We hope that this review may provide useful information for future development of anti-flavivirus drugs and vaccines.
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Affiliation(s)
- Rong Zhao
- Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan 030001, China; (R.Z.); (M.W.); (J.C.); (J.S.)
- Department of Physiology, Shanxi Medical University, Taiyuan 030001, China
| | - Meiyue Wang
- Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan 030001, China; (R.Z.); (M.W.); (J.C.); (J.S.)
- Department of Physiology, Shanxi Medical University, Taiyuan 030001, China
| | - Jing Cao
- Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan 030001, China; (R.Z.); (M.W.); (J.C.); (J.S.)
- Department of Physiology, Shanxi Medical University, Taiyuan 030001, China
| | - Jing Shen
- Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan 030001, China; (R.Z.); (M.W.); (J.C.); (J.S.)
- Department of Physiology, Shanxi Medical University, Taiyuan 030001, China
| | - Xin Zhou
- Department of Medical Imaging, Shanxi Medical University, Taiyuan 030001, China;
| | - Deping Wang
- Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan 030001, China; (R.Z.); (M.W.); (J.C.); (J.S.)
- Department of Physiology, Shanxi Medical University, Taiyuan 030001, China
- Correspondence: (D.W.); (J.C.)
| | - Jimin Cao
- Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan 030001, China; (R.Z.); (M.W.); (J.C.); (J.S.)
- Department of Physiology, Shanxi Medical University, Taiyuan 030001, China
- Correspondence: (D.W.); (J.C.)
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Sevvana M, Keck Z, Foung SK, Kuhn RJ. Structural perspectives on HCV humoral immune evasion mechanisms. Curr Opin Virol 2021; 49:92-101. [PMID: 34091143 DOI: 10.1016/j.coviro.2021.05.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 05/15/2021] [Accepted: 05/17/2021] [Indexed: 12/20/2022]
Abstract
The molecular mechanisms of hepatitis C virus (HCV) persistence and pathogenesis are poorly understood. The design of an effective HCV vaccine is challenging despite a robust humoral immune response against closely related strains of HCV. This is primarily because of the huge genetic diversity of HCV and the molecular evolution of various virus escape mechanisms. These mechanisms are steered by the presence of a high mutational rate in HCV, structural plasticity of the immunodominant regions on the virion surface of diverse HCV genotypes, and constant amino acid substitutions on key structural components of HCV envelope glycoproteins. Here, we review the molecular basis of neutralizing antibody (nAb)-mediated immune response against diverse HCV variants, HCV-steered humoral immune evasion strategies and explore the essential structural elements to consider for designing a universal HCV vaccine. Structural perspectives on key escape pathways mediated by a point mutation within the epitope, allosteric modulation of the epitope by distant mutations and glycan shift on envelope glycoproteins will be highlighted (abstract graphic).
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Affiliation(s)
- Madhumati Sevvana
- Department of Biological Sciences, Purdue University, West Lafayette, IN 47904, USA; Purdue Institute of Inflammation, Immunology, and Infectious Disease, Purdue University, West Lafayette, IN 47904, USA
| | - Zhenyong Keck
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Steven Kh Foung
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
| | - Richard J Kuhn
- Department of Biological Sciences, Purdue University, West Lafayette, IN 47904, USA; Purdue Institute of Inflammation, Immunology, and Infectious Disease, Purdue University, West Lafayette, IN 47904, USA.
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Han D, Wang H, Wujieti B, Zhang B, Cui W, Chen BZ. Insight into the drug resistance mechanisms of GS-9669 caused by mutations of HCV NS5B polymerase via molecular simulation. Comput Struct Biotechnol J 2021; 19:2761-2774. [PMID: 34093991 PMCID: PMC8134009 DOI: 10.1016/j.csbj.2021.04.026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 04/08/2021] [Accepted: 04/09/2021] [Indexed: 12/17/2022] Open
Abstract
GS-9669 is a non-nucleos(t)ide inhibitor (NNI) binding to the thumb site II of the Hepatitis C virus (HCV) NS5B polymerase and has advanced into phase II trials. To clarify the drug resistance mechanisms of GS-9669 caused by M423T/I/V, L419M, R422K, and I482L mutations of NS5B polymerase (GT1b) and the receptor-ligand interactions during the binding process, a series of molecular simulation methods including molecular dynamics (MD) simulations and adaptive steered molecular dynamics (ASMD) simulations were performed for the wild-type (WT) and six mutant NS5B/GS-9669 complexes. The calculated results indicate that the binding free energies of the mutant systems are less negative than that of the WT system, indicating that these mutations will indeed cause NS5B to produce different degrees of resistance to GS-9669. The mutation-induced drug resistances are mainly caused by the loss of binding affinities of Leu419 and Trp528 with GS-9669 or the formation of multiple solvent bridges. Moreover, the ASMD calculations show that GS-9669 binds to the thumb II sites of the seven NS5B polymerases in distinct pathways without any obvious energy barriers. Although the recognition methods and binding pathways are distinct, the binding processes of GS-9669 with the WT and mutant NS5B polymerases are basically controlled thermodynamically. This study clearly reveals the resistance mechanisms of GS-9669 caused by M423T/I/V, L419M, R422K, and I482L mutations of HCV NS5B polymerase and provides some valuable clues for further optimization and design of novel NS5B inhibitors.
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Affiliation(s)
- Di Han
- School of Chemical Sciences, University of Chinese Academy of Sciences, No. 19A, YuQuan Road, Beijing 100049, China
- School of Medical Engineering, Xinxiang Medical University, Xinxiang 453003, China
| | - Huiqun Wang
- Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, 800 E Leigh Street, Richmond, VA 23298, USA
| | - Baerlike Wujieti
- School of Chemical Sciences, University of Chinese Academy of Sciences, No. 19A, YuQuan Road, Beijing 100049, China
| | - Beibei Zhang
- School of Chemical Sciences, University of Chinese Academy of Sciences, No. 19A, YuQuan Road, Beijing 100049, China
| | - Wei Cui
- School of Chemical Sciences, University of Chinese Academy of Sciences, No. 19A, YuQuan Road, Beijing 100049, China
| | - Bo-Zhen Chen
- School of Chemical Sciences, University of Chinese Academy of Sciences, No. 19A, YuQuan Road, Beijing 100049, China
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Barenie RE, Avorn J, Tessema FA, Kesselheim AS. Public funding for transformative drugs: the case of sofosbuvir. Drug Discov Today 2021; 26:273-281. [PMID: 33011345 PMCID: PMC7528745 DOI: 10.1016/j.drudis.2020.09.024] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 08/03/2020] [Accepted: 09/23/2020] [Indexed: 11/21/2022]
Abstract
The approval of sofosbuvir (Sovaldi) in 2013 transformed chronic hepatitis C virus (HCV) care, but its high cost was criticized in part because of reports of substantial public involvement in its development. We developed a methodology to assess the public's contribution through the National Institutes of Health (NIH) in developing sofosbuvir. Using key terms from the timeline of sofosbuvir, we identified articles in PubMed; linked them to federal funding using the NIH RePORTER; reviewed the title, organization, and investigator of each resulting award for relatedness; and converted related awards to 2018 US dollars. Of 6043 unique awards, we identified 29 that were directly (US$7.7 million) and 110 that were indirectly (US$53.2 million) related awards made to major academic institutions and companies engaged in the development of the drug. These findings indicate that public funding had a key role in developing sofosbuvir, with an estimated US$60.9 million provided in NIH funding.
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Affiliation(s)
- Rachel E Barenie
- Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont St, Suite 3030, Boston, MA 02120, USA.
| | - Jerry Avorn
- Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont St, Suite 3030, Boston, MA 02120, USA
| | - Frazer A Tessema
- Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont St, Suite 3030, Boston, MA 02120, USA
| | - Aaron S Kesselheim
- Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont St, Suite 3030, Boston, MA 02120, USA
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Panduro A. Viruses and the Liver 2020: Before COVID-19 and the beginning of a new age in medicine. Ann Hepatol 2021; 20:100293. [PMID: 33388122 PMCID: PMC7834516 DOI: 10.1016/j.aohep.2020.100293] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 11/19/2020] [Indexed: 02/04/2023]
Affiliation(s)
- Arturo Panduro
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, "Fray Antonio Alcalde" and Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico.
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Abstract
Hepatitis C virus (HCV) accounts for hepatitis, cirrhosis, hepatocellular carcinoma, and liver transplantation. Every year, millions of people develop chronic liver diseases. This article provides novel insights into the major breakthroughs in the discovery of hepatitis C virus. 2020 Nobel Prize in Medicine was awarded to Michael Houghton, Harvey Alter, and Charles Rice for their outstanding contribution in the discovery of HCV. Also, this article deals with current findings, challenges, and future prospects in the diagnosis of HCV infection. DAA, along with protease inhibitors, is found to have higher SVR and is a promising drug to treat HCV infection. However, with regard to the emergence of resistance to DAAs, CRISPR-Cas can be the future technique in preventing resistance. Although the current knowledge of molecular mechanisms associated with HCV infection is insufficient, the better understanding of it provides better hope in the treatment of HCV. Lymphoma A cancer causing infection on lymphocytes. Fulminant hepatitis A decrease in the size of the liver accompanied even by the death of liver parenchyma with the onset of infection with hepatitis virus. Transfection The process of introducing nucleic acids into eukaryotic cells without using viral methods. Huh-7 cells A type of liver cells grown in the laboratory for research purposes. Immunoscreening A biomedical method that helps to detect a protein produced from a cloned gene after it undergoes transcription, followed by the translation process within the cell. cDNA library A group of only the genes that are encoded into proteins by an organism. Sustained virologic response Absence of any evidence of the presence of HCV in the blood of patients with chronic HCV infection after undergoing antiviral treatment. Pegylated interferon A covalent conjugate of recombinant interferon and polyethylene glycol, used as an antiviral and antineoplastic agent. Immunoelectron microscopy A technique to localize ultrastructure antigens or antibodies in cells or tissues for the diagnosis of viral infections. Stellate cells A major type of liver cell involved in liver cirrhosis. Hepatitis C virus (HCV) accounts for hepatitis, liver cirrhosis, hepatocellular carcinoma, and liver transplantation. This virus is a single-stranded RNA virus that belongs to the Flaviviridae family. According to the WHO, about 71 million people have chronic HCV infections around the globe in 2020, and hence, it is a plague of humankind. The credit of discovery of HCV goes to Michael Houghton, Harvey Alter, and Charles Rice for which they are awarded 2020 Nobel Prize in Medicine. Their contribution has given better hope to mankind to cure HCV for the first time in the history. With the use of pegylated interferon and ribavirin jointly, higher SVR has been found comparatively, even in patients with chronic liver diseases. However, due to excessive pain tolerated by patients, interferon (IFN)-based therapy is rapidly being replaced with IFN-free DAA regimens. With the onset of resistance to DAA drugs, CRISPR-Cas system can be used to modify the viral genome to impair their ability to develop resistance. How to cite this article: Laugi H. Discovery of Hepatitis C Virus: 2020 Nobel Prize in Medicine. Euroasian J Hepato-Gastroenterol 2020;10(2): 105–108.
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Oancea CN, Butaru AE, Streba CT, Pirici D, Rogoveanu I, Diculescu MM, Gheonea DI. Global hepatitis C elimination: history, evolution, revolutionary changes and barriers to overcome. ROMANIAN JOURNAL OF MORPHOLOGY AND EMBRYOLOGY = REVUE ROUMAINE DE MORPHOLOGIE ET EMBRYOLOGIE 2020; 61:643-653. [PMID: 33817705 PMCID: PMC8112794 DOI: 10.47162/rjme.61.3.02] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 03/25/2021] [Indexed: 02/05/2023]
Abstract
The fundamental discovery of the hepatitis C virus (HCV) in 1989 has led to winning this year's Nobel Prize in Medicine. This achievement guided all the steps in identifying the elements of the virus, in order to develop the treatment and to increase the screening solutions, which have slowed the exposure to the virus. The management of infection started with interferon-alpha (IFN-α), which has later enhanced by adding Ribavirin. Nowadays, HCV treatment is based on direct-acting antiviral agents (DAAs). Currently, HCV infection benefits of curative treatment, with which most patients can be cured. When speaking about hepatitis C future, we can say it is looking bright, considering all the progress that has been made in recent years and all the options that we have for curing all genotypes of HCV infection. The aim of this review is to sum up the historical characteristics of HCV discovery, the evolution of treatment and screening actions, gaps, and stages for achieving the international elimination target of the World Health Organization.
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Affiliation(s)
- Carmen Nicoleta Oancea
- Department of Scientific Research Methodology and Department of Pulmonology, University of Medicine and Pharmacy of Craiova, Romania;
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Schmit D, Milewicz U, Boerneke MA, Burley S, Walsworth K, Um J, Hecht D, Hermann T, Bergdahl BM. Syntheses and Binding Testing of N1-Alkylamino-Substituted 2-Aminobenzimidazole Analogues Targeting the Hepatitis C Virus Internal Ribosome Entry Site. Aust J Chem 2020. [DOI: 10.1071/ch19526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
A series of 2-aminobenzimidazole analogues have been synthesised and tested for binding to a previously established RNA target for viral translation inhibitors in the internal ribosome entry site (IRES) of the hepatitis C virus (HCV). Synthesis of new inhibitor compounds followed a highly convergent strategy which allowed for incorporation of diverse tertiary amino substituents in high overall yields (eight-steps, 4–22%). Structure–activity relationship (SAR) studies focussed on the tertiary amine substituent involved in hydrogen bonding with the RNA backbone at the inhibitor binding site. The SAR study was further correlated with in silico docking experiments. Analogous compounds showed promising activities (half maximal effective concentration, EC50: 21–89µM). Structures of the synthesised analogues and a correlation to their mode of binding, provided the opportunity to explore parameters required for selective targeting of the HCV IRES at the subdomain IIa which acts as an RNA conformational switch in HCV translation.
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Abouelasrar Salama S, Lavie M, De Buck M, Van Damme J, Struyf S. Cytokines and serum amyloid A in the pathogenesis of hepatitis C virus infection. Cytokine Growth Factor Rev 2019; 50:29-42. [PMID: 31718982 DOI: 10.1016/j.cytogfr.2019.10.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 10/17/2019] [Accepted: 10/21/2019] [Indexed: 02/07/2023]
Abstract
Expression of the acute phase protein serum amyloid A (SAA) is dependent on the release of the pro-inflammatory cytokines IL-1, IL-6 and TNF-α during infection and inflammation. Hepatitis C virus (HCV) upregulates SAA-inducing cytokines. In line with this, a segment of chronically infected individuals display increased circulating levels of SAA. SAA has even been proposed to be a potential biomarker to evaluate treatment efficiency and the course of disease. SAA possesses antiviral activity against HCV via direct interaction with the viral particle, but might also divert infectivity through its function as an apolipoprotein. On the other hand, SAA shares inflammatory and angiogenic activity with chemotactic cytokines by activating the G protein-coupled receptor, formyl peptide receptor 2. These latter properties might promote chronic inflammation and hepatic injury. Indeed, up to 80 % of infected individuals develop chronic disease because they cannot completely clear the infection, due to diversion of the immune response. In this review, we summarize the interconnection between SAA and cytokines in the context of HCV infection and highlight the dual role SAA could play in this disease. Nevertheless, more research is needed to establish whether the balance between those opposing activities can be tilted in favor of the host defense.
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Affiliation(s)
- Sara Abouelasrar Salama
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, Leuven, 3000, Belgium
| | - Muriel Lavie
- University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019, UMR 8204, Centre d'Infection et d'Immunité de Lille, Lille, France
| | - Mieke De Buck
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, Leuven, 3000, Belgium
| | - Jo Van Damme
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, Leuven, 3000, Belgium
| | - Sofie Struyf
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, Leuven, 3000, Belgium.
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Palanisamy N, Kalaghatgi P, Akaberi D, Lundkvist Å, Chen ZW, Hu P, Lennerstrand J. Worldwide prevalence of baseline resistance-associated polymorphisms and resistance mutations in HCV against current direct-acting antivirals. Antivir Ther 2019; 23:485-493. [PMID: 29745936 DOI: 10.3851/imp3237] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/27/2018] [Indexed: 10/16/2022]
Abstract
BACKGROUND HCV infections can now be completely cured, thanks to the currently marketed direct-acting antivirals (DAAs). It is known that HCV patients carry viral populations with baseline polymorphisms and/or mutations that make them resistant against some of these DAAs, which can negatively impact the patient's treatment outcome. Using complete HCV coding sequences isolated from 1,306 treatment-naive patients of genotypes (GTs) 1, 2, 3, 4 and 6 from around the globe, we studied the prevalence of baseline resistance-associated polymorphisms (RAPs) and resistance mutations (RMs) against DAAs that are currently on the market or in clinical trials. METHODS The HCV genome sequences used in this study were retrieved from the NCBI database. RAPs and RMs, with reference to HCV GT1a, were identified using the HCV Geno2pheno web server. RESULTS Nearly 50% of the total amino acid positions (including NS3 protease, NS5A and NS5B) studied are baseline polymorphisms that differentiated one GT from the rest. A proportion of these baseline polymorphisms and baseline non-polymorphic RMs could confer a significant increase in resistance against DAAs. CONCLUSIONS In this study, we show the presence and prevalence of RAPs and RMs in DAA treatment-naive patients against currently used DAAs or DAAs in clinical trials. Our study suggests that RAPs and RMs profiling of HCV patients should be performed before the start of the therapy. Our results should be relevant especially in low- and middle-income countries, where the patients have a large variation of GTs and subtypes, and where the generic HCV treatment is now increasingly available.
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Affiliation(s)
- Navaneethan Palanisamy
- HBIGS, University of Heidelberg, Heidelberg, Germany.,Molecular and Cellular Engineering Group, BioQuant, University of Heidelberg, Heidelberg, Germany
| | - Prabhav Kalaghatgi
- Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, Saarbrücken, Germany
| | - Dario Akaberi
- Clinical Microbiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.,Department of Medical Biochemistry and Microbiology, Zoonosis Science Center, Uppsala University, Uppsala, Sweden
| | - Åke Lundkvist
- Clinical Microbiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.,Department of Medical Biochemistry and Microbiology, Zoonosis Science Center, Uppsala University, Uppsala, Sweden
| | - Zhi-Wei Chen
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Peng Hu
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Johan Lennerstrand
- Clinical Microbiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
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Torbenson M, Washington K. Pathology of liver disease: advances in the last 50 years. Hum Pathol 2019; 95:78-98. [PMID: 31493428 DOI: 10.1016/j.humpath.2019.08.023] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 08/28/2019] [Indexed: 02/07/2023]
Abstract
Liver disease has been recognized in various forms for centuries. Incredible advances, however, have been made especially in the last 50 years, driven by improvements in histology, the development of immunostains, the development of high resolution imaging methods, improved biopsy and resection methods, and the emergence of the molecular era. With these tools, pathologists and their clinical and basic science colleagues moved from classifying liver disease using an observational, pattern-based approach to a refined classification of disease, one based on etiology for medical disease and tumor classification for neoplastic disease. Examples of liver specific diseases are used to illustrate these exciting advances. These impressive advances of the past provide the foundation for hope in the future, as liver pathology continues to play an important role in improving patient care through disease identification and classification and emerging roles in guiding therapy for cures.
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Affiliation(s)
- Michael Torbenson
- Department of Pathology and Laboratory Medicine, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905.
| | - Kay Washington
- C-3321 MCN, Department of Pathology, Vanderbilt University Medical Center, 1161 21(st) Avenue S, Nashville, TN 37232.
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Pavlov CS, Varganova DL, Casazza G, Tsochatzis E, Nikolova D, Gluud C, Cochrane Hepato‐Biliary Group. Glucocorticosteroids for people with alcoholic hepatitis. Cochrane Database Syst Rev 2019; 4:CD001511. [PMID: 30964545 PMCID: PMC6455893 DOI: 10.1002/14651858.cd001511.pub4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Alcoholic hepatitis is a form of alcoholic liver disease characterised by steatosis, necroinflammation, fibrosis, and complications to the liver. Typically, alcoholic hepatitis presents in people between 40 and 50 years of age. Alcoholic hepatitis can be resolved if people abstain from drinking, but the risk of death will depend on the severity of the liver damage and abstinence from alcohol. Glucocorticosteroids have been studied extensively in randomised clinical trials to assess their benefits and harms. However, the results have been contradictory. OBJECTIVES To assess the benefits and harms of glucocorticosteroids in people with alcoholic hepatitis. SEARCH METHODS We identified trials through electronic searches in Cochrane Hepato-Biliary's (CHB) Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS, and Science Citation Index Expanded. We looked for ongoing or unpublished trials in clinical trials registers and pharmaceutical company sources. We also scanned reference lists of the studies retrieved. The last search was 18 January 2019. SELECTION CRITERIA Randomised clinical trials assessing glucocorticosteroids versus placebo or no intervention in people with alcoholic hepatitis, irrespective of year, language of publication, or format. We considered trials with adults diagnosed with alcoholic hepatitis, which could have been established through clinical or biochemical diagnostic criteria or both. We defined alcoholic hepatitis as mild (Maddrey's score less than 32) and severe (Maddrey's score 32 or more). We allowed cointerventions in the trial groups, provided they were similar. DATA COLLECTION AND ANALYSIS We followed Cochrane methodology, performing the meta-analyses using Review Manager 5. We presented the results of dichotomous outcomes as risk ratios (RR) and of continuous outcomes as mean difference (MD), with 95% confidence intervals (CI). We used both the fixed-effect and the random-effects models for meta-analyses. Whenever there were significant discrepancies in the results, we reported the more conservative point estimate of the two. We considered a P value of 0.01 or less, two-tailed, as statistically significant if the required information size was reached for our three primary outcomes (all-cause mortality, health-related quality of life, and serious adverse events during treatment) and our post hoc decision to include analyses of mortality at more time points. We presented heterogeneity using the I² statistic. If trialists used intention-to-treat analysis to deal with missing data, we used these data in our primary analysis; otherwise, we used the available data. We assessed the bias risk of the trials using bias risk domains and the certainty of the evidence using GRADE. MAIN RESULTS Sixteen trials fulfilled our inclusion criteria. All trials but one were at overall high risk of bias. Fifteen trials (one of which was an abstract) provided data for analysis (927 participants received glucocorticosteroids and 934 participants received placebo or no intervention). Glucocorticosteroids were administered orally or parenterally for a median 28 days (range 3 days to 12 weeks). The participants were between 25 and 70 years old, had different stages of alcoholic liver disease, and 65% were men. Follow-up, when reported, was up to the moment of discharge from the hospital, until they died (median of 63 days), or for at least one year. There was no evidence of effect of glucocorticosteroids on all-cause mortality up to three months following randomisation (random-effects RR 0.90, 95% CI 0.70 to 1.15; participants = 1861; trials = 15; very low-certainty evidence) or on health-related quality of life up to three months, measured with the European Quality of Life - 5 Dimensions - 3 Levels scale (MD -0.04 points, 95% CI -0.11 to 0.03; participants = 377; trial = 1; low-certainty evidence). There was no evidence of effect on the occurrence of serious adverse events during treatment (random-effects RR 1.05, 95% CI 0.85 to 1.29; participants = 1861; trials = 15; very low-certainty evidence), liver-related mortality up to three months following randomisation (random-effects RR 0.89, 95% CI 0.69 to 1.14; participants = 1861; trials = 15; very low-certainty evidence), number of participants with any complications up to three months following randomisation (random-effects RR 1.04, 95% CI 0.86 to 1.27; participants = 1861; very low-certainty evidence), and number of participants of non-serious adverse events up to three months' follow-up after end of treatment (random-effects RR 1.99, 95% CI 0.72 to 5.48; participants = 160; trials = 4; very low-certainty evidence). Based on the information that we collected from the published trial reports, only one of the trials seems not to be industry-funded, and the remaining 15 trials did not report clearly whether they were partly or completely funded by the industry. AUTHORS' CONCLUSIONS We are very uncertain about the effect estimate of no difference between glucocorticosteroids and placebo or no intervention on all-cause mortality and serious adverse events during treatment because the certainty of evidence was very low, and low for health-related quality of life. Due to inadequate reporting, we cannot exclude increases in adverse events. As the CIs were wide, we cannot rule out significant benefits or harms of glucocorticosteroids. Therefore, we need placebo-controlled randomised clinical trials, designed according to the SPIRIT guidelines and reported according to the CONSORT guidelines. Future trials ought to report depersonalised individual participant data, so that proper individual participant data meta-analyses of the effects of glucocorticosteroids in subgroups can be conducted.
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Affiliation(s)
- Chavdar S Pavlov
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalCochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
- Kazan Federal University18 KremlyovskayaKazanRussian Federation420008
- Center for Evidence‐Based Medicine'Sechenov' First Moscow State Medical UniversityPogodinskja st. 1\1MoscowRussian Federation119881
| | - Daria L Varganova
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalCochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
- Center for Evidence‐Based Medicine'Sechenov' First Moscow State Medical UniversityPogodinskja st. 1\1MoscowRussian Federation119881
- Ulyanovsk Regional Clinical HospitalDepartment of GastroenterologyInternational 3UlyanovskRussian Federation432063
| | - Giovanni Casazza
- Università degli Studi di MilanoDipartimento di Scienze Biomediche e Cliniche "L. Sacco"via GB Grassi 74MilanItaly20157
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | - Emmanuel Tsochatzis
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentrePond StreetLondonUKNW3 2QG
| | - Dimitrinka Nikolova
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalCochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalCochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
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Abstract
Treatment of hepatitis C with interferon therapy produced some cures early on, but was associated with significant side effects. Because of further advances in the molecular understanding of hepatitis C, by 2014 effective treatments became available that far surpassed all prior interferon-based regimens in efficacy, tolerability, and safety. This led to rapid transformation of a hard-to-treat disease to simple, safe, and effective treatment offered to anyone. This article focuses on hepatitis C epidemiology; the clinical impact and consequences; discussion of past hepatitis C treatments; and a review of current recommendations for screening, diagnosis, and treatment of this ubiquitous virus.
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Affiliation(s)
- Jordan Mayberry
- Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA
| | - William M Lee
- Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
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Pavlov CS, Varganova DL, Casazza G, Tsochatzis E, Nikolova D, Gluud C. Glucocorticosteroids for people with alcoholic hepatitis. Cochrane Database Syst Rev 2017; 11:CD001511. [PMID: 29096421 PMCID: PMC6491283 DOI: 10.1002/14651858.cd001511.pub3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Alcoholic hepatitis is a form of alcoholic liver disease, characterised by steatosis, necroinflammation, fibrosis, and potential complications to the liver disease. Typically, alcoholic hepatitis presents in people between 40 and 50 years of age. Alcoholic hepatitis can be resolved if people abstain from drinking, but the risk of death will depend on the severity of the liver damage and abstinence from alcohol. Glucocorticosteroids are used as anti-inflammatory drugs for people with alcoholic hepatitis. Glucocorticosteroids have been studied extensively in randomised clinical trials in order to assess their benefits and harms. However, the results have been contradictory. OBJECTIVES To assess the benefits and harms of glucocorticosteroids in people with alcoholic hepatitis. SEARCH METHODS We identified trials through electronic searches in Cochrane Hepato-Biliary's (CHB) Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS, and Science Citation Index Expanded. We looked for ongoing or unpublished trials in clinical trials registers and pharmaceutical company sources. We also scanned reference lists of the studies retrieved. The last search was 20 October 2016. SELECTION CRITERIA Randomised clinical trials assessing glucocorticosteroids versus placebo or no intervention in people with alcoholic hepatitis, irrespective of year, language of publication, or format. We considered trials with adult participants diagnosed with alcoholic hepatitis, which could have been established through clinical or biochemical diagnostic criteria or both. We defined alcoholic hepatitis as mild (Maddrey's score less than 32) and severe (Maddrey's score 32 or more). We allowed co-interventions in the trial groups, provided they were similar. DATA COLLECTION AND ANALYSIS We followed Cochrane and CHB methodology, performing the meta-analyses using Review Manager 5 and Trial Sequential Analysis. We presented the results of dichotomous outcomes as risk ratios (RR) and those of the continuous outcomes as mean difference (MD). We applied both the fixed-effect model and the random-effects model meta-analyses. Whenever there were significant discrepancies in the results, we reported the more conservative point estimate of the two. We considered a P value of 0.01 or less, two-tailed, as statistically significant if the required information size was reached due to our three primary outcomes (all-cause mortality, health-related quality of life, and serious adverse events during treatment) and our post hoc decision to include analyses of mortality at more time points. We presented heterogeneity using the I² statistic. If trialists used intention-to-treat analysis to deal with missing data, we used these data in our primary analysis; otherwise, we used the available data. We assessed the bias risk of the trials using bias risk domains and the quality of the evidence using GRADE. MAIN RESULTS Sixteen trials fulfilled the inclusion criteria. All trials were at high risk of bias. Fifteen trials provided data for analysis (927 participants received glucocorticosteroids and 934 participants received placebo or no intervention). The glucocorticosteroids were administered orally or parenterally for a median of 28 days (range 3 days to 12 weeks). The participants were between 25 and 70 years old, had different stages of alcoholic liver disease, and 65% were men. The follow-up of trial participants, when it was reported, was up to the moment of discharge from the hospital, until they died (a median of 63 days), or for at least a year. There was no evidence of effect of glucocorticosteroids on all-cause mortality up to three months following randomisation neither with traditional meta-analysis (random-effects RR 0.90, 95% CI 0.70 to 1.15; participants = 1861; trials = 15; I² = 45% (moderate heterogeneity) nor with Trial Sequential Analysis. Meta-analysis showed no evidence of effect on health-related quality of life up to three months (MD -0.04 points; 95% CI -0.11 to 0.03; participants = 377; trial = 1; low-quality evidence), measured with the European Quality of Life - 5 Dimensions-3 Levels (EQ- 5D-3L) scale. There was no evidence of effect on the occurrence of serious adverse events during treatment, neither with traditional meta-analysis (random-effects RR 1.05, 95% CI 0.85 to 1.29; participants = 1861; trials = 15; I² = 36% (moderate heterogeneity), liver-related mortality up to three months following randomisation (random-effects RR 0.89, 95% CI 0.69 to 1.14; participants = 1861; trials = 15; I² = 46% (moderate heterogeneity), frequency of any complications up to three months following randomisation (random-effects RR 1.04, 95% CI 0.86 to 1.27; participants = 1861; I² = 42% (moderate heterogeneity), and frequency of non-serious adverse events up to three months' follow-up after end of treatment (random-effects RR 1.99, 95% CI 0.72 to 5.48; participants = 160; trials = 4; I² = 0% (no heterogeneity) nor with Trial Sequential Analysis. Nine of the trials were industry-funded. AUTHORS' CONCLUSIONS We found no evidence of a difference between glucocorticosteroids and placebo or no intervention on all-cause mortality, health-related quality of life, and serious adverse events during treatment. The risk of bias was high and the quality of evidence was very low or low. Therefore, we are very uncertain about this effect estimate. Due to inadequate reporting, we cannot exclude increases in adverse events. As the confidence intervals were wide, we cannot rule out significant benefits and harms of glucocorticosteroids. Therefore, we need placebo-controlled, randomised clinical trials, designed according to the SPIRIT guidelines and reported according to the CONSORT guidelines. Future trials ought to report depersonalised individual participant data, so that proper individual participant data meta-analyses of the effects of glucocorticosteroids in subgroups can be conducted.
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Affiliation(s)
| | - Daria L Varganova
- Ulyanovsk Regional Clinical HospitalDepartment of GastroenterologyInternational 3UlyanovskRussian Federation432063
| | | | - Emmanuel Tsochatzis
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentrePond StreetLondonUKNW3 2QG
| | - Dimitrinka Nikolova
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
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Arias IM. Coming of age and building of bridges … reflections on the past, present, and, hesitatingly, future. Hepatology 2017; 65:1785-1788. [PMID: 28256730 DOI: 10.1002/hep.29142] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Accepted: 02/23/2017] [Indexed: 12/07/2022]
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Hayes CN, Chayama K. Why highly effective drugs are not enough: the need for an affordable solution to eliminating HCV. Expert Rev Clin Pharmacol 2017; 10:583-594. [PMID: 28374641 DOI: 10.1080/17512433.2017.1313111] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Because of the rapid pace of development of new direct-acting antiviral (DAA) drugs, chronic hepatitis C virus (HCV) infection is now increasingly considered curable. However, the emphasis on DAA therapies disregards key issues related to cost, availability, and antiviral resistance. Areas covered: This perspective provides an overview of current HCV therapies and the development of DAAs, followed by a discussion of the limitations of DAA therapy. A literature search was used to select relevant studies, and a web search for relevant news articles and press releases was conducted. Expert commentary: Despite cure rates exceeding 90%, now is not the time to declare victory against HCV but to reinforce recent progress by addressing the issues of cost and availability as well as by developing strategies to manage antiviral resistance. Future drug development efforts should place greater emphasis on targeting host factors required for HCV replication, for which the barrier to resistance is higher, and effort should continue to develop a vaccine against HCV. Finally, efforts should be made to facilitate large-scale screening in endemic areas to identify and treat patients as early as possible to reduce long-term risks of advanced liver disease and their attendant costs of management.
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Affiliation(s)
- C Nelson Hayes
- a Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences , Hiroshima University , Hiroshima , Japan.,b Liver Research Project Center , Hiroshima University , Hiroshima , Japan
| | - Kazuaki Chayama
- a Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences , Hiroshima University , Hiroshima , Japan.,b Liver Research Project Center , Hiroshima University , Hiroshima , Japan.,c Laboratory for Digestive Diseases, Center for Genomic Medicine , RIKEN , Hiroshima , Japan
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Ganesan A, Barakat K. Applications of computer-aided approaches in the development of hepatitis C antiviral agents. Expert Opin Drug Discov 2017; 12:407-425. [PMID: 28164720 DOI: 10.1080/17460441.2017.1291628] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
INTRODUCTION Hepatitis C virus (HCV) is a global health problem that causes several chronic life-threatening liver diseases. The numbers of people affected by HCV are rising annually. Since 2011, the FDA has approved several anti-HCV drugs; while many other promising HCV drugs are currently in late clinical trials. Areas covered: This review discusses the applications of different computational approaches in HCV drug design. Expert opinion: Molecular docking and virtual screening approaches have emerged as a low-cost tool to screen large databases and identify potential small-molecule hits against HCV targets. Ligand-based approaches are useful for filtering-out compounds with rich physicochemical properties to inhibit HCV targets. Molecular dynamics (MD) remains a useful tool in optimizing the ligand-protein complexes and understand the ligand binding modes and drug resistance mechanisms in HCV. Despite their varied roles, the application of in-silico approaches in HCV drug design is still in its infancy. A more mature application should aim at modelling the whole HCV replicon in its active form and help to identify new effective druggable sites within the replicon system. With more technological advancements, the roles of computer-aided methods are only going to increase several folds in the development of next-generation HCV drugs.
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Affiliation(s)
- Aravindhan Ganesan
- a Faculty of Pharmacy and Pharmaceutical Sciences , University of Alberta , Edmonton , Canada
| | - Khaled Barakat
- a Faculty of Pharmacy and Pharmaceutical Sciences , University of Alberta , Edmonton , Canada
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Manickam C, Wachtman L, Martinot AJ, Giavedoni LD, Reeves RK. Metabolic Dysregulation in Hepacivirus Infection of Common Marmosets (Callithrix jacchus). PLoS One 2017; 12:e0170240. [PMID: 28085952 PMCID: PMC5234844 DOI: 10.1371/journal.pone.0170240] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Accepted: 12/31/2016] [Indexed: 12/13/2022] Open
Abstract
Chronic hepatitis C has been associated with metabolic syndrome that includes insulin resistance, hepatic steatosis and obesity. These metabolic aberrations are risk factors for disease severity and treatment outcome in infected patients. Experimental infection of marmosets with GBV-B serves as a tangible, small animal model for human HCV infection, and while virology and pathology are well described, a full investigation of clinical disease and the metabolic milieu is lacking. In this study six marmosets were infected intravenously with GBV-B and changes in hematologic, serum biochemical and plasma metabolic measures were investigated over the duration of infection. Infected animals exhibited signs of lymphocytopenia, but platelet and RBC counts were generally stable or even increased. Although most animals showed a transient decline in blood glucose, infection resulted in several fold increases in plasma insulin, glucagon and glucagon-like peptide 1 (GLP-1). All infected animals experienced transient weight loss within the first 28 days of infection, but also became hypertriglyceridemic and had up to 10-fold increases in adipocytokines such as resistin and plasminogen activator inhibitor 1 (PAI-1). In liver, moderate to severe cytoplasmic changes associated with steatotic changes was observed microscopically at 168 days post infection. Collectively, these results suggest that GBV-B infection is accompanied by hematologic, biochemical and metabolic abnormalities that could lead to obesity, diabetes, thrombosis and atherosclerosis, even after virus has been cleared. Our findings mirror those found in HCV patients, suggesting that metabolic syndrome could be conserved among hepaciviruses, and both mechanistic and interventional studies for treating HCV-induced metabolic complications could be evaluated in this animal model.
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Affiliation(s)
- Cordelia Manickam
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America
| | - Lynn Wachtman
- New England Primate Research Center, Harvard Medical School, Southborough Campus, Southborough, Massachusetts, United States of America
| | - Amanda J. Martinot
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America
| | - Luis D. Giavedoni
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas, United States of America
| | - R. Keith Reeves
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America
- New England Primate Research Center, Harvard Medical School, Southborough Campus, Southborough, Massachusetts, United States of America
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Abstract
It was widely believed in the late 1960s that infectious diseases had been conquered by vaccines and antibiotics and humans were no longer under threat by microbial pathogens. Yet, since that time more than 60 pathogens have been discovered that can cause serious emerging infectious diseases. Molecular methods have played critical roles in the discovery, monitoring, and clinical diagnostics of emerging pathogens. In this chapter, we present well-recognized emerging pathogens. We provide examples of the utility of molecular assays in research and clinical care of emerging infectious diseases. We also discuss some theoretical and practical limitations of molecular tests and the future prospects of expanding molecular diagnostics for emerging pathogens based on new advances of knowledge and technologies.
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Vahedi F, Giles EC, Ashkar AA. The Application of Humanized Mouse Models for the Study of Human Exclusive Viruses. Methods Mol Biol 2017; 1656:1-56. [PMID: 28808960 DOI: 10.1007/978-1-4939-7237-1_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/14/2025]
Abstract
The symbiosis between humans and viruses has allowed human tropic pathogens to evolve intricate means of modulating the human immune response to ensure its survival among the human population. In doing so, these viruses have developed profound mechanisms that mesh closely with our human biology. The establishment of this intimate relationship has created a species-specific barrier to infection, restricting the virus-associated pathologies to humans. This specificity diminishes the utility of traditional animal models. Humanized mice offer a model unique to all other means of study, providing an in vivo platform for the careful examination of human tropic viruses and their interaction with human cells and tissues. These types of animal models have provided a reliable medium for the study of human-virus interactions, a relationship that could otherwise not be investigated without questionable relevance to humans.
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Affiliation(s)
- Fatemeh Vahedi
- Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Hamilton, ON, Canada, L8N 3Z5
- MG DeGroote Institute for Infectious Disease Research, McMaster Immunology Research Centre, Hamilton, ON, Canada, L8N 3Z5
| | - Elizabeth C Giles
- Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Hamilton, ON, Canada, L8N 3Z5
- MG DeGroote Institute for Infectious Disease Research, McMaster Immunology Research Centre, Hamilton, ON, Canada, L8N 3Z5
| | - Ali A Ashkar
- Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Hamilton, ON, Canada, L8N 3Z5.
- MG DeGroote Institute for Infectious Disease Research, McMaster Immunology Research Centre, Hamilton, ON, Canada, L8N 3Z5.
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Lee KY, Chen YH, Hsu SC, Yu MJ. Phosphorylation of Serine 235 of the Hepatitis C Virus Non-Structural Protein NS5A by Multiple Kinases. PLoS One 2016; 11:e0166763. [PMID: 27875595 PMCID: PMC5119781 DOI: 10.1371/journal.pone.0166763] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 11/03/2016] [Indexed: 12/14/2022] Open
Abstract
Phosphorylation at serine 235 (S235) of the hepatitis C virus (HCV) non-structural protein 5A (NS5A) plays a critical role in the viral life cycle. For medical and virological interests, we exploited the HEK293T kidney cells to test 3 candidate protein kinases on NS5A S235 phosphorylation. Inhibitors that inhibit casein kinase I α (CKIα), polo-like kinase I (PlKI) or calmodulin-dependent kinase II (CaMKII) all reduced NS5A S235 phosphorylation. CKIα was studied previously and PlKI had severe cytotoxicity, thus CaMKII was selected for validation in the Huh7.5.1 liver cells. In the HCV (J6/JFH1)-infected Huh7.5.1 cells, CaMKII inhibitor reduced NS5A S235 phosphorylation and HCV RNA levels without apparent cytotoxicity. RT-PCR analysis showed expression of CaMKII γ and δ isoforms in the Huh7.5.1 cells. Both CaMKII γ and δ directly phosphorylated NS5A S235 in vitro. CaMKII γ or δ single knockdown did not affect NS5A S235 phosphorylation but elevated the HCV RNA levels in the infected cells. CKIα plus CaMKII (γ or δ) double knockdown reduced NS5A S235 phosphorylation and reduced HCV RNA levels; however, the HCV RNA levels were higher than those in the infected cells with CKIα single knockdown. We conclude that CKIα-mediated NS5A S235 phosphorylation is critical for HCV replication. CaMKII γ and δ may have negative roles in the HCV life cycle.
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Affiliation(s)
- Kuan-Ying Lee
- Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei, 10051, Taiwan
| | - Yi-Hung Chen
- Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei, 10051, Taiwan
| | - Shih-Chin Hsu
- Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei, 10051, Taiwan
| | - Ming-Jiun Yu
- Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei, 10051, Taiwan
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44
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Abstract
Cancer has been recognized for thousands of years. Egyptians believed that cancer occurred at the will of the gods. Hippocrates believed human disease resulted from an imbalance of the four humors: blood, phlegm, yellow bile, and black bile with cancer being caused by excess black bile. The lymph theory of cancer replaced the humoral theory and the blastema theory replaced the lymph theory. Rudolph Virchow was the first to recognize that cancer cells like all cells came from other cells and believed chronic irritation caused cancer. At the same time there was a belief that trauma caused cancer, though it never evolved after many experiments inducing trauma. The birth of virology occurred in 1892 when Dimitri Ivanofsky demonstrated that diseased tobacco plants remained infective after filtering their sap through a filter that trapped bacteria. Martinus Beijerinck would call the tiny infective agent a virus and both Dimitri Ivanofsky and Marinus Beijerinck would become the fathers of virology. Not to long thereafter, Payton Rous founded the field of tumor virology in 1911 with his discovery of a transmittable sarcoma of chickens by what would come to be called Rous sarcoma virus or RSV for short. The first identified human tumor virus was the Epstein-Barr virus (EBV), named after Tony Epstein and Yvonne Barr who visualized the virus particles in Burkitt's lymphoma cells by electron microscopy in 1965. Since that time, many viruses have been associated with carcinogenesis including the most studied, human papilloma virus associated with cervical carcinoma, many other anogenital carcinomas, and oropharyngeal carcinoma. The World Health Organization currently estimates that approximately 22% of worldwide cancers are attributable to infectious etiologies, of which viral etiologies is estimated at 15-20%. The field of tumor virology/viral carcinogenesis has not only identified viruses as etiologic agents of human cancers, but has also given molecular insights to all human cancers including the oncogene activation and tumor suppressor gene inactivation.
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Affiliation(s)
- A J Smith
- Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - L A Smith
- Texas Tech University Health Sciences Center, Lubbock, TX, United States.
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Bukh J. The history of hepatitis C virus (HCV): Basic research reveals unique features in phylogeny, evolution and the viral life cycle with new perspectives for epidemic control. J Hepatol 2016; 65:S2-S21. [PMID: 27641985 DOI: 10.1016/j.jhep.2016.07.035] [Citation(s) in RCA: 175] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 07/29/2016] [Indexed: 12/11/2022]
Abstract
The discovery of hepatitis C virus (HCV) in 1989 permitted basic research to unravel critical components of a complex life cycle for this important human pathogen. HCV is a highly divergent group of viruses classified in 7 major genotypes and a great number of subtypes, and circulating in infected individuals as a continuously evolving quasispecies destined to escape host immune responses and applied antivirals. Despite the inability to culture patient viruses directly in the laboratory, efforts to define the infectious genome of HCV resulted in development of experimental recombinant in vivo and in vitro systems, including replicons and infectious cultures in human hepatoma cell lines. And HCV has become a model virus defining new paradigms in virology, immunology and biology. For example, HCV research discovered that a virus could be completely dependent on microRNA for its replication since microRNA-122 is critical for the HCV life cycle. A number of other host molecules critical for HCV entry and replication have been identified. Thus, basic HCV research revealed important molecules for development of host targeting agents (HTA). The identification and characterization of HCV encoded proteins and their functional units contributed to the development of highly effective direct acting antivirals (DAA) against the NS3 protease, NS5A and the NS5B polymerase. In combination, these inhibitors have since 2014 permitted interferon-free therapy with cure rates above 90% among patients with chronic HCV infection; however, viral resistance represents a challenge. Worldwide control of HCV will most likely require the development of a prophylactic vaccine, and numerous candidates have been pursued. Research characterizing features critical for antibody-based virus neutralization and T cell based virus elimination from infected cells is essential for this effort. If the world community promotes an ambitious approach by applying current DAA broadly, continues to develop alternative viral- and host- targeted antivirals to combat resistant variants, and invests in the development of a vaccine, it would be possible to eradicate HCV. This would prevent about 500 thousand deaths annually. However, given the nature of HCV, the millions of new infections annually, a high chronicity rate, and with over 150 million individuals with chronic infection (which are frequently unidentified), this effort remains a major challenge for basic researchers, clinicians and communities.
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Affiliation(s)
- Jens Bukh
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases and Clinical Research Centre, Hvidovre Hospital and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
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Verstrepen BE, Nieuwenhuis IG, Mooij P, Verschoor EJ, Fagrouch ZC, Kondova I, Boonstra A, Koopman G. Role of microbial translocation in soluble CD14 up-regulation in HIV-, but not in HCV-, infected chimpanzees. J Gen Virol 2016; 97:2599-2607. [PMID: 27534537 DOI: 10.1099/jgv.0.000577] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
During human immunodeficiency virus (HIV) infection, soluble CD14 (sCD14) is up-regulated as a consequence of pathological disruption of the gut epithelial barrier, and subsequent increased microbial translocation. Also in hepatitis C virus (HCV)-infected patients with advanced liver fibrosis, increased levels of sCD14 have been reported. Since the liver plays an important role in clearance of translocated bacterial products, hepatic fibrosis may negatively affect clearance and thus contribute to higher sCD14 levels. Chimpanzees (Pan troglodytes) infected with HCV typically show no signs of liver fibrosis. Here, we have tested the hypothesis that increased levels of sCD14 occur in the absence of hepatic fibrosis or microbial translocation in chimpanzees chronically infected with HCV. sCD14 was up-regulated in both HIV/simian immunodeficiency virus (SIV)- and HCV-infected chimpanzees. In HIV/SIV-infected chimpanzees, intestinal fatty acid-binding protein, a marker for gut perturbation, lipopolysaccharide (LPS)-binding-protein and LPS core antibodies, confirm that sCD14 up-regulation was caused by increased microbial translocation. In HCV-infected chimpanzees, no evidence was found for increased microbial translocation despite up-regulation of sCD14. Additionally, the impact of liver fibrosis on microbial translocation was addressed by direct comparison of chimpanzees with a high HCV load and human patients with advanced fibrosis. These data suggest that only in a small minority of HCV patients, hepatic fibrosis corroborates microbial translocation.
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Affiliation(s)
- Babs E Verstrepen
- Department of Virology, Biomedical Primate Research Centre, 2280 GH Rijswijk, The Netherlands
| | - Ivonne G Nieuwenhuis
- Department of Virology, Biomedical Primate Research Centre, 2280 GH Rijswijk, The Netherlands
| | - Petra Mooij
- Department of Virology, Biomedical Primate Research Centre, 2280 GH Rijswijk, The Netherlands
| | - Ernst J Verschoor
- Department of Virology, Biomedical Primate Research Centre, 2280 GH Rijswijk, The Netherlands
| | - Zahra C Fagrouch
- Department of Virology, Biomedical Primate Research Centre, 2280 GH Rijswijk, The Netherlands
| | - Ivanela Kondova
- Division of Pathology and Microbiology, Biomedical Primate Research Centre, 2280 GH Rijswijk, The Netherlands
| | - André Boonstra
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, 3015 CE Rotterdam, The Netherlands
| | - Gerrit Koopman
- Department of Virology, Biomedical Primate Research Centre, 2280 GH Rijswijk, The Netherlands
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Meanwell NA. 2015 Philip S. Portoghese Medicinal Chemistry Lectureship. Curing Hepatitis C Virus Infection with Direct-Acting Antiviral Agents: The Arc of a Medicinal Chemistry Triumph. J Med Chem 2016; 59:7311-51. [PMID: 27501244 DOI: 10.1021/acs.jmedchem.6b00915] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The development of direct-acting antiviral agents that can cure a chronic hepatitis C virus (HCV) infection after 8-12 weeks of daily, well-tolerated therapy has revolutionized the treatment of this insidious disease. In this article, three of Bristol-Myers Squibb's HCV programs are summarized, each of which produced a clinical candidate: the NS3 protease inhibitor asunaprevir (64), marketed as Sunvepra, the NS5A replication complex inhibitor daclatasvir (117), marketed as Daklinza, and the allosteric NS5B polymerase inhibitor beclabuvir (142), which is in late stage clinical studies. A clinical study with 64 and 117 established for the first time that a chronic HCV infection could be cured by treatment with direct-acting antiviral agents alone in the absence of interferon. The development of small molecule HCV therapeutics, designed by medicinal chemists, has been hailed as "the arc of a medical triumph" but may equally well be described as "the arc of a medicinal chemistry triumph".
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Affiliation(s)
- Nicholas A Meanwell
- Department of Discovery Chemistry, Bristol-Myers Squibb Research & Development , Wallingford, Connecticut 06492, United States
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48
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Kaushik-Basu N, Ratmanova NK, Manvar D, Belov DS, Cevik O, Basu A, Yerukhimovich MM, Lukyanenko ER, Andreev IA, Belov GM, Manfroni G, Cecchetti V, Frick DN, Kurkin AV, Altieri A, Barreca ML. Bicyclic octahydrocyclohepta[b]pyrrol-4(1H)one derivatives as novel selective anti-hepatitis C virus agents. Eur J Med Chem 2016; 122:319-325. [PMID: 27376494 DOI: 10.1016/j.ejmech.2016.06.041] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Revised: 06/01/2016] [Accepted: 06/21/2016] [Indexed: 01/27/2023]
Abstract
We report the discovery of the bicyclic octahydrocyclohepta[b]pyrrol-4(1H)-one scaffold as a new chemotype with anti-HCV activity on genotype 1b and 2a subgenomic replicons. The most potent compound 34 displayed EC50 values of 1.8 μM and 4.5 μM in genotype 1b and 2a, respectively, coupled with the absence of any antimetabolic effect (gt 1b SI = 112.4; gt 2a SI = 44.2) in a cell-based assay. Compound 34 did not target HCV NS5B, IRES, NS3 helicase, or selected host factors, and thus future work will involve the unique mechanism of action of these new antiviral compounds.
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Affiliation(s)
- Neerja Kaushik-Basu
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers, The State University of New Jersey, New Jersey Medical School, NJ 07103, USA.
| | - Nina K Ratmanova
- Chemistry Department of Lomonosov Moscow State University, Moscow 119991, GSP-2, Leninskie gory, 1/3, Russia
| | - Dinesh Manvar
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers, The State University of New Jersey, New Jersey Medical School, NJ 07103, USA
| | - Dmitry S Belov
- Chemistry Department of Lomonosov Moscow State University, Moscow 119991, GSP-2, Leninskie gory, 1/3, Russia; EDASA Scientific srls., Via Stingi, 37, 66050 San Salvo, CH, Italy
| | - Ozge Cevik
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers, The State University of New Jersey, New Jersey Medical School, NJ 07103, USA
| | - Amartya Basu
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers, The State University of New Jersey, New Jersey Medical School, NJ 07103, USA
| | - Mark M Yerukhimovich
- Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 3210 N. Cramer St., Milwaukee, WI 53211, USA
| | - Evgeny R Lukyanenko
- Chemistry Department of Lomonosov Moscow State University, Moscow 119991, GSP-2, Leninskie gory, 1/3, Russia; EDASA Scientific srls., Via Stingi, 37, 66050 San Salvo, CH, Italy
| | - Ivan A Andreev
- Chemistry Department of Lomonosov Moscow State University, Moscow 119991, GSP-2, Leninskie gory, 1/3, Russia; EDASA Scientific srls., Via Stingi, 37, 66050 San Salvo, CH, Italy
| | - Grigory M Belov
- Chemistry Department of Lomonosov Moscow State University, Moscow 119991, GSP-2, Leninskie gory, 1/3, Russia; EDASA Scientific srls., Via Stingi, 37, 66050 San Salvo, CH, Italy
| | - Giuseppe Manfroni
- Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti, 48, 06123 Perugia, Italy
| | - Violetta Cecchetti
- Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti, 48, 06123 Perugia, Italy
| | - David N Frick
- Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 3210 N. Cramer St., Milwaukee, WI 53211, USA
| | - Alexander V Kurkin
- Chemistry Department of Lomonosov Moscow State University, Moscow 119991, GSP-2, Leninskie gory, 1/3, Russia.
| | - Andrea Altieri
- EDASA Scientific srls., Via Stingi, 37, 66050 San Salvo, CH, Italy.
| | - Maria Letizia Barreca
- Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti, 48, 06123 Perugia, Italy.
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Bell AM, Wagner JL, Barber KE, Stover KR. Elbasvir/Grazoprevir: A Review of the Latest Agent in the Fight against Hepatitis C. Int J Hepatol 2016; 2016:3852126. [PMID: 27403342 PMCID: PMC4925941 DOI: 10.1155/2016/3852126] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 05/24/2016] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C virus (HCV) is estimated to affect up to 150 million people worldwide. Despite worldwide prevalence, treatment modalities prior to 2011 remained suboptimal, with low virologic response rates and intolerable side effect profiles. Fortunately, the landscape of treatment for chronic hepatitis C has rapidly evolved since the introduction of HCV NS3/4 protease inhibitors in 2011. Elbasvir, a NS5A inhibitor, combined with grazoprevir, a NS3/4A protease inhibitor, is the latest FDA-approved therapy for patients with genotype 1 or 4 chronic hepatitis C, with or without compensated cirrhosis. This review will focus on the current literature and clinical evidence supporting elbasvir/grazoprevir as first-line therapy in patients with genotypes 1 and 4 chronic hepatitis C.
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Affiliation(s)
- Allison M. Bell
- Department of Pharmacy Practice, University of Mississippi School of Pharmacy, Jackson, MS 39216, USA
| | - Jamie L. Wagner
- Department of Pharmacy Practice, University of Mississippi School of Pharmacy, Jackson, MS 39216, USA
| | - Katie E. Barber
- Department of Pharmacy Practice, University of Mississippi School of Pharmacy, Jackson, MS 39216, USA
| | - Kayla R. Stover
- Department of Pharmacy Practice, University of Mississippi School of Pharmacy, Jackson, MS 39216, USA
- Department of Medicine-Infectious Diseases, University of Mississippi Medical Center, Jackson, MS 39216, USA
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50
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Panduro A, Roman S. Need of righteous attitudes towards eradication of hepatitis C virus infection in Latin America. World J Gastroenterol 2016; 22:5137-5142. [PMID: 27298556 PMCID: PMC4893460 DOI: 10.3748/wjg.v22.i22.5137] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Revised: 04/22/2016] [Accepted: 05/04/2016] [Indexed: 02/07/2023] Open
Abstract
Over the last few years, we have expanded our knowledge on numerous facets of the hepatitis C virus (HCV). Beginning with its discovery and viral life cycle, its impact on health, the development of liver disease and currently, effective antiviral treatments. The latter point has become of great interest throughout the developed world, where the possible eradication of HCV through specific strategies to reach all HCV-infected people has been announced. However, this scenario is very different in the countries of Latin America (LA), in which < 2% of infected patients requiring treatment have access to HCV medications. It has been estimated that at least ten million Latin Americans may be infected with HCV. Despite the numbers, viral hepatitis does not seem to be considered a health problem in this region of the world. This reality poses a challenge for politicians and governments of these countries, as well as to the pharmaceutical industry, the medical practitioners, and academics in LA. In this editorial, we state the need for alterations in the attitudes of the integral players involved in this situation. A recognition shift could help to create preventive strategies of viral hepatitis and to advocate for accessibility to new HCV treatments.
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