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Lee JS, Lee HW, Kim MN, Kim BK, Park JY, Kim DY, Ahn SH, Kim SU. Hepatitis C virus infection in patients undergoing surgery in a single tertiary academic center. J Gastroenterol Hepatol 2024; 39:1155-1163. [PMID: 38357836 DOI: 10.1111/jgh.16506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 12/30/2023] [Accepted: 01/23/2024] [Indexed: 02/16/2024]
Abstract
BACKGROUND AND AIM Lack of awareness disturbs proper care for hepatitis C virus (HCV) infections in patients undergoing surgery. We investigated the status of HCV screening, confirmation, and treatment in patients who underwent surgery. METHODS Patients who underwent surgery at a tertiary academic center between 2019 and 2021 were eligible for this retrospective study. RESULTS Between 2019 and 2021, 96 894 patients (40 121 males; 41.4%) who underwent surgery under general anesthesia were recruited. The median age of the participants was 55.0 years. Of the 83 920 (86.6%) patients who tested positive for anti-HCV antibodies, 576 (0.7%) showed positive results, with a higher proportion of patients with diabetes mellitus (32.6% vs 18.5%), hypertension (50.5% vs 28.6%), liver cirrhosis (13.2% vs 1.7%), and unfavorable laboratory test results when compared with those with negative results (all P < 0.05). HCV RNA was tested in 215 patients (37.3%), with a positivity rate of 20.5% (n = 44). Of the 44 patients, 42 (95.5%) were referred for antiviral treatment, and 29 (69.0%) were successfully treated with direct-acting antiviral therapy. HCV RNA confirmation rates were higher in the Department of Hepatobiliary and Transplant Surgery (76.6%) than in the other surgical departments (25.0-33.5%) (P < 0.001). CONCLUSIONS The proportion of patients who were positive for anti-HCV antibodies and failed to receive proper management after surgery was not negligible. Increased awareness of HCV infection among surgeons through appropriate education may be required.
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Affiliation(s)
- Jae Seung Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
- Yonsei Liver Center, Severance Hospital, Seoul, South Korea
| | - Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
- Yonsei Liver Center, Severance Hospital, Seoul, South Korea
| | - Mi Na Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
- Yonsei Liver Center, Severance Hospital, Seoul, South Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
- Yonsei Liver Center, Severance Hospital, Seoul, South Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
- Yonsei Liver Center, Severance Hospital, Seoul, South Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
- Yonsei Liver Center, Severance Hospital, Seoul, South Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
- Yonsei Liver Center, Severance Hospital, Seoul, South Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
- Yonsei Liver Center, Severance Hospital, Seoul, South Korea
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Hsia JZ, Liu D, Haynes L, Cruz-Cosme R, Tang Q. Lipid Droplets: Formation, Degradation, and Their Role in Cellular Responses to Flavivirus Infections. Microorganisms 2024; 12:647. [PMID: 38674592 PMCID: PMC11051834 DOI: 10.3390/microorganisms12040647] [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: 02/26/2024] [Revised: 03/18/2024] [Accepted: 03/22/2024] [Indexed: 04/28/2024] Open
Abstract
Lipid droplets (LDs) are cellular organelles derived from the endoplasmic reticulum (ER), serving as lipid storage sites crucial for maintaining cellular lipid homeostasis. Recent attention has been drawn to their roles in viral replication and their interactions with viruses. However, the precise biological functions of LDs in viral replication and pathogenesis remain incompletely understood. To elucidate the interaction between LDs and viruses, it is imperative to comprehend the biogenesis of LDs and their dynamic interactions with other organelles. In this review, we explore the intricate pathways involved in LD biogenies within the cytoplasm, encompassing the uptake of fatty acid from nutrients facilitated by CD36-mediated membranous protein (FABP/FATP)-FA complexes, and FA synthesis via glycolysis in the cytoplasm and the TCL cycle in mitochondria. While LD biogenesis primarily occurs in the ER, matured LDs are intricately linked to multiple organelles. Viral infections can lead to diverse consequences in terms of LD status within cells post-infection, potentially involving the breakdown of LDs through the activation of lipophagy. However, the exact mechanisms underlying LD destruction or accumulation by viruses remain elusive. The significance of LDs in viral replication renders them effective targets for developing broad-spectrum antivirals. Moreover, considering that reducing neutral lipids in LDs is a strategy for anti-obesity treatment, LD depletion may not pose harm to cells. This presents LDs as promising antiviral targets for developing therapeutics that are minimally or non-toxic to the host.
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Affiliation(s)
| | | | | | | | - Qiyi Tang
- Department of Microbiology, Howard University College of Medicine, Washington, DC 20059, USA; (J.Z.H.); (D.L.); (L.H.); (R.C.-C.)
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Chon YE, Jo A, Yoon EL, Lee J, Shin HG, Ko MJ, Jun DW. The Incidence and Care Cascade of the Hepatitis C Virus in Korea. Gut Liver 2023; 17:926-932. [PMID: 36860161 PMCID: PMC10651381 DOI: 10.5009/gnl220322] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Revised: 09/19/2022] [Accepted: 11/01/2022] [Indexed: 03/03/2023] Open
Abstract
Background/Aims The 2030 hepatitis C virus (HCV) elimination targets of the World Health Organization are an 80% reduction in incidence and 65% reduction in mortality compared to the 2015 rates. However, information on the nationwide incidence and treatment rates of HCV infection are limited. We aimed to investigate the nationwide incidence and status of the care cascade for HCV infection in Korea. Methods This study used data from the Korea Disease Control and Prevention Agency linked with the data of the Korea National Health Insurance Service. Linkage to care was defined as visiting hospitals twice or more due to HCV infection within 1.5 years of the index date. The treatment rate was the number who had been prescribed antiviral medication within 1.5 years from the index date out of patients newly diagnosed with HCV. Results The new HCV infection rate was 17.2 per 100,000 person-years (n=8,810) in 2019. The number of new HCV infections was the highest in patients aged 50 to 59 years (n=2,480), and the new HCV infection rate significantly increased with age (p<0.001). Among newly infected patients with HCV, the linkage to care rate was 78.2% (78.2% men, 78.2% women) and the treatment rate was 58.1% (56.8% men, 59.3% women) within 1.5 years. Conclusions The new HCV infection rate was 17.2 per 100,000 person-years in Korea. It is necessary to continuously monitor the incidence and care cascade of HCV to establish proper strategies to reach the goal of HCV elimination by 2030.
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Affiliation(s)
- Young Eun Chon
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Aejeong Jo
- Division for Healthcare Technology Assessment Research, National Evidence-based Healthcare Collaborating Agency, Seoul, Korea
| | - Eileen L. Yoon
- Department of Internal Medicine, Hanyang University School of Medicine, Seoul, Korea
| | - Jonghyun Lee
- Department of Medical and Digital Engineering, Hanyang University College of Engineering, Seoul, Korea
| | - Ho Gyun Shin
- Division for Healthcare Technology Assessment Research, National Evidence-based Healthcare Collaborating Agency, Seoul, Korea
| | - Min Jung Ko
- Division for Healthcare Technology Assessment Research, National Evidence-based Healthcare Collaborating Agency, Seoul, Korea
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University School of Medicine, Seoul, Korea
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Hong YM, Yoon KT, Park YJ, Woo HY, Heo J. Seroprevalence of Hepatitis C Virus Infection in North Korean Defectors Residing in Korea. J Korean Med Sci 2023; 38:e270. [PMID: 37644684 PMCID: PMC10462482 DOI: 10.3346/jkms.2023.38.e270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 07/04/2023] [Indexed: 08/31/2023] Open
Abstract
BACKGROUND This study aimed to investigate the prevalence rate of hepatitis C virus (HCV) infection and identify the demographic, and sociological characteristics and changes in awareness of HCV infection by participating the study for North Korean defectors residing in South Korea. METHODS This study prospectively enrolled participants. Demographic, sociological and clinical data, and questionnaire surveys focused on awareness of HCV infection were collected. RESULTS In total, 211 North Korean defectors participated in this study from September 2020 until June 2021. There were 174 women (82.5%), and the overall mean age was 48.9 years (range, 20 to 80 years). Of these participants, 112 (53.1%) had immigrated to South Korea since 2011. The overall prevalence of anti-HCV antibody among North Korean defectors was 1.9%. Thirty participants (14.2%) had hepatitis B surface antigens. A huge lack of awareness regarding HCV infection has been observed among North Korean defectors. CONCLUSION This is the first prospective study to investigate the prevalence rate of HCV infection among North Korean defectors residing in South Korea. As North Korean defectors are a vulnerable group concerning HCV infection, they may benefit from HCV screening policies and educational interventions for HCV infection.
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Affiliation(s)
- Young Mi Hong
- Department of Internal Medicine, College of Medicine, Pusan National University, Busan, Korea
- Department of Internal Medicine, Pusan National University Yangsan Hospital, Yangsan, Korea
| | - Ki Tae Yoon
- Department of Internal Medicine, College of Medicine, Pusan National University, Busan, Korea
- Department of Internal Medicine, Pusan National University Yangsan Hospital, Yangsan, Korea
| | - Young Joo Park
- Department of Internal Medicine, College of Medicine, Pusan National University, Busan, Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Hyun Young Woo
- Department of Internal Medicine, College of Medicine, Pusan National University, Busan, Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Jeong Heo
- Department of Internal Medicine, College of Medicine, Pusan National University, Busan, Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan, Korea.
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Maasoumy B, Lampertico P. Hepatitis Delta: Ready for primetime? Liver Int 2023; 43 Suppl 1:1-4. [PMID: 37658668 DOI: 10.1111/liv.15679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Accepted: 07/10/2023] [Indexed: 09/03/2023]
Affiliation(s)
- Benjamin Maasoumy
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- German Centre for Infection Research (DZIF), Braunschweig, Germany
| | - Pietro Lampertico
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- CRC "A. M. and A. Migliavacca" Center for Liver Disease, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
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Faiz S, Irfan M, Farooq S, Khan IA, Iqbal H, Wahab AT, Shakeel M, Gong P, Iftner T, Choudhary MI. Study of drug resistance-associated genetic mutations, and phylo-genetic analysis of HCV in the Province of Sindh, Pakistan. Sci Rep 2023; 13:12213. [PMID: 37500705 PMCID: PMC10374889 DOI: 10.1038/s41598-023-39339-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 07/24/2023] [Indexed: 07/29/2023] Open
Abstract
Current management of HCV infection is based on Direct-Acting Antiviral Drugs (DAAs). However, resistance-associated mutations, especially in the NS3 and NS5B regions are gradually decreasing the efficacy of DAAs. The aim of the current study was to identify such mutations in the NS3, and NS5B genes in DAAs treatment-naïve Pakistani chronic HCV 3a patients. Peripheral blood samples were collected from 233 chronic HCV 3a patients at different tertiary care hospitals in Karachi, Pakistan, between August 2020 to September 2021. PCR-amplified target regions of the NS3/NS5B gene were subjected to Sanger sequencing to identify resistance-associated mutations. Phylogenetic analysis of the identified amino acid sequences was performed using HCV3a sequences of the global population in the virus pathogen resource (VIPR) database. Sequence analysis identified five amino acid mutations, Leu36Pro, Gln41His, Gln80Lys/Arg, Ala156Tyr, and Gln168Arg in the NS3 region, and two mutations Leu159Phe and Cys316Arg in the NS5B region. Phylogenetic analysis revealed a high genetic diversity in the studied isolates. Overall, the prevalence of resistance-associated substitutions was almost similar to other geographic regions worldwide. This data could be helpful in selecting the most effective treatment regimen for HCV chronically infected people in Pakistan.
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Affiliation(s)
- Sirmast Faiz
- Dr. Panjwani Centre for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, National Institute of Virology, University of Karachi, Karachi, 75270, Pakistan
| | - Muhammad Irfan
- Dr. Panjwani Centre for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, Jamil-ur-Rahman Center for Genome Research, University of Karachi, Karachi, 75270, Pakistan
| | - Saba Farooq
- Dr. Panjwani Centre for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, National Institute of Virology, University of Karachi, Karachi, 75270, Pakistan.
| | - Ishtiaq Ahmad Khan
- Dr. Panjwani Centre for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, Jamil-ur-Rahman Center for Genome Research, University of Karachi, Karachi, 75270, Pakistan.
| | - Hana'a Iqbal
- Dr. Panjwani Centre for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, National Institute of Virology, University of Karachi, Karachi, 75270, Pakistan
| | - Atia-Tul Wahab
- Dr. Panjwani Centre for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Muhammad Shakeel
- Dr. Panjwani Centre for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, Jamil-ur-Rahman Center for Genome Research, University of Karachi, Karachi, 75270, Pakistan
| | - Peng Gong
- Wuhan Institute of Virology, Chinese Academy of Sciences, No.44 Xiao Hong Shan, Wuhan, 430071, Hubei, China
| | - Thomas Iftner
- Dr. Panjwani Centre for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, National Institute of Virology, University of Karachi, Karachi, 75270, Pakistan
- Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital and Medical Faculty, Eberhard Karls University, Tuebingen, Germany
| | - M Iqbal Choudhary
- Dr. Panjwani Centre for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, National Institute of Virology, University of Karachi, Karachi, 75270, Pakistan.
- Dr. Panjwani Centre for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, Jamil-ur-Rahman Center for Genome Research, University of Karachi, Karachi, 75270, Pakistan.
- Dr. Panjwani Centre for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
- Dr. Panjwani Centre for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, H.E.J. Research Institute of Chemistry, University of Karachi, Karachi, 75270, Pakistan.
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den Boogert EM, Veldhuijzen IK, Generaal E, Prins M, Sonneveld MJ, van der Meer AJ, Zantkuijl P, van Benthem BHB, de Coul ELMO. Substantial impact of the COVID-19 pandemic on the reported number of diagnosed chronic hepatitis C virus infections in the Netherlands, 2019-2021. BMC Public Health 2023; 23:1244. [PMID: 37370036 DOI: 10.1186/s12889-023-16143-3] [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: 03/21/2023] [Accepted: 06/17/2023] [Indexed: 06/29/2023] Open
Abstract
BACKGROUND The COVID-19 pandemic has widespread consequences for health facilities, social contacts, and health-seeking behaviour, affecting the incidence, diagnosis and reporting of other infectious diseases. We examined trends in reported chronic hepatitis C virus (HCV) infections and associated transmission routes in the Netherlands to identify the potential impact of COVID-19 on access to healthcare (testing) services. METHODS We analysed notification data of patients with chronic HCV reported to the National Notifiable Disease Surveillance System from January 2019 until December 2021 in the Netherlands. Rates of newly reported chronic cases per 100,000 population with 95% confidence intervals (CI) were calculated, and we compared proportional changes in transmission routes for chronic HCV between 2019, 2020 and 2021. RESULTS During the study period, a total of 1,521 chronic HCV infections were reported, 72% males, median age 52 years, and an overall rate of 8.8 (95%CI 8.4-9.2) per 100,000 population. We observed an overall decline (-41.9%) in the number of reported chronic HCV in 2020 compared to 2019, with the sharpest decline in men who have sex with men (MSM)-related transmission (-57.9% in 2020, p = 0.005). CONCLUSIONS Reported cases of chronic HCV strongly declined during the COVID-19 pandemic when healthcare services were scaled down. Between February and June 2021, reported chronic HCV cases increased again, indicating a recovery of healthcare services. MSM showed the largest decline compared to other groups. Further research is needed to fully understand the impact of access to healthcare, health seeking behaviour, and (sexual) transmission risks of HCV during the COVID-19 pandemic.
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Affiliation(s)
- Elisabeth M den Boogert
- Centre for Infectious Disease Control, Epidemiology and Surveillance, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.
- ECDC Fellowship Programme, Field Epidemiology Path (EPIET), European Centre for Disease Prevention and Control (ECDC), Stockholm, Sweden.
| | - Irene K Veldhuijzen
- Centre for Infectious Disease Control, Epidemiology and Surveillance, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands
| | - Ellen Generaal
- Department of Infectious Diseases, Research and Prevention, Public Health Service of Amsterdam, Amsterdam, the Netherlands
| | - Maria Prins
- Department of Infectious Diseases, Research and Prevention, Public Health Service of Amsterdam, Amsterdam, the Netherlands
- Department of Infectious Diseases, Amsterdam UMC, Amsterdam Infection and Immunity (AII), University of Amsterdam, Amsterdam, the Netherlands
| | - Milan J Sonneveld
- Department of Gastroenterology & Hepatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Adriaan J van der Meer
- Department of Gastroenterology & Hepatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | | | - Birgit H B van Benthem
- Centre for Infectious Disease Control, Epidemiology and Surveillance, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands
| | - Eline L M Op de Coul
- Centre for Infectious Disease Control, Epidemiology and Surveillance, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands
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Abstract
Hepatitis C virus (HCV) infection contributes significantly to liver cirrhosis and hepatocellular carcinoma (HCC), often requiring liver transplantation. Introducing direct-acting antiviral agents (DAAs) has radically changed HCV treatment. DAAs achieve high rates of sustained virological response (>98%). Even then, resistant-associated substitution and HCC during or after treatment have become prominent clinical concerns. Further, several clinically significant issues remain unresolved after successful HCV eradication by DAAs, including treating patients with chronic kidney disease or decompensated liver cirrhosis. Extensive and large-scale screening and treatment implementation programs are needed to make DAA therapies effective at the population level.
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Seok Y, Yin Q, Li R, Mauk MG, Bai H, Bau HH. Manually-Operated, Slider Cassette for Multiplexed Molecular Detection at the Point of Care. SENSORS AND ACTUATORS. B, CHEMICAL 2022; 369:132353. [PMID: 38756788 PMCID: PMC11097106 DOI: 10.1016/j.snb.2022.132353] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/18/2024]
Abstract
Effective control of epidemics, individualized medicine, and new drugs with virologic response-dependent dose and timing require, among other things, simple, inexpensive, multiplexed molecular detection platforms suitable for point of care and home use. Herein, we describe our progress towards developing such a platform that includes sample lysis, nucleic acid isolation, concentration, purification, and amplification. Our diagnostic device comprises a sliding component that houses the nucleic acid isolation membrane and a housing containing three amplification reaction chambers with dry stored reagents, blisters with buffers and wash solutions, and absorption pads to facilitate capillarity pull and waste storage. After sample introduction, the user slides the slider within the housing from one station to another to carry out various unit operations. The slider motion induces blisters to discharge their contents, effectuating washes, and eventual elution of captured nucleic acids into reaction chambers. The slider cassette mates with a processor that incubates isothermal amplification but can also be made to operate instrumentation-free. We demonstrate our cassette's utility for the co-detection of the human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV). These three blood-borne pathogens co-infect many people worldwide with severe personal and public health consequences.
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Affiliation(s)
- Youngung Seok
- Department of Mechanical Engineering and Applied Mechanics, School of Engineering and Applied Science, University of Pennsylvania, 216 Towne Building, 220 S. 33 Street, Philadelphia, PA 19104, USA
| | - Qingtian Yin
- Department of Mechanical Engineering and Applied Mechanics, School of Engineering and Applied Science, University of Pennsylvania, 216 Towne Building, 220 S. 33 Street, Philadelphia, PA 19104, USA
| | - Ruijie Li
- Department of Mechanical Engineering and Applied Mechanics, School of Engineering and Applied Science, University of Pennsylvania, 216 Towne Building, 220 S. 33 Street, Philadelphia, PA 19104, USA
- Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, 29 Zhongguancun East Road, Haidian District, Beijing, 100190, China
| | - Michael G. Mauk
- Department of Mechanical Engineering and Applied Mechanics, School of Engineering and Applied Science, University of Pennsylvania, 216 Towne Building, 220 S. 33 Street, Philadelphia, PA 19104, USA
| | - Huiwen Bai
- Department of Mechanical Engineering and Applied Mechanics, School of Engineering and Applied Science, University of Pennsylvania, 216 Towne Building, 220 S. 33 Street, Philadelphia, PA 19104, USA
| | - Haim H. Bau
- Department of Mechanical Engineering and Applied Mechanics, School of Engineering and Applied Science, University of Pennsylvania, 216 Towne Building, 220 S. 33 Street, Philadelphia, PA 19104, USA
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Ikram A, Rauff B, Alzahrani B, Awan FM, Obaid A, Naz A, Kakar SJ, Janjua HA. Integrated analysis to study the interplay between post-translational modifications (PTM) in hepatitis C virus proteins and hepatocellular carcinoma (HCC) development. Sci Rep 2022; 12:15648. [PMID: 36123370 PMCID: PMC9483894 DOI: 10.1038/s41598-022-19854-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 09/06/2022] [Indexed: 02/05/2023] Open
Abstract
Many PTMs dysregulation is known to be the major cause of many cancers including HCV induced HCC. PTMs of hepatitis C virus (HCV) regions NS3/4A, NS5A and NS5B are crucial for proper protein functions and replication that directly affect the generation of infectious virus particles and completion of its life cycle. In this study, we have performed comprehensive analysis of PTMs within HCV non-structural proteins (NS3/4A, NS5A and NS5B) through bioinformatics analysis to examine post-translational crosstalk between phosphorylation, palmitoylation, methylation, acetylation and ubiquitination sites in selected viral proteins. Our analysis has revealed many highly putative PTMs sites that are also conserved among major genotypes conferring the importance of these sites. We have also analysed viral 3D structures in their modified and unmodified forms to address extent and signatures of structural changes upon PTM. This study provides evidence that PTMs induce significant conformational changes and make viral proteins more stable. To find the potential role of PTMs in HCV induced HCC, docking analysis between selected viral proteins and p38-MAPK has been performed which also confirms their strong association with HCV induced HCC. The major findings proposed that PTMs at specific sites of HCV viral proteins could dysregulate specific pathways that cause the development of HCC.
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Affiliation(s)
- Aqsa Ikram
- Institute of Molecular Biology and Biotechnology (IMBB), University of Lahore (UOL), Lahore, Pakistan.
| | - Bisma Rauff
- Department of Biomedical Engineering, UET Lahore, Narowal campus, Narowal, Pakistan
| | - Badr Alzahrani
- Department of Clinical Laboratory Sciences, Jouf University, Sakaka, Saudi Arabia
| | - Faryal Mehwish Awan
- Department of Medical Lab Technology, University of Haripur (UOH), Haripur, Pakistan
| | - Ayesha Obaid
- Department of Medical Lab Technology, University of Haripur (UOH), Haripur, Pakistan
| | - Anam Naz
- Institute of Molecular Biology and Biotechnology (IMBB), University of Lahore (UOL), Lahore, Pakistan
| | - Salik Javed Kakar
- Atta Ur Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad, Pakistan
| | - Hussnain Ahmed Janjua
- Atta Ur Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad, Pakistan.
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Direct-Acting Antiviral Agents for Hepatitis C Virus Infection-From Drug Discovery to Successful Implementation in Clinical Practice. Viruses 2022; 14:v14061325. [PMID: 35746796 PMCID: PMC9231290 DOI: 10.3390/v14061325] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 06/13/2022] [Accepted: 06/15/2022] [Indexed: 12/13/2022] Open
Abstract
Today, hepatitis C virus infection affects up to 1.5 million people per year and is responsible for 29 thousand deaths per year. In the 1970s, the clinical observation of unclear, transfusion-related cases of hepatitis ignited scientific curiosity, and after years of intensive, basic research, the hepatitis C virus was discovered and described as the causative agent for these cases of unclear hepatitis in 1989. Even before the description of the hepatitis C virus, clinicians had started treating infected individuals with interferon. However, intense side effects and limited antiviral efficacy have been major challenges, shaping the aim for the development of more suitable and specific treatments. Before direct-acting antiviral agents could be developed, a detailed understanding of viral properties was necessary. In the years after the discovery of the new virus, several research groups had been working on the hepatitis C virus biology and finally revealed the replication cycle. This knowledge was the basis for the later development of specific antiviral drugs referred to as direct-acting antiviral agents. In 2011, roughly 22 years after the discovery of the hepatitis C virus, the first two drugs became available and paved the way for a revolution in hepatitis C therapy. Today, the treatment of chronic hepatitis C virus infection does not rely on interferon anymore, and the treatment response rate is above 90% in most cases, including those with unsuccessful pretreatments. Regardless of the clinical and scientific success story, some challenges remain until the HCV elimination goals announced by the World Health Organization are met.
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Su X, Zheng L, Zhang H, Shen T, Liu Y, Hu X. Secular Trends of Acute Viral Hepatitis Incidence and Mortality in China, 1990 to 2019 and Its Prediction to 2030: The Global Burden of Disease Study 2019. Front Med (Lausanne) 2022; 9:842088. [PMID: 35360747 PMCID: PMC8962367 DOI: 10.3389/fmed.2022.842088] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 02/21/2022] [Indexed: 11/13/2022] Open
Abstract
Background Understanding the patterns and trends in the context of both incidence and mortality and anticipating future trends is important for viral hepatitis prevention, treatment, and guiding resource allocation in China. The objective of this study is to provide a comprehensive temporal analysis of acute viral hepatitis and its type using the most updated data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD 2019) to estimate the incidence and mortality of hepatitis from 1990 to 2019 and make predictions to 2030. Methods The age-standardized incidence (ASIR) and mortality rate (ASMR) of viral hepatitis in China were obtained from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD 2019). Trends of ASIR and ASMR for viral hepatitis were plotted using locally weighted regression (LOESS). We used joinpoint regression analysis to detect temporal changes and estimate the annual percent of change (APC) of each trend segment and the corresponding 95% confidence interval (CI). A Bayesian age-period-cohort analysis was employed to describe ASIR and ASMR trends between 1990 and 2019 and projections to 2030. Results In 1990, there were 67 million incident cases of acute viral hepatitis, which then decreased to 47 million incidence cases in 2019. Hepatitis A and hepatitis B account for the majority of acute viral hepatitis, and the most pronounced declines in hepatitis B (−48.7%) and hepatitis C (−39.0%) were observed between 1990 and 2019. The ASIR of overall acute viral hepatitis shows a persistent decline, with an average annual percent of change (AAPC) of −1.9% (95% CI: −1.9, −1.8) between 1990 and 2019. The trend of ASMR demonstrated a rapid decline between 1990 and 2005, followed by a slow decline until 2030. Conclusion Our study reveals favorable declining trends of incidence and mortality for acute viral hepatitis in China from 1990 and 2019, and these favorable trends are predicted to continue up to 2030. Despite the favorable trends observed, the absolute number of viral hepatitis, especially hepatitis A and B, is still substantial in China. A scaled-up vaccine campaign is still needed to tackle the large number of vaccine preventable hepatitis infections.
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13
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The utility of
HCV
core antigen for evaluation of viremia at 48 weeks post‐treatment with direct‐acting antivirals. ADVANCES IN DIGESTIVE MEDICINE 2022. [DOI: 10.1002/aid2.13316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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14
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Aranda EB, Marcos CF, Maestu AP, Marín VG, Campo RV, Simal SC, Camarero JG. EVOLUCIÓN DE LOS PACIENTES CON INFECCIÓN CRÓNICA POR HEPATITIS C CON FIBROSIS AVANZADA O CIRROSIS CURADOS CON ANTIVIRALES DE ACCIÓN DIRECTA. SEGUIMIENTO A LARGO PLAZO. GASTROENTEROLOGIA Y HEPATOLOGIA 2022; 45:767-779. [PMID: 35189262 DOI: 10.1016/j.gastrohep.2022.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 02/06/2022] [Accepted: 02/15/2022] [Indexed: 11/30/2022]
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Abstract
In the 1970s, an unknown virus was suspected for documented cases of transfusion-associated hepatitis, a phenomenon called non-A, non-B hepatitis. In 1989, the infectious transmissible agent was identified and named hepatitis C virus (HCV) and, soon enough, the first diagnostic HCV antibody test was developed, which led to a dramatic decrease in new infections. Today, HCV infection remains a global health burden and a major cause of liver cirrhosis, hepatocellular carcinoma and liver transplantation. However, tremendous advances have been made over the decades, and HCV became the first curable, chronic viral infection. The introduction of direct antiviral agents revolutionized antiviral treatment, leading to viral eradication in more than 98% of all patients infected with HCV. This Perspective discusses the history of HCV research, which reads like a role model for successful translational research: starting from a clinical observation, specific therapeutic agents were developed, which finally were implemented in national and global elimination programmes.
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Affiliation(s)
- Michael P. Manns
- grid.10423.340000 0000 9529 9877Hannover Medical School, Hannover, Germany
| | - Benjamin Maasoumy
- grid.10423.340000 0000 9529 9877Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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16
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Rafiq S, Majeed MI, Nawaz H, Rashid N, Yaqoob U, Batool F, Bashir S, Akbar S, Abubakar M, Ahmad S, Ali S, Kashif M, Amin I. Surface-enhanced Raman spectroscopy for analysis of PCR products of viral RNA of hepatitis C patients. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2021; 259:119908. [PMID: 33989976 DOI: 10.1016/j.saa.2021.119908] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 04/22/2021] [Accepted: 05/02/2021] [Indexed: 06/12/2023]
Abstract
In the current study, for a qualitative and quantitative study of Polymerase Chain Reaction (PCR) products of viral RNA of Hepatitis C virus (HCV) infection, surface-enhanced Raman spectroscopy (SERS) methodology has been developed. SERS was used to identify the spectral features associated with the PCR products of viral RNA of Hepatitis C in various samples of HCV-infected patients with predetermined viral loads. The measurements for SERS were performed on 30 samples of PCR products, which included three PCR products of RNA of healthy individuals, six negative controls, and twenty-one HCV positive samples of varying viral loads (VLs) using Silver nanoparticles (Ag NPs) as a SERS substrates. Additionally, on SERS spectral data, the multivariate data analysis methods including Principal Component Analysis (PCA) and Partial Least Squares Regression (PLSR) were also carried out which help to illustrate the diagnostic capabilities of this method. The PLSR model is designed to predict HCV viral loads based on biochemical changes observed as SERS spectral features which can be associated directly with HCV RNA. Several SERS characteristic features are observed in the RNA of HCV which are not detected in the spectra of healthy RNA/controls. PCA is found helpful to differentiate the SERS spectral data sets of HCV RNA samples from healthy and negative controls. The PLSR model is found to be 99% accurate in predicting VLs of HCV RNA samples of unknown samples based on SERS spectral changes associated with the Hepatitis C development.
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Affiliation(s)
- Sidra Rafiq
- Department of Chemistry, University of Agriculture, Faisalabad 38040, Pakistan
| | | | - Haq Nawaz
- Department of Chemistry, University of Agriculture, Faisalabad 38040, Pakistan.
| | - Nosheen Rashid
- Department of Chemistry, University of Central Punjab, Faisalabad Campus, Pakistan
| | - Umer Yaqoob
- Department of Chemistry, University of Agriculture, Faisalabad 38040, Pakistan
| | - Fatima Batool
- Department of Chemistry, University of Agriculture, Faisalabad 38040, Pakistan
| | - Saba Bashir
- Department of Chemistry, University of Agriculture, Faisalabad 38040, Pakistan
| | - Saba Akbar
- Department of Chemistry, University of Agriculture, Faisalabad 38040, Pakistan
| | - Muhammad Abubakar
- Department of Chemistry, University of Agriculture, Faisalabad 38040, Pakistan
| | - Shamsheer Ahmad
- Department of Chemistry, University of Agriculture, Faisalabad 38040, Pakistan
| | - Saqib Ali
- Department of Chemistry, University of Agriculture, Faisalabad 38040, Pakistan
| | - Muhammad Kashif
- Department of Chemistry, University of Agriculture, Faisalabad 38040, Pakistan
| | - Imran Amin
- PCR Laboratory, PINUM Hospital, Faisalabad, Pakistan
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Ohlendorf V, Schäfer A, Christensen S, Heyne R, Naumann U, Link R, Herold C, Schiffelholz W, Günther R, Cornberg M, Serfert Y, Maasoumy B, Wedemeyer H, Kraus MR. Only partial improvement in health-related quality of life after treatment of chronic hepatitis C virus infection with direct acting antivirals in a real-world setting-results from the German Hepatitis C-Registry (DHC-R). J Viral Hepat 2021; 28:1206-1218. [PMID: 34003549 DOI: 10.1111/jvh.13546] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 03/10/2021] [Accepted: 04/17/2021] [Indexed: 12/12/2022]
Abstract
Improvement of health-related quality of life (HRQoL) is frequently reported as a benefit when treating hepatitis C virus infection (HCV) with direct acting antivirals (DAA). As most of the available data were obtained from clinical trials, limited generalizability to the real-world population might exist. This study aimed to investigate the impact of DAA therapy on changes in HRQoL in a real-world setting. HRQoL of 1180 participants of the German Hepatitis C-Registry was assessed by Short-Form 36 (SF-36) questionnaires. Scores at post-treatment weeks 12-24 (FU12/24) were compared to baseline (BL). Changes of ≥2.5 in mental and physical component summary scores (MCS and PCS) were defined as a minimal clinical important difference (MCID). Potential predictors of HRQoL changes were analysed. Overall, a statistically significant increase in HRQoL after DAA therapy was observed, that was robust among various subgroups. However, roughly half of all patients failed to achieve a clinically important improvement in MCS and PCS. Low MCS (p < .001, OR = 0.925) and PCS (p < .001, OR = 0.899) BL levels were identified as predictors for achieving a clinically important improvement. In contrast, presence of fatigue (p = .023, OR = 1.518), increased GPT levels (p = .005, OR = 0.626) and RBV containing therapy regimens (p = .001, OR = 1.692) were associated with a clinically important decline in HRQoL after DAA therapy. In conclusion, DAA treatment is associated with an overall increase of HRQoL in HCV-infected patients. Nevertheless, roughly half of the patients fail to achieve a clinically important improvement. Especially patients with a low HRQoL seem to benefit most from the modern therapeutic options.
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Affiliation(s)
| | - Arne Schäfer
- Diabetes-Klinik Bad Mergentheim, Bad Mergentheim, Germany
| | - Stefan Christensen
- CIM Münster, Münster, Germany.,Department of Gastroenterology and Hepatology, Münster University Hospital (UKM), Münster, Germany
| | | | | | - Ralph Link
- MVZ-Offenburg GmbH /St. Josefs-Klinik, Offenburg, Germany
| | | | | | - Rainer Günther
- Department of Internal Medicine I, Universitätsklinikum Schleswig-Holstein (UKSH, Kiel, Germany
| | | | | | | | - Heiner Wedemeyer
- Hannover Medical School, Hannover, Germany.,Department of Internal Medicine I, Universitätsklinikum Schleswig-Holstein (UKSH, Kiel, Germany
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Khalsa JH, Mathur P. Hepatitis C Virus Infection in Persons Who Inject Drugs in the Middle East and North Africa: Intervention Strategies. Viruses 2021; 13:1363. [PMID: 34372569 PMCID: PMC8310161 DOI: 10.3390/v13071363] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 07/04/2021] [Accepted: 07/11/2021] [Indexed: 12/12/2022] Open
Abstract
There is a high incidence and prevalence of hepatitis C viral infection in persons with or without substance use disorders (SUDs) in the Middle East and North Africa (MENA) region, but only a small number receive comprehensive care. Highly effective direct-acting antiviral (DAA) medications are available at substantially lower costs; however, complete elimination of the hepatitis C virus (HCV) can only be achieved if integrated care strategies target those at highest risk for HCV infection and transmission and improve access to care. Due to the high prevalence of SUD in the MENA region, strategies to eliminate HCV must focus on integrated healthcare across multiple subspecialties, including addiction medicine, psychiatry, infectious diseases, hepatology, and social work. In this invited manuscript, we review the epidemiology of HCV in the MENA region and highlight intervention strategies to attain the WHO's goal of HCV eradication by 2030.
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Affiliation(s)
- Jag H. Khalsa
- Medical Consequences of Drug Abuse and Infections Branch, Division of Therapeutics and Medical Consequences, National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD 20892, USA
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
| | - Poonam Mathur
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
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19
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HCV Infection and Chronic Renal Disease. SERBIAN JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2021. [DOI: 10.2478/sjecr-2021-0010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Chronic Hepatitis C virus (HCV) infection is defined as persistence of HCV RNA in the blood for more than six months. HCV is a major cause of chronic liver disease and cirrhosis. It’s serious public health problem, affects about 71 million people worldwide. HCV doesn’t destroy hepatocytes directly. It activates the host's innate and acquired immune system and causes liver injury indirectly. Behind hepatic, HCV can cause extra-hepatic manifestations. One of them is renal disease which can lead to end-stage renal disease, ESRD. The prevalence of HCV infection in patients on hemodialysis is high, ranging from 5% to 60%. HCV infection is a significant cause of morbidity and mortality in patients with ESRD on hemodialysis. In this review, we discuss HCV infection and chronic renal disease as comorbidities, their severity and outcome.
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Hepatitis C virus modulates signal peptide peptidase to alter host protein processing. Proc Natl Acad Sci U S A 2021; 118:2026184118. [PMID: 34035171 PMCID: PMC8179148 DOI: 10.1073/pnas.2026184118] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The mechanism by which hepatitis C virus (HCV) evades immune surveillance and causes chronic infection is unclear. We demonstrate here that HCV core protein interferes with the maturation of major histocompatibility complex (MHC) class I catalyzed by signal peptide peptidase (SPP) and induces degradation via HMG-CoA reductase degradation 1 homolog. In addition, we found that the core protein transmembrane domain is homologous to the human cytomegalovirus US2 protein, whose transmembrane region also targets SPP to impair MHC class I molecule expression in a similar manner. Therefore, our data suggest that SPP represents a potential target for the impairment of MHC class I molecules by DNA and RNA viruses. Immunoevasins are viral proteins that prevent antigen presentation on major histocompatibility complex (MHC) class I, thus evading host immune recognition. Hepatitis C virus (HCV) evades immune surveillance to induce chronic infection; however, how HCV-infected hepatocytes affect immune cells and evade immune recognition remains unclear. Herein, we demonstrate that HCV core protein functions as an immunoevasin. Its expression interfered with the maturation of MHC class I molecules catalyzed by the signal peptide peptidase (SPP) and induced their degradation via HMG-CoA reductase degradation 1 homolog, thereby impairing antigen presentation to CD8+ T cells. The expression of MHC class I in the livers of HCV core transgenic mice and chronic hepatitis C patients was impaired but was restored in patients achieving sustained virological response. Finally, we show that the human cytomegalovirus US2 protein, possessing a transmembrane region structurally similar to the HCV core protein, targets SPP to impair MHC class I molecule expression. Thus, SPP represents a potential target for the impairment of MHC class I molecules by DNA and RNA viruses.
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Llaneras J, Riveiro-Barciela M, Rando-Segura A, Marcos-Fosch C, Roade L, Velázquez F, Rodríguez-Frías F, Esteban R, Buti M. Etiologies and Features of Acute Viral Hepatitis in Spain. Clin Gastroenterol Hepatol 2021; 19:1030-1037. [PMID: 32663522 DOI: 10.1016/j.cgh.2020.07.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 06/13/2020] [Accepted: 07/07/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIM Etiologies of acute viral hepatitis in high-income countries change with migration of populations, lifestyle changes, and emergence of new pathogens. We analyzed etiologies, characteristics, and outcomes of patients with acute viral hepatitis at a tertiary hospital in Spain. METHODS We analyzed data from all patients with acute hepatitis (n = 100; 71% male; median age, 42 years; 72% Spanish nationals), older than 16 years, diagnosed in the emergency department of an academic hospital in Barcelona, Spain, from January 2014 through December 2018. Blood samples were collected and patients with serum levels of alanine aminotransferase more than 10-fold the upper limit of normal and markers viral infection were considered to have acute viral hepatitis. We collected clinical information from patients, and samples were analyzed for IgM antibody to hepatitis B (HB) core antigen, HB surface antigen, antibody against hepatitis C virus (HCV), HCV RNA, IgM against hepatitis E virus (HEV), HEV RNA, and IgM against hepatitis A virus (HAV). Patients were followed until resolution of infections or evidence of chronic infection. RESULTS The most common etiologies of acute hepatitis were HBV infection (28%), HEV infection (18%), HCV infection (17%), and HAV infection (14%). The main risk factors of the cohort were sexual risk contact and intravenous drug use; 79% of cases of HAV had sexual risk behavior. Twenty-nine percent of patients with acute HAV infection and 29% of patients with HBV infection were immigrants to Spain. Fifty-four patients were hospitalized; jaundice and HCV infection were associated with hospital admission. Three patients died (2 from acute liver failure related to acute HBV infection or HBV and HDV co-infection). Chronic infections developed in 5/28 patients (18%) with acute HBV infection and 7/17 patients (41%) with acute HCV infection. CONCLUSIONS Despite universal vaccination against HBV in Spain, HBV remains the most frequent cause of acute viral hepatitis in our emergency department. Almost one-third of cases of acute HBV and HAV infections were immigrants, possibly from countries with suboptimal vaccination programs. A high proportion of patients with acute hepatitis have HEV infection (18%); acute HAV infection was associated with sexual risk behavior.
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Affiliation(s)
- Jordi Llaneras
- Emergency Room Department, Vall d'Hebron University Hospital, Barcelona, Spain; Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; Liver Unit, Internal Medicine Department, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Mar Riveiro-Barciela
- Liver Unit, Internal Medicine Department, Vall d'Hebron University Hospital, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto Carlos III, Barcelona, Spain
| | - Ariadna Rando-Segura
- Biochemistry and Microbiology Department, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Cristina Marcos-Fosch
- Emergency Room Department, Vall d'Hebron University Hospital, Barcelona, Spain; Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; Liver Unit, Internal Medicine Department, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Luisa Roade
- Liver Unit, Internal Medicine Department, Vall d'Hebron University Hospital, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto Carlos III, Barcelona, Spain
| | - Fernando Velázquez
- Biochemistry and Microbiology Department, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Francisco Rodríguez-Frías
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto Carlos III, Barcelona, Spain; Biochemistry and Microbiology Department, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Rafael Esteban
- Liver Unit, Internal Medicine Department, Vall d'Hebron University Hospital, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto Carlos III, Barcelona, Spain
| | - Maria Buti
- Liver Unit, Internal Medicine Department, Vall d'Hebron University Hospital, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto Carlos III, Barcelona, Spain.
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22
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Elkwafi G, Mohamed N, Elabbar F, Alnajjar R. Flavonoid content of the Libyan Onosma Cyrenaicum: isolation, identification, electronic chemical reactivity, drug likeness, docking, and MD study. J Biomol Struct Dyn 2021; 40:7351-7366. [PMID: 33685329 DOI: 10.1080/07391102.2021.1897046] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In this work, an attempt to identify the flavonoid content of the Libyan Onosma Cyrenaicum led to the isolation of three flavonoids 7,8-dihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one(GE-001), 5,7-dihydroxy-2-(3-hydroxy-4-methoxy phenyl)-4H-chromen-4-one (GE-002) and 5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-chromen-4-one (GE-003), the isolated compounds were characterized using 1H and 13C-NMR techniques. A further DFT study at ωB97-XD with 6-311++G** basis set in water was conducted to calculate the isolated compounds' global and local reactivity descriptors and Fukui indices along with their antioxidant activity. The drug-likeness and bioactivity properties of the isolated compounds were estimated and discussed. Finally, GE-001, GE-002, and GE-003 were docked into HCV NS5B polymerase active siteand this was followed by molecular dynamic simulation to certify the obtained docking result and to obtain the MM-GBSA free binding energyy of the isolated compounds. Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Ghazala Elkwafi
- Department of Chemistry, Faculty of Science, University of Benghazi, Benghazi, Libya
| | - Najwa Mohamed
- Department of Medicinal Chemistry, Faculty of Pharmacy, University of Benghazi, Benghazi, Libya
| | - Fakhri Elabbar
- Department of Chemistry, Faculty of Science, University of Benghazi, Benghazi, Libya
| | - Radwan Alnajjar
- Department of Chemistry, Faculty of Science, University of Benghazi, Benghazi, Libya.,Department of Chemistry, University of Cape Town, Rondebosch, South Africa
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Qureshi N, Tadesse M, Tran N, Henderson S. Establishing an Epidemiologic Profile of Hepatitis C Virus Infection at the Los Angeles County Jail. Public Health Rep 2021; 136:726-735. [PMID: 33602004 DOI: 10.1177/0033354920988610] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022] Open
Abstract
OBJECTIVE The hepatitis C virus (HCV) is the most common blood-borne infection in the United States. Although 2% to 3% of the global population is estimated to be infected with HCV, an estimated 18% of the US prison population may be infected. The objective of this study was to establish an epidemiologic profile of HCV infection in the largest urban jail system in the United States. METHODS We retrospectively analyzed 20 years of data on demographic characteristics, risk factors, and HCV positivity among 80 681 individuals incarcerated at the Los Angeles County Jail who were tested for HCV infection from January 1, 2000, through December 31, 2019. We used multivariate logistic regression analysis to determine predictors of HCV positivity. RESULTS Of the 80 681 individuals tested, 27 881 (34.6%) had positive test results for HCV infection. In the multivariate analysis, HCV positivity was most strongly associated with injection drug use (adjusted odds ratio [aOR] = 34.9; 95% CI, 24.6-49.5) and being born during 1946-1955 (aOR = 13.0; 95% CI, 11.9-14.2). Men were more likely than women to have HCV infection (aOR = 1.4; 95% CI, 1.3-1.5), and Hispanic (aOR = 4.2; 95% CI, 3.9-4.4) and non-Hispanic White (aOR = 3.8; 95% CI, 3.5-4.0) individuals were more likely than non-Hispanic African American individuals to have HCV infection. Noninjection drug use, homelessness, and mental health issues were also significantly associated with HCV positivity. CONCLUSION Even in the absence of resources for universal screening for HCV infection, the creation of a risk profile and its implementation into a screening program may be a beneficial first step toward improving HCV surveillance and establishing an accurate estimate of HCV infection in the incarcerated population.
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Affiliation(s)
- Nazia Qureshi
- 5141 Correctional Health Services, Los Angeles County Department of Health Services, Los Angeles, CA, USA
| | - Martha Tadesse
- 5141 Correctional Health Services, Los Angeles County Department of Health Services, Los Angeles, CA, USA
| | - NgocDung Tran
- 5141 Correctional Health Services, Los Angeles County Department of Health Services, Los Angeles, CA, USA
| | - Sean Henderson
- 5141 Correctional Health Services, Los Angeles County Department of Health Services, Los Angeles, CA, USA
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de Bitencorte JT, Rech TF, Lunge VR, dos Santos DC, Álvares-da-Silva MR, Simon D. Association of interferon lambda-4 rs12979860 polymorphism with hepatocellular carcinoma in patients with chronic hepatitis C infection. World J Hepatol 2021; 13:109-119. [PMID: 33584990 PMCID: PMC7856861 DOI: 10.4254/wjh.v13.i1.109] [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: 07/31/2020] [Revised: 11/09/2020] [Accepted: 11/17/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatitis C virus (HCV) infection is a public health concern worldwide. Several factors, including genetic polymorphisms, may be evolved in the progression of HCV infection to liver diseases. Interferon lambdas (IFNLs) modulate the immune response during viral infections. IFNLs induce antiviral activity, interfering in the viral replication by promoting the expression of several genes that regulate immunological functions. The interferon lambda-4 (IFNL4) rs12979860 polymorphism, which is characterized by a C to T transition in intron 1, is associated with spontaneous and treatment-induced clearance of HCV infection and may play a role in the development of HCV-associated liver diseases, including hepatocellular carcinoma (HCC).
AIM To investigate the association of IFNL4 rs12979860 polymorphism with fibrosis, cirrhosis, and HCC in patients with chronic HCV infection.
METHODS This study was comprised of 305 chronic HCV-infected patients (53 fibrosis, 154 cirrhosis, and 98 HCC cases). The control group was comprised of 260 HCV-negative healthy individuals. The IFNL4 rs12979860 polymorphism was genotyped using the TaqMan assay. Fibrosis was diagnosed based on liver biopsy findings, while cirrhosis was diagnosed through clinical, laboratory, anatomopathological, and/or imaging data. HCC was diagnosed through imaging tests, tumor, and/or anatomopathological markers.
RESULTS The T allele was observed in the three groups of patients (fibrosis, cirrhosis, and HCC) at a significantly higher frequency when compared with the control group (P = 0.047, P < 0.001, and P = 0.01, respectively). Also, genotype frequencies presented significant differences between the control group and cirrhosis patients (P < 0.001) as well as HCC patients (P = 0.002). The risk analysis was performed using the codominant and dominant T allele models. In the codominant model, it was observed that the CT genotype showed an increased risk of developing cirrhosis in comparison with the CC genotype [odds ratio (OR) = 2.53; 95% confidence interval (CI): 1.55-4.15; P < 0.001] as well as with HCC (OR = 2.54; 95%CI: 1.44-4.56; P = 0.001). A similar result was observed in the comparison of the TT vs CC genotype between the control group and cirrhosis group (OR = 2.88; 95%CI: 1.44-5.77; P = 0.001) but not for HCC patients. In the dominant T allele model, the CT + TT genotypes were associated with an increased risk for progression to cirrhosis (OR = 2.60; 95%CI: 1.63-4.19; P < 0.001) and HCC (OR = 2.45; 95%CI: 1.42-4.31; P = 0.001).
CONCLUSION These findings suggest that the T allele of IFNL4 rs12979860 polymorphism is associated with the development of cirrhosis and HCC in chronic HCV-infected patients.
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Affiliation(s)
- Jóice Teixeira de Bitencorte
- PPG Biologia Celular e Molecular Aplicada à Saúde, Universidade Luterana do Brasil, Canoas 92425-900, Rio Grande do Sul, Brazil
| | - Tássia Flores Rech
- PPG Biologia Celular e Molecular Aplicada à Saúde, Universidade Luterana do Brasil, Canoas 92425-900, Rio Grande do Sul, Brazil
| | - Vagner Ricardo Lunge
- PPG Biologia Celular e Molecular Aplicada à Saúde, Universidade Luterana do Brasil, Canoas 92425-900, Rio Grande do Sul, Brazil
| | - Deivid Cruz dos Santos
- Division of Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil
| | - Mário Reis Álvares-da-Silva
- Division of Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil
| | - Daniel Simon
- PPG Biologia Celular e Molecular Aplicada à Saúde, Universidade Luterana do Brasil, Canoas 92425-900, Rio Grande do Sul, Brazil
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Mohamed AA, Hemeda AA, Aziz RK, Abdel-Hakeem MS, Ali-Tammam M. Body mass index (BMI) and alpha-fetoprotein (AFP) level correlate with the severity of HCV-induced fibrosis in a cohort of Egyptian patients with chronic HCV. FUTURE JOURNAL OF PHARMACEUTICAL SCIENCES 2020. [DOI: 10.1186/s43094-020-00085-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Abstract
Background
Viral hepatitis is the seventh leading cause of mortality globally, and half of this mortality is attributed to hepatitis C virus (HCV). Egypt has the highest HCV prevalence worldwide, with an estimated 14.7% of the population being HCV-positive. HCV infection is the primary cause of liver fibrosis, cirrhosis, and hepatocellular carcinoma. Liver fibrosis varies in severity during chronic HCV infection, and 10–20% of chronic hepatitis C (CHC) patients with severe fibrosis develop cirrhosis. The goal of this work was to assess the clinico-demographic predictors of severity of HCV-induced fibrosis in a cohort of Egyptian patients.
Results
A cohort of Egyptian patients with chronic HCV genotype 4a infection showed significant association between severe fibrosis stages and obesity, represented by a higher body mass index (BMI), low albumin level, high alpha-fetoprotein (AFP) level, low thyroid-stimulating hormone (TSH) level, and high alkaline phosphatase (ALP) level. Multivariate analysis delineated BMI, TSH, and ALP as independent significant variables that could predict the risk of fibrosis severity in HCV infections.
Conclusion
This study argues in favor of using the biomarker profile of CHC patients infected with HCV genotype 4a to identify patients at higher risk of developing severe fibrosis, which is a necessary first step towards precision medicine via patient stratification.
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Xu L, Yu D, Yao YL, Gu T, Zheng X, Wu Y, Luo RH, Zheng YT, Zhong J, Yao YG. Tupaia MAVS Is a Dual Target during Hepatitis C Virus Infection for Innate Immune Evasion and Viral Replication via NF-κB. THE JOURNAL OF IMMUNOLOGY 2020; 205:2091-2099. [PMID: 32907995 DOI: 10.4049/jimmunol.2000376] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 08/07/2020] [Indexed: 01/02/2023]
Abstract
Hepatitis C virus (HCV) infection is the cause of severe liver disease in many people. The restricted species tropism of HCV hinders the research and development of drugs and vaccines. The Chinese tree shrew (Tupaia belangeri chinensis) is a close relative of primates and can be infected by HCV, but the underlying mechanisms are unknown. In this study, we have characterized the functions of tree shrew MAVS (tMAVS) in response to HCV infection and defined the capacity of HCV replication. HCV was shown to be colocalized with tMAVS in primary tree shrew hepatocytes and cleaved tMAVS at site Cys508 via its NS3/4A protease, with a modulating effect by site Glu506 of tMAVS. The tMAVS cleavage by HCV NS3/4A impaired the IRF3-mediated induction of IFN-β but maintained the activated NF-κB signaling in the tree shrew primary cells. Activation of the tMAVS-dependent NF-κB signaling inversely inhibited HCV replication and might limit the establishment of persistent infection. Overall, our study has revealed an elegant example of the balance between the host defenses and HCV infection via the MAVS-mediated antiviral signaling and has provided an insight into the mechanisms underpinning HCV infection in the Chinese tree shrew.
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Affiliation(s)
- Ling Xu
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.,Kunming Institute of Zoology - Chinese University of Hong Kong Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
| | - Dandan Yu
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.,Kunming Institute of Zoology - Chinese University of Hong Kong Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
| | - Yu-Lin Yao
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.,Kunming Institute of Zoology - Chinese University of Hong Kong Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.,Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China
| | - Tianle Gu
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.,Kunming Institute of Zoology - Chinese University of Hong Kong Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.,Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China
| | - Xiao Zheng
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.,Kunming Institute of Zoology - Chinese University of Hong Kong Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.,School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230026, China
| | - Yong Wu
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.,Kunming Institute of Zoology - Chinese University of Hong Kong Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
| | - Rong-Hua Luo
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.,Kunming Institute of Zoology - Chinese University of Hong Kong Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
| | - Yong-Tang Zheng
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.,Kunming Institute of Zoology - Chinese University of Hong Kong Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
| | - Jin Zhong
- Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yong-Gang Yao
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China; .,Kunming Institute of Zoology - Chinese University of Hong Kong Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.,Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China.,National Resource Center for Non-Human Primates, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650107, China; and.,National Research Facility for Phenotypic and Genetic Analysis of Model Animals (Primate Facility), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650107, China
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Nanowire Aptamer-Sensitized Biosensor Chips with Gas Plasma-Treated Surface for the Detection of Hepatitis C Virus Core Antigen. COATINGS 2020. [DOI: 10.3390/coatings10080753] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Herein, we have demonstrated highly sensitive real-time biospecific detection of a protein marker of hepatitis C—the core antigen of hepatitis C virus (HCVcoreAg)—using a nanowire (NW) biosensor. The primary element of the NW-biosensor is a chip with p-type conductance, bearing silicon-on-insulator (SOI) nanowire structures on its surface. The nanowire structures are fabricated by gas-plasma treatment and electron beam lithography. The detection specificity was provided by sensitization of the sensor surface with aptamers against HCVcoreAg. The influence of buffer pH on the sensor response signal was studied. The effect of reverse polarity of the biosensor response signal with change from the acidic buffer pH to the neutral one was found. The lowest detectable HCVcoreAg concentration was determined to be 2.0 × 10−15 M in both acidic (pH 5.1) and neutral (pH 7.4) buffer solution. The proposed aptamer-sensitized sensor was also successfully applied to detect HCVcoreAg in serum samples of hepatitis C patients.
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Impact of Apo Lipoprotein E Gene Polymorphism on Hepatitis C Virus Disease Progression and Response to Direct Acting Antivirals in the Egyptian Population. HEPATITIS MONTHLY 2020. [DOI: 10.5812/hepatmon.101516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
Background: Hepatitis C virus infection is a major health problem in Egypt. Apo lipoprotein E and lipid metabolism are closely associated with the life cycle of the virus and play an important role in facilitating this infection. Objectives: To identify the role of apolipoprotein E gene polymorphism on hepatitis C virus disease progression and response to direct-acting antivirals (DAAs). Methods: We included twenty patients with chronic hepatitis C virus infection (CHC) from those who failed to respond to DAAs treatment and 76 subjects from responders. Apo lipoprotein E genotypes were determined using PCR restriction enzyme fragment length polymorphism (RFLP). Results: Apolipoprotein genotype E3/E3 was prevalent in 75.9% of patients. The distribution for the rest of genotypes was 16.9%, 3.6%, 2.4% and 1.2 % for Apo E3/E4, E2/E3, E4/E4, and E2/E2 respectively. No statistically significant difference was found regarding any of the Apo E genotypes with liver cirrhosis or response to therapy. Conclusions: No significant impact for any Apo E genotypes on CHC disease severity or response to therapy with direct-acting antivirals was detected among Egyptian patients.
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Pietrosi G, Russelli G, Barbera F, Curcio G, Tuzzolino F, Gallo A, Volpes R, Vizzini G, Conaldi PG. Direct-acting antivirals ability to clear intestinal HCV-RNA in liver transplant patients. Transpl Infect Dis 2020; 22:e13345. [PMID: 32495971 PMCID: PMC7685120 DOI: 10.1111/tid.13345] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 02/21/2020] [Accepted: 05/24/2020] [Indexed: 12/11/2022]
Abstract
The hepatitis C virus mainly infects the liver but is also able to infect and replicate in other body compartments by creating an extra-hepatic reservoir that may influence the persistence of the infection after transplantation. It is unknown whether antiviral drugs affect the viral extra-hepatic sites. We evaluated the ability of pegylated/interferon + ribavirin and sofosbuvir + ribavirin to clear the virus from the gastrointestinal mucosa of liver-transplanted patients with HCV recurrence after transplantation. A total of 51 liver-transplanted patients, 30 treated with pegylated/interferon + ribavirin (ERA1) and 21 treated with sofosbuvir + ribavirin (ERA2), were enrolled, and blood serum and gastrointestinal tissues analyzed for the presence of HCV-RNA. In the ERA1 group, the 46.6% of patients had a sustained viral response to antiviral treatment, and gastrointestinal biopsies were positive for HCV in 73.3% of cases, 54.5% of responders, and 45.5% of non-responders. In the ERA2 group, the 66.6% had a sustained viral response, and gastrointestinal HCV-RNA was present in the 14.3% of patients, all relapsers. Sofosbuvir + ribavirin cleared the intestinal HCV in 85.7% of patients with recurrent HCV infection, while pegylated/interferon + ribavirin cleared it in 26.6% of treated patients, demonstrating the better effectiveness of new direct antiviral agents in clearing HCV intestinal reservoir.
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Affiliation(s)
- Giada Pietrosi
- Hepatology Unit, Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, IRCCS ISMETT, Palermo, Italy
| | | | | | - Gabriele Curcio
- Endoscopy Service, Department of Diagnostic and Therapeutic Services, IRCCS ISMETT, Palermo, Italy
| | | | - Alessia Gallo
- Department of Research, IRCCS ISMETT, Palermo, Italy
| | - Riccardo Volpes
- Hepatology Unit, Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, IRCCS ISMETT, Palermo, Italy
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30
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Abstract
Hepatitis C virus (HCV) is associated with increased mortality and morbidity in patients with chronic kidney disease (CKD). The early detection and treatment of Hepatitis C associated with kidney disease is paramount to preventing the progressive loss of kidney function. HCV treatment until the advent of direct acting anti-viral agents (DAAs) was limited to interferon and ribavirin. Interferon and ribavirin treatment resulted in only modest success but with frequent adverse events and poor tolerability. Furthermore, interferon and ribavirin could not be used in certain patient populations including those with advanced CKD, were on dialysis, or those who have received a kidney transplant. DAAs have now made treatment possible in these sub-groups with a sustained viral response (SVR) of 90-100% and minimal side effects. DAAs have helped increase transplant rates by allowing for the use of HCV positive kidneys in recipients who are HCV negative. Although the choice of DAAs should be carefully considered and based on patient characteristics, concomitant medications, and HCV genotype.
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31
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Wu SF, Tseng CW, Ho YC, Chen YC, Ko PH, He YT, Tseng KC. Regulatory T Cell Function Modulated After Successful Direct-Acting Antiviral Treatment for Chronic Hepatitis C Patients. Dig Dis Sci 2020; 65:1385-1395. [PMID: 31559553 DOI: 10.1007/s10620-019-05850-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 09/17/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUNDS Regulatory T cells (Tregs) affect the pathogenesis of chronic hepatitis C (CHC) infection. AIMS This study evaluated the function of Tregs in CHC patients receiving the standard direct-acting antiviral agents (DAA) treatment. METHODS CHC patients (n = 20) who received DAA treatment, clinical data, and function of Tregs were checked at baseline, Week 4, end of treatment (EOT), and 12 weeks after EOT (SVR 12). Treg-mediated inhibition was measured. The cytokine expression and fold change of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, IL-10, and transforming growth factor (TGF)-β with/without Treg inhibition were also detected. RESULTS The cohort included 14 females with a mean age of 59.8 ± 11.5 years. Nineteen had HCV genotype 1. The HCV RNA level was 6.17 ± 0.70 log IU/mL. All patients reached the sustained virologic response. The frequency of CD4+Foxp3+T cells decreased from baseline to EOT and returned at SVR 12. The inhibitory function of Tregs decreased during treatment and then restored (baseline vs. EOT, P = 0.0393; EOT vs. SVR 12, P = 0.0052). The cytokine expression and fold change of IFN-γ and TNF-α were highest at EOT and then decreased at SVR 12. The fold change of IL-10 was lowest at EOT and then increased at SVR 12. The fold change of TGF-β was significantly increased at Week 4 and SVR 12 compared to baseline. CONCLUSIONS The frequency and inhibitory function of Tregs declined gradually from baseline to EOT and then increased from EOT to SVR 12 in CHC patients receiving DAA therapy. The expression of IFN-γ, TNF-α, IL-10, and TGF-β parallelled Treg function.
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Affiliation(s)
- Shu-Fen Wu
- Department of Biomedical Sciences and Institute of Molecular Biology, National Chung Cheng University, Chia-yi, Taiwan.,Center for Innovative Research on Aging Society (CIRAS), National Chung Cheng University, Chia-yi, Taiwan
| | - Chih-Wei Tseng
- Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No 2, Ming-Shen Road, Dalin Town, Chia-yi, 622, Taiwan.,School of Medicine, Tzuchi University, Hualien, Taiwan
| | - Yun-Che Ho
- Department of Biomedical Sciences and Institute of Molecular Biology, National Chung Cheng University, Chia-yi, Taiwan
| | - Yen-Chun Chen
- Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No 2, Ming-Shen Road, Dalin Town, Chia-yi, 622, Taiwan
| | - Ping-Hung Ko
- Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No 2, Ming-Shen Road, Dalin Town, Chia-yi, 622, Taiwan
| | - Yi-Ting He
- Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No 2, Ming-Shen Road, Dalin Town, Chia-yi, 622, Taiwan
| | - Kuo-Chih Tseng
- Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No 2, Ming-Shen Road, Dalin Town, Chia-yi, 622, Taiwan. .,School of Medicine, Tzuchi University, Hualien, Taiwan.
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32
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Kim J, Haacker M, Keshavjee S, Atun R. Cost-effectiveness of scaling up of hepatitis C screening and treatment: a modelling study in South Korea. BMJ Glob Health 2019; 4:e001441. [PMID: 31263587 PMCID: PMC6570985 DOI: 10.1136/bmjgh-2019-001441] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 04/22/2019] [Accepted: 04/27/2019] [Indexed: 12/20/2022] Open
Abstract
Background The prices and the coverage of effective direct-acting antivirals (DAAs) to treat hepatitis C vary across countries. South Korea expanded DAAs coverage through national health insurance. This study aims to analyse the cost-effectiveness of scale-up of hepatitis C screening and treatment with DAAs in South Korea, a high-income country. Methods This study uses a compartmental age–sex structured model of progression of hepatitis C to analyse effects of different policy choices for the scale up of screening and treatment with DAAs on hepatitis C disease burden and costs from 2017 to 2050. Policy scenarios considered in our study are (1) no treatment, (2) status quo, (3) screening population aged over 60 years, (4) screening population over 40 years and (5) screening population aged over 20 years. Results The continuation of current policy with the expansion of DAAs coverage is estimated to reduce the prevalence of hepatitis C antibody from 0.6% in 2015 to 0.25% in 2050 of the adult population. Status quo policy, screening from age 60, screening from age 40 and screening from age 20 are cost-effective in terms of averted infection at estimated incremental cost-effective ratio of US$101 208, US$111 770, US$107 909 and US$229 604. Conclusions The expansion of DAAs coverage by the national health insurance is highly effective in alleviating hepatitis C disease burden. The scale-up of screening and treatment with DAAs for targeted adult population with high prevalence of hepatitis C is cost-effective. This study provides a case for policy-makers to invest in rapid expansion of hepatitis C comprehensive screening and treatment with DAAs.
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Affiliation(s)
- Jungyeon Kim
- Department of Global Health and Population, Harvard TH Chan School of Public Health, Harvard University, Boston, Massachusetts, USA
| | - Markus Haacker
- Department of Global Health and Population, Harvard TH Chan School of Public Health, Harvard University, Boston, Massachusetts, USA
- Centre for Global Health Economics, University College London, London, UK
| | - Salmaan Keshavjee
- Center for Global Health Delivery - Dubai, Harvard Medical School, Harvard University, Boston, Massachusetts, USA
| | - Rifat Atun
- Department of Global Health and Population, Harvard TH Chan School of Public Health, Harvard University, Boston, Massachusetts, USA
- Department of Global Health and Social Medicine, Harvard Medical School, Harvard University, Boston, Massachusetts, USA
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Ghazal K, Morales O, Barjon C, Dahlqvist G, Aoudjehane L, Ouaguia L, Delhem N, Conti F. Early high levels of regulatory T cells and T helper 1 may predict the progression of recurrent hepatitis C after liver transplantation. Clin Res Hepatol Gastroenterol 2019; 43:273-281. [PMID: 30713032 DOI: 10.1016/j.clinre.2018.10.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 09/25/2018] [Accepted: 10/02/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Immune response failure against hepatitis C virus (HCV) has been associated with an increased regulatory T cell (Treg) activity. After liver transplantation (LT), 80% of patients experience an accelerated progression of hepatitis C recurrence. The aim of this work was to assess the involvement of Tregs, T helper (Th) 1, 2 and 17 cells in recurrent hepatitis C. METHODS Peripheral blood cells obtained before and one month after LT from 22 recipients were analysed. Forty-four key molecules related to Treg, Th1, 2 and 17 responses, were evaluated using qRT-PCR. Liver recipients were classified in two groups according to graft fibrosis evaluated by the METAVIR score on the biopsy performed one year after LT (mild: F ≤ 1, n = 13; severe: F > 1, n = 9). Patients developing a severe recurrence were compared with patients with a mild recurrence. RESULTS mRNA levels of Treg markers obtained one month after LT were significantly increased in patients with a severe disease course when compared to patients with a mild recurrence. Markers of the Th1 response were elevated in the same group. No differences in the markers determined before LT were observed. CONCLUSION These findings suggest that Treg, induced by a multifactorial process, which could include a strong Th1 response itself, may play a role in suppressing the early antiviral response, leading to a severe recurrence of hepatitis C.
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Affiliation(s)
- K Ghazal
- Sorbonne Universités, UPMC Université Paris 06, INSERM, UMR_S 938, Saint-Antoine Research Center, 75012 Paris, France; AP-HP, Bicêtre Hospital, Biochemistry Laboratory, 94275 Le Kremlin-Bicêtre cedex, France.
| | - O Morales
- CNRS, UMR8161, Institut de Biologie de Lille, Université de Lille, Institut Pasteur de Lille, IFR 142, 59021 Lille cedex, France
| | - C Barjon
- Sorbonne Universités, UPMC Université Paris 06, INSERM, UMR_S 938, Saint-Antoine Research Center, 75012 Paris, France; De Duve Institute, Université catholique de Louvain, 1200 Brussels, Belgium
| | - G Dahlqvist
- Sorbonne Universités, UPMC Université Paris 06, INSERM, UMR_S 938, Saint-Antoine Research Center, 75012 Paris, France; Cliniques Universitaires Saint-Luc, 1200 Woluwe-Saint-Lambert, Belgium
| | - L Aoudjehane
- Sorbonne Universités, UPMC Université Paris 06, INSERM, UMR_S 938, Saint-Antoine Research Center, 75012 Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), 75013 Paris, France
| | - L Ouaguia
- CNRS, UMR8161, Institut de Biologie de Lille, Université de Lille, Institut Pasteur de Lille, IFR 142, 59021 Lille cedex, France
| | - N Delhem
- CNRS, UMR8161, Institut de Biologie de Lille, Université de Lille, Institut Pasteur de Lille, IFR 142, 59021 Lille cedex, France
| | - F Conti
- Sorbonne Universités, UPMC Université Paris 06, INSERM, UMR_S 938, Saint-Antoine Research Center, 75012 Paris, France; AP-HP, Pitié-Salpêtrière hospital, Unité Médicale de Transplantation Hépatique, 75013 Paris, France
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Management of Hepatitis C in Delaware Prisons: : Approaching Microenvironmental Eradication. Dela J Public Health 2019; 5:20-27. [PMID: 34467026 PMCID: PMC8396757 DOI: 10.32481/djph.2019.05.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
The management of chronic hepatitis C virus (HCV) infection has been transformed due to the arrival of HCV-specific Direct-Acting Antivirals (DAAs), which are safer, more effective, and better tolerated than the interferon-based therapies that preceded them. Compared with community healthcare systems, many prison healthcare systems have been slower to adopt the routine use of HCV DAAs despite the fact that HCV infection disproportionately affects individuals in correctional institutions. In 2015, the Delaware Department of Correction (DDOC) launched a treatment program that prioritized treatment for patients who were at greatest risk of disease complications. To date, 327/345 (95%) of eligible current HCV patients have initiated DAA therapy. A total of 196/199 (98.4%) patients who have initiated treatment and who have post-treatment data available have achieved sustained virologic response, defined as undetectable HCV viral load 12 weeks after treatment. Applying a concept of microenvironmental eradication, it can reasonably be concluded that that DDOC is approaching this benchmark with regard to chronic HCV infection and will soon enter a “maintenance phase,” during which it will be feasible to treat new cases of HCV in real time. Correctional systems with significant numbers of untreated hepatitis C patients may want to consider implementing HCV treatment programs that focus on cost-effectiveness and prioritize treatment for patients who are at greatest risk of disease complications.
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Sandmann L, Schulte B, Manns MP, Maasoumy B. Treatment of Chronic Hepatitis C: Efficacy, Side Effects and Complications. Visc Med 2019; 35:161-170. [PMID: 31367613 DOI: 10.1159/000500963] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Accepted: 05/14/2019] [Indexed: 12/13/2022] Open
Abstract
Background Chronic hepatitis C virus (HCV) infection can lead to liver cirrhosis and its complications. Viral eradication is essential to prevent disease progression and reduces liver-related mortality and morbidity. Since the availability of direct-acting antivirals (DAA), HCV treatment has changed significantly. Current treatment strategies for different groups of patients as well as potential risks and caveats will be discussed in this review. Summary Interferon-free (IFN-free) treatment not only shortens treatment duration, but also achieves high rates of viral clearance and is overall well tolerated. Genotype-restricted but also pangenotypic combinations are available. Usually two DAA of different drug classes are combined. For the majority of the patients, treatment duration ranges from 8 to 12 weeks. Liver and kidney function as well as prior treatment experience and potential drug-drug interactions influence substance choices and treatment duration. However, modern IFN-free treatment is not only safer, but also overall far more simplified and effective. Global HCV eradication might be an ambitious but not completely unrealistic goal to pursue. Key Messages IFN-free antiviral treatment is safe and well tolerated. Patients can be treated almost independently of liver function or concomitant disease. Viral eradication is associated with reduced morbidity and mortality and better quality of life.
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Affiliation(s)
- Lisa Sandmann
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Benjamin Schulte
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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Shen Z, Zhu X, Zhang H, Chen H, Niu J, Chen G, Li X, Ding Y. Pharmacokinetic Profile of a Generic Formulation of Sofosbuvir and Its Metabolite GS-331007 in Healthy Chinese Subjects. Clin Pharmacol Drug Dev 2019; 8:1073-1080. [PMID: 30900816 DOI: 10.1002/cpdd.674] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 02/26/2019] [Indexed: 01/08/2023]
Abstract
Sofosbuvir is an NS5B nucleotide inhibitor for the treatment of hepatitis C viral infection. In this study the pharmacokinetics (PK) and safety of single and multiple doses of generic sofosbuvir were investigated in healthy Chinese subjects. Twelve subjects (6 male and 6 female) were enrolled in this study. The PK parameters of sofosbuvir and its metabolite (GS-331007) in both blood and urine samples were analyzed after dosing by the established liquid chromatography tandem mass spectrometry analytical method. The safety/tolerability assessment consisted of documenting adverse events, vital signs, electrocardiogram, and laboratory test results. Sofosbuvir was well tolerated. Major PK parameters of the generic formulation of sofosbuvir were similar to those found in previous reports. These data support further clinical evaluation of this generic formulation of sofosbuvir.
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Affiliation(s)
- Zhenwei Shen
- Institute of Immunology, Academy of Translational Medicine, The First Hospital of Jilin University, Jilin University, Changchun, People's Republic of China
| | - Xiaoxue Zhu
- Phase I Clinical Trial Unit, China-Frontage USA, The First Hospital of Jilin University, Jilin University, Changchun, People's Republic of China
| | - Hong Zhang
- Phase I Clinical Trial Unit, China-Frontage USA, The First Hospital of Jilin University, Jilin University, Changchun, People's Republic of China
| | - Hong Chen
- Phase I Clinical Trial Unit, China-Frontage USA, The First Hospital of Jilin University, Jilin University, Changchun, People's Republic of China
| | - Junqi Niu
- Phase I Clinical Trial Unit, China-Frontage USA, The First Hospital of Jilin University, Jilin University, Changchun, People's Republic of China
| | - Guiling Chen
- Phase I Clinical Trial Unit, China-Frontage USA, The First Hospital of Jilin University, Jilin University, Changchun, People's Republic of China
| | - Xiaojiao Li
- Phase I Clinical Trial Unit, China-Frontage USA, The First Hospital of Jilin University, Jilin University, Changchun, People's Republic of China
| | - Yanhua Ding
- Phase I Clinical Trial Unit, China-Frontage USA, The First Hospital of Jilin University, Jilin University, Changchun, People's Republic of China
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USP15 Participates in Hepatitis C Virus Propagation through Regulation of Viral RNA Translation and Lipid Droplet Formation. J Virol 2019; 93:JVI.01708-18. [PMID: 30626683 DOI: 10.1128/jvi.01708-18] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Accepted: 12/23/2018] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C virus (HCV) utilizes cellular factors for efficient propagation. Ubiquitin is covalently conjugated to the substrate to alter its stability or to modulate signal transduction. In this study, we examined the importance of ubiquitination for HCV propagation. We found that inhibition of deubiquitinating enzymes (DUBs) or overexpression of nonspecific DUBs impaired HCV replication, suggesting that ubiquitination regulates HCV replication. To identify specific DUBs involved in HCV propagation, we set up RNA interference (RNAi) screening against DUBs and successfully identified ubiquitin-specific protease 15 (USP15) as a novel host factor for HCV propagation. Our studies showed that USP15 is involved in translation of HCV RNA and production of infectious HCV particles. In addition, deficiency of USP15 in human hepatic cell lines (Huh7 and Hep3B/miR-122 cells) but not in a nonhepatic cell line (293T cells) impaired HCV propagation, suggesting that USP15 participates in HCV propagation through the regulation of hepatocyte-specific functions. Moreover, we showed that loss of USP15 had no effect on innate immune responses in vitro and in vivo We also found that USP15-deficient Huh7 cells showed reductions in the amounts of lipid droplets (LDs), and the addition of palmitic acids restored the production of infectious HCV particles. Taken together, these data suggest that USP15 participates in HCV propagation by regulating the translation of HCV RNA and the formation of LDs.IMPORTANCE Although ubiquitination has been shown to play important roles in the HCV life cycle, the roles of deubiquitinating enzymes (DUBs), which cleave ubiquitin chains from their substrates, in HCV propagation have not been investigated. Here, we identified USP15 as a DUB regulating HCV propagation. USP15 showed no interaction with viral proteins and no participation in innate immune responses. Deficiency of USP15 in Huh7 cells resulted in suppression of the translation of HCV RNA and reduction in the amounts of lipid droplets, and the addition of fatty acids partially restored the production of infectious HCV particles. These data suggest that USP15 participates in HCV propagation in hepatic cells through the regulation of viral RNA translation and lipid metabolism.
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Negash AA, Olson RM, Griffin S, Gale M. Modulation of calcium signaling pathway by hepatitis C virus core protein stimulates NLRP3 inflammasome activation. PLoS Pathog 2019; 15:e1007593. [PMID: 30811485 PMCID: PMC6392285 DOI: 10.1371/journal.ppat.1007593] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Accepted: 01/23/2019] [Indexed: 12/19/2022] Open
Abstract
Hepatitis C virus (HCV) infection remains a major cause of hepatic inflammation and liver disease. HCV triggers NLRP3 inflammasome activation and interleukin-1β (IL-1β) production from hepatic macrophages, or Kupffer cells, to drive the hepatic inflammatory response. Here we examined HCV activation of the NLRP3 inflammasome signaling cascade in primary human monocyte derived macrophages and THP-1 cell models of hepatic macrophages to define the HCV-specific agonist and cellular processes of inflammasome activation. We identified the HCV core protein as a virion-specific factor of inflammasome activation. The core protein was both necessary and sufficient for IL-1β production from macrophages exposed to HCV or soluble core protein alone. NLRP3 inflammasome activation by the HCV core protein required calcium mobilization linked with phospholipase-C activation. Our findings reveal a molecular basis of hepatic inflammasome activation and IL-1β release triggered by HCV core protein. This study deciphers the molecular mechanism of Hepatitis C virus (HCV)-induced hepatic inflammation. HCV triggers NLRP3 inflammasome activation and IL-1β release from hepatic macrophages, thus driving liver inflammation. Using biochemical, virological, and genetic approaches we identified the HCV core protein as the specific viral stimulus that triggers intracellular calcium signaling linked with phospholipase-C activation to drive NLRP3 inflammasome activation and IL-1β release in macrophages.
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Affiliation(s)
- Amina A. Negash
- Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, Washington, United States of America
| | - Rebecca M. Olson
- Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, Washington, United States of America
| | - Stephen Griffin
- School of Medicine, Faculty of Medicine and Health, University of Leeds, St James’ University Hospital, Leeds, United Kingdom
| | - Michael Gale
- Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, Washington, United States of America
- * E-mail:
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Outcomes and costs of treating hepatitis C patients with second-generation direct-acting antivirals: results from the German Hepatitis C-Registry. Eur J Gastroenterol Hepatol 2019; 31:230-240. [PMID: 30325794 DOI: 10.1097/meg.0000000000001283] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE Chronic hepatitis C virus infection is associated with a significant health burden. Long-term consequences are the development of liver cirrhosis and hepatocellular carcinoma. The introduction of direct-acting antivirals (DAA) has led to an increase in sustained virologic response rates (SVR), but is accompanied by higher treatment costs. The aim of this study was to assess the outcomes and costs of treating hepatitis C virus infected patients with DAAs in clinical practice in Germany. PATIENTS AND METHODS Data were derived from a noninterventional study including a pharmacoeconomic subset of 2673 patients with genotypes 1 and 3 who initiated and completed treatment between February 2014 and February 2017. Sociodemographic and clinical parameters as well as resource utilization were collected using a web-based data recording system. Costs were calculated using official remuneration schemes. RESULTS The mean age of the patients was 54.6 years; 48% were men. 93.5% of all patients achieved an SVR. The average total treatment costs were &OV0556;67 979 (&OV0556;67 131 medication costs, &OV0556;824 ambulatory care, &OV0556;24 hospital costs). The average costs per SVR of &OV0556;72 705 were calculated. Differences in SVR and costs according to genotype, treatment regimen, treatment experience, and cirrhosis were observed. Quality-of-life data showed no or a minimal decrease during treatment. CONCLUSION This analysis confirms high SVR rates for newly introduced DAAs in a real-world setting. Costs per SVR estimated are comparable to first-generation DAA. Given the fact that the costs for the currently used treatment regimens have declined, it can be assumed that the costs per SVR have also decreased. Our insight into real-world outcomes and costs can serve as a basis for a comparison with the mentioned newly introduced treatment regimens.
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Nguyen E, Trinh S, Trinh H, Nguyen H, Nguyen K, Do A, Levitt B, Do S, Nguyen M, Purohit T, Shieh E, Nguyen MH. Sustained virologic response rates in patients with chronic hepatitis C genotype 6 treated with ledipasvir+sofosbuvir or sofosbuvir+velpatasvir. Aliment Pharmacol Ther 2019; 49:99-106. [PMID: 30467877 DOI: 10.1111/apt.15043] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Revised: 09/19/2018] [Accepted: 10/10/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatitis C virus (HCV) genotype 6 (GT 6) is the predominant genotype among certain Asian populations. The availability of newer DAA options is limited in many parts of Asia. AIM To compare sustained virologic response (SVR-12) rates between ledipasvir and sofosbuvir (LDV+SOF) and velpatasvir+SOF (SOF+VEL) for patients with HCVGT6 infection. METHOD Retrospective study of consecutive adult HCVGT6 patients identified via ICD 9 code: 070.5 from United States treatment centers. Treatment was LDV+SOF or SOF+VEL for 8-24 weeks. A 1:1 propensity score matching (PSM) on HCV RNA, cirrhosis, alanine aminotransferase, aspartate aminotransferase, platelets, and fibrosis score was conducted among the treatment-naïve HCVGT6 patients to balance groups and isolate treatment effects. RESULTS After exclusion criteria, 149 patients remained (n = 135 treatment-naïve; n = 14 treatment-experienced). The mean age was 63.8 ± 10.2 years, 66.9% male, and 93.9% Vietnamese. In treatment-naïve arm, 52.2% LDV+SOF cohort were cirrhotic compared to 11.6% SOF+VEL cohort (P < 0.0001). SVR-12 for LDV+SOF was 96.4% and 100% for the SOF+VEL cohort (P = 0.22). SVR-12 for cirrhotic patients was 95.4% (n = 41/43) for LDV+SOF and 100.0% (n = 5/5) for SOF+VEL (P = 0.62). After PSM (n = 33 per group), LDV+SOF SVR-12 rate was 97.0% compared to SOF+VEL SVR-12 of 100% (P = 0.31). The treatment-experienced group (n = 14), were all treated with LDV+SOF with an SVR-12 of 92.3%. CONCLUSION Whether treatment-naïve, treatment-experienced, or cirrhotic patients with HCV GT 6 residing in the US had excellent outcomes when treated with SOF+VEL or LDV+SOF. Since LDV+SOF is more readily available globally, our results may provide clinicians with a treatment option when cost and availability limit the treatment choice.
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Affiliation(s)
| | - Sam Trinh
- Division of Gastroenterology and Hepatology, Stanford University, Stanford, California
| | - Huy Trinh
- San Jose Gastroenterology, San Jose, California
| | - Huy Nguyen
- San Jose Gastroenterology, San Jose, California
| | | | - Aivien Do
- Digestive Health Associates of Texas, P.A., Richardson, Texas
| | | | - Son Do
- Digestive Health Associates of Texas, P.A., Richardson, Texas
| | - My Nguyen
- San Jose Gastroenterology, San Jose, California
| | | | | | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Stanford University, Stanford, California
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Cacoub P, Comarmond C. Considering hepatitis C virus infection as a systemic disease. Semin Dial 2018; 32:99-107. [PMID: 30549107 DOI: 10.1111/sdi.12758] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatitis C virus (HCV) infection has been demonstrated to result in several adverse hepatic outcomes and has been associated with a number of important extrahepatic manifestations. The scope of extrahepatic clinical possibilities includes systemic diseases such as vasculitis and lymphoproliferative disorders, cardiovascular disease, myalgia, arthritis, and sicca syndrome. These end-organ effects of HCV may dominate the clinical course beyond the hepatic complications and significantly worsen the long-term prognosis of infected patients. Until several years ago, the standard of care for the treatment of HCV infection had been interferon-alpha-based regimens, which not only had limited effectiveness in achieving a cure but were often poorly tolerated, especially in patients with kidney disease. In those HCV-infected patients with significant systemic manifestations, the interferon-based regimens were problematic given their association with a wide variety of toxicities. The development of highly effective direct-acting antiviral agents to treat HCV infection presented an opportunity to improve the HCV care cascade with the eradication of HCV in most infected patients and by reducing the burden of both hepatic and extrahepatic complications.
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Affiliation(s)
- Patrice Cacoub
- UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Sorbonne Universités, UPMC Univ Paris 06, Paris, France.,INSERM, UMR_S 959, Paris, France.,CNRS, FRE3632, Paris, France.,Department of Internal Medicine and Clinical Immunology, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
| | - Cloé Comarmond
- UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Sorbonne Universités, UPMC Univ Paris 06, Paris, France.,INSERM, UMR_S 959, Paris, France.,CNRS, FRE3632, Paris, France.,Department of Internal Medicine and Clinical Immunology, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
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Gebrekristos G, Teweldemedhin M, Hagos L, Gebrewahid T, Gidey B, Gebreyesus H. Hepatitis C virus infections and associated risk factors in patients with diabetes mellitus; case control study in North West Tigray, Ethiopia. BMC Res Notes 2018; 11:873. [PMID: 30526647 PMCID: PMC6288925 DOI: 10.1186/s13104-018-3983-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 12/04/2018] [Indexed: 12/19/2022] Open
Abstract
Objective The objective of this study was to determine the seroprevalence of Hepatitis C virus among patients with Diabetes mellitus and healthy control groups in North West Tigray. Blood samples from each study subject was tested for Hepatitis C virus by using anti Hepatitis C virus antibody rapid test kits and confirmed using enzyme linked immuno sorbent assy. Result The overall seroprevalence of Hepatitis C virus, Hepatitis C virus among diabetic and non diabetic study subjects were found (16.7, 28, and 6) % respectively. Multi varate logistic regression analysis result shows that study subject with uvulotomy, previous history of immunosuppressive disease, and study subjects with fast blood glucose (≥ 126 mg/dl) showed statistically significant association with anti Hepatitis C virus antibody sero status [AOR (12.4 (3.5–18.3); 0.1 (0.03–0.5); and 8.6 (1.7–13)] respectively.
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Affiliation(s)
- Gebretsakan Gebrekristos
- Department of Medical Laboratory Sciences, College of Health Sciences, Aksum University, P.O. Box 298, Aksum, Tigray, Ethiopia.
| | - Mebrahtu Teweldemedhin
- Department of Medical Laboratory Sciences, College of Health Sciences, Aksum University, P.O. Box 298, Aksum, Tigray, Ethiopia
| | - Letebrhan Hagos
- Department of Medical Laboratory Sciences, College of Health Sciences, Aksum University, P.O. Box 298, Aksum, Tigray, Ethiopia
| | - Tuom Gebrewahid
- Department of Medical Laboratory Sciences, College of Health Sciences, Aksum University, P.O. Box 298, Aksum, Tigray, Ethiopia
| | - Berihu Gidey
- Department of Public Health, College of Health Science, Aksum University, Aksum, Tigray, Ethiopia
| | - Hailay Gebreyesus
- Department of Public Health, College of Health Science, Aksum University, Aksum, Tigray, Ethiopia
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Gong W, Guo X, Zhang Y. Depletion of MicroRNA-373 Represses the Replication of Hepatitis C Virus via Activation of Type 1 Interferon Response by Targeting IRF5. Yonsei Med J 2018; 59:1181-1189. [PMID: 30450852 PMCID: PMC6240574 DOI: 10.3349/ymj.2018.59.10.1181] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 09/18/2018] [Accepted: 10/16/2018] [Indexed: 02/06/2023] Open
Abstract
PURPOSE Hepatitis C virus (HCV) poses a risk of chronic liver disease and threatens a significant number of people worldwide. MicroRNAs (miRNAs) are linked to the regulation of hepatocarcinogenesis. Although miR-373 is required for HCV infection, the underlying mechanisms of miR-373 involvement in HCV replication remain elusive. MATERIALS AND METHODS Quantitative reverse transcription PCR assays were performed to detect the abundances of miR-373 and HCV RNA either in Huh 7.5 cells or liver biopsy specimens with HCV infection. Luciferase assay was employed to probe the interactions between miR-373 and interferon regulatory factor 5 (IRF5). Western blot was conducted to investigate the effect of miR-373 and IRF5 on HCV replication and activation of type 1 interferon (IFN) response in JFH1-infected Huh 7.5 cells. RESULTS HCV infection appeared to be caused by increased miR-373 expression. Addition of miR-373 promoted HCV RNA expression, while miR-373 depletion led to an inhibitive effect on HCV replication. Concordantly, IRF5, as a direct target, was limited by miR-373 in JFH1-infected Huh 7.5 cells. In addition, introduction of IRF5 protected HCV replication in the presence of abundant miR-373. Furthermore, the miR-373-mediated inhibitory effect on type 1 IFN response was ablated following IRF5 accumulation. CONCLUSION miR-373 abrogation reduced HCV replication via activation of type 1 IFN responses by targeting IRF5 in JFH1-infected Huh 7.5 cells, suggesting a promising therapeutic for treating HCV infection.
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Affiliation(s)
- Weifeng Gong
- Department of Blood Transfusion, Xi'an Central Hospital, Xi'an, China.
| | - Xiaobo Guo
- Hematological Research Institute, Xi'an Central Hospital, Xi'an, China
| | - Yangmin Zhang
- Department of Blood Transfusion, Xi'an Central Hospital, Xi'an, China
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Mori H, Fukuhara T, Ono C, Tamura T, Sato A, Fauzyah Y, Wada M, Okamoto T, Noda T, Yoshimori T, Matsuura Y. Induction of selective autophagy in cells replicating hepatitis C virus genome. J Gen Virol 2018; 99:1643-1657. [DOI: 10.1099/jgv.0.001161] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Affiliation(s)
- Hiroyuki Mori
- 1Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita-shi, Osaka 565-0871, Japan
| | - Takasuke Fukuhara
- 1Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita-shi, Osaka 565-0871, Japan
| | - Chikako Ono
- 1Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita-shi, Osaka 565-0871, Japan
| | - Tomokazu Tamura
- 1Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita-shi, Osaka 565-0871, Japan
| | - Asuka Sato
- 1Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita-shi, Osaka 565-0871, Japan
| | - Yuzy Fauzyah
- 1Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita-shi, Osaka 565-0871, Japan
| | - Masami Wada
- 1Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita-shi, Osaka 565-0871, Japan
- †Present address: Division of Virology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita-shi, Osaka 565-0871, Japan
| | - Toru Okamoto
- 1Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita-shi, Osaka 565-0871, Japan
| | - Takeshi Noda
- 2Center for Frontier Oral Science, Graduate School of Dentistry, Osaka University, 1-8 Yamadaoka, Suita-shi, Osaka 565-0871, Japan
| | - Tamotsu Yoshimori
- 3Department of Genetics, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita-shi, Osaka 565-0871, Japan
| | - Yoshiharu Matsuura
- 1Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita-shi, Osaka 565-0871, Japan
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Takamizawa S, Yamada T, Kitamura K, Hiraoka E. Difficulty of acute hepatitis C diagnosis in a hospitalised patient. BMJ Case Rep 2018; 11:11/1/e226907. [PMID: 30567115 DOI: 10.1136/bcr-2018-226907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
The hepatitis C virus (HCV) causes acute hepatitis C and is commonly detected via HCV antibody testing. However, delayed seroconversion of HCV antibodies and non-specific symptoms may hinder the diagnosis of this disease. A 71-year-old woman developed acute hepatitis while hospitalised for back pain. An HCV antibody test was negative, and she had no risk factors for hepatitis C. She was referred to our hospital for further evaluation. The HCV antibody test was repeated 16 days after the initial test; owing to a positive result, she was diagnosed with acute hepatitis C. Several months thereafter, the HCV spontaneously cleared. When diagnosing an HCV infection, the time at which the testing is performed needs to coincide with the time at which HCV antibody seroconversion occurs. Timely diagnosis of an HCV infection allows appropriate treatment during the acute phase which may prevent disease progression to the chronic phase.
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Affiliation(s)
- Shigemasa Takamizawa
- Department of Internal Medicine, Tokyo Bay Urayasu Ichikawa Medical Center, Urayasu, Japan
| | - Toru Yamada
- Department of Internal Medicine, Tokyo Bay Urayasu Ichikawa Medical Center, Urayasu, Japan
| | - Koichi Kitamura
- Department of Nephrology, Endocrinology, and Diabetes, Tokyo Bay Urayasu Ichikawa Medical Center, Urayasu, Japan
| | - Eiji Hiraoka
- Department of Internal Medicine, Tokyo Bay Urayasu Ichikawa Medical Center, Urayasu, Japan
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Cacoub P, Desbois AC, Comarmond C, Saadoun D. Impact of sustained virological response on the extrahepatic manifestations of chronic hepatitis C: a meta-analysis. Gut 2018; 67:2025-2034. [PMID: 29703790 DOI: 10.1136/gutjnl-2018-316234] [Citation(s) in RCA: 89] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 03/15/2018] [Accepted: 04/05/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Extrahepatic manifestations of HCV are responsible for morbidity and mortality in many chronically infected patients. New, interferon-free antiviral treatment regimens, which present the opportunity to treat all HCV-infected patients, call for a better understanding of the benefits of treating non-cirrhotic chronically infected individuals. METHODS A systematic review was conducted. Identified studies from targeted database searches on Embase and Medline were screened. The methodological quality of the included publications was evaluated. Random-effect model meta-analyses were performed. Strength of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation system. RESULTS Data were extracted from a total of 48 identified studies. Achieving sustained virological response (SVR) was associated with reduced extrahepatic mortality (vs no SVR, OR 0.44 (95% CI 0.28 to 0.67)). SVR was associated with higher complete remissions in patients with cryoglobulinemia vasculitis (OR 20.76 (6.73 to 64.05)) and a higher objective response in those with malignant B-cell lymphoproliferative diseases (OR 6.49 (2.02 to 20.85)). Achieving SVR was also associated with reduced insulin resistance at follow-up (OR 0.42 (0.33 to 0.53)) and a significant protective effect on the incidence of diabetes (OR 0.34 (0.21 to 0.56)). Lack of randomised data comparing SVR versus non-SVR patients for the relevant extrahepatic indications attenuated these analyses. CONCLUSION Antiviral therapy can reduce extrahepatic manifestations related to HCV when SVR is achieved. Higher quality data, and reporting over longer follow-up periods, will be required to thoroughly explore comprehensive HCV treatment strategies.
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Affiliation(s)
- Patrice Cacoub
- Sorbonne Universités, UPMC Univ Paris, Paris, France.,Inflammation-Immunopathology-Biotherapy Department, DHU i2B, Paris, France.,INSERM, UMRS 959, Paris, France.,Department of Internal Medicine and Clinical Immunology, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
| | - Anne Claire Desbois
- Sorbonne Universités, UPMC Univ Paris, Paris, France.,Inflammation-Immunopathology-Biotherapy Department, DHU i2B, Paris, France.,INSERM, UMRS 959, Paris, France.,Department of Internal Medicine and Clinical Immunology, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
| | - Cloe Comarmond
- Sorbonne Universités, UPMC Univ Paris, Paris, France.,Inflammation-Immunopathology-Biotherapy Department, DHU i2B, Paris, France.,INSERM, UMRS 959, Paris, France.,Department of Internal Medicine and Clinical Immunology, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
| | - David Saadoun
- Sorbonne Universités, UPMC Univ Paris, Paris, France.,Inflammation-Immunopathology-Biotherapy Department, DHU i2B, Paris, France.,INSERM, UMRS 959, Paris, France.,Department of Internal Medicine and Clinical Immunology, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
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Alcohol-induced autophagy via upregulation of PIASy promotes HCV replication in human hepatoma cells. Cell Death Dis 2018; 9:898. [PMID: 30185779 PMCID: PMC6123814 DOI: 10.1038/s41419-018-0845-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 06/28/2018] [Accepted: 07/02/2018] [Indexed: 02/07/2023]
Abstract
Both alcohol and hepatitis C virus (HCV) infection could induce cellular autophagy in liver cells, which is considered to be essential for productive HCV replication. However, whether alcohol-induced autophagy is involved in the pathogenesis of HCV infection is still poorly understood. Alcohol treatment could induce autophagy in Huh7 cells (a hepatoma cell line that supports HCV JFH-1 replication), evidenced by the increase of LC3B-II levels, the conversion of LC3B-I to LC3B-II, and the formation of GFP-LC3 puncta as well as the decrease of p62 level in alcohol-treated cells compared with control cells. Alcohol treatment also significantly increased PIASy (a member of the PIAS family) expression, which can act as a SUMO (small ubiquitin-like modifier protein) E3 ligase to regulate a broader range of cellular processes including autophagy. Overexpression or the silencing expression of PIASy in alcohol-treated Huh7 cells could increase or decrease autophagic activation caused by alcohol treatment, respectively, and thus affect HCV replication correspondingly. In the absence of alcohol, overexpression or silencing expression of PIASy increase or decrease the level of cellular autophagy, judged by the changes of LC3B-II and p62 levels in the presence or absence of chloroquine (CQ), a lysosome inhibitor. More importantly, in the presence of 3-methyladenine (3-MA), an inhibitor in the early stage of autophagy, the effects of overexpression or silencing expression of PIASy on HCV replication were largely blocked. Furthermore, PIASy could selectively drive the accumulation of SUMO1-conjugated proteins, along with upregulation of the expression of several important autophagy factors, including ATG7 and ATG5–ATG12. In conclusion, alcohol promotes HCV replication through activation of autophagy in Huh7 cells, which partly attributes to its induction of PIASy expression. PIASy-enhanced accumulation of SUMO1-conjugated proteins may contribute to its inducing effect of autophagy. Our findings provide a novel mechanism for the action of alcohol-promoting HCV replication in the context of cellular autophagy.
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Hepacivirus A Infection in Horses Defines Distinct Envelope Hypervariable Regions and Elucidates Potential Roles of Viral Strain and Adaptive Immune Status in Determining Envelope Diversity and Infection Outcome. J Virol 2018; 92:JVI.00314-18. [PMID: 29976666 DOI: 10.1128/jvi.00314-18] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Accepted: 06/12/2018] [Indexed: 12/12/2022] Open
Abstract
Hepacivirus A (also known as nonprimate hepacivirus and equine hepacivirus) is a hepatotropic virus that can cause both transient and persistent infections in horses. The evolution of intrahost viral populations (quasispecies) has not been studied in detail for hepacivirus A, and its roles in immune evasion and persistence are unknown. To address these knowledge gaps, we first evaluated the envelope gene (E1 and E2) diversity of two different hepacivirus A strains (WSU and CU) in longitudinal blood samples from experimentally infected adult horses, juvenile horses (foals), and foals with severe combined immunodeficiency (SCID). Persistent infection with the WSU strain was associated with significantly greater quasispecies diversity than that observed in horses who spontaneously cleared infection (P = 0.0002) or in SCID foals (P < 0.0001). In contrast, the CU strain was able to persist despite significantly lower (P < 0.0001) and relatively static envelope diversity. These findings indicate that envelope diversity is a poor predictor of hepacivirus A infection outcomes and could be dependent on strain-specific factors. Next, entropy analysis was performed on all E1/E2 genes entered into GenBank. This analysis defined three novel hypervariable regions (HVRs) in E2, at residues 391 to 402 (HVR1), 450 to 461 (HVR2), and 550 to 562 (HVR3). For the experimentally infected horses, entropy analysis focusing on the HVRs demonstrated that these regions were under increased selective pressure during persistent infection. Increased diversity in the HVRs was also temporally associated with seroconversion in some horses, suggesting that these regions may be targets of neutralizing antibody and may play a role in immune evasion.IMPORTANCE Hepacivirus C (hepatitis C virus) is estimated to infect 150 million people worldwide and is a leading cause of cirrhosis and hepatocellular carcinoma. In contrast, its closest relative, hepacivirus A, causes relatively mild disease in horses and is frequently cleared. The relationship between quasispecies evolution and infection outcome has not been explored for hepacivirus A. To address this knowledge gap, we examined envelope gene diversity in horses with resolving and persistent infections. Interestingly, two strain-specific patterns of quasispecies diversity emerged. Persistence of the WSU strain was associated with increased quasispecies diversity and the accumulation of amino acid changes within three novel hypervariable regions following seroconversion. These findings provided evidence that envelope gene mutation is influenced by adaptive immune pressure and may contribute to hepacivirus persistence. However, the CU strain persisted despite relative evolutionary stasis, suggesting that some hepacivirus strains may use alternative mechanisms to persist in the host.
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Pietsch V, Deterding K, Attia D, Ringe KI, Heidrich B, Cornberg M, Gebel M, Manns MP, Wedemeyer H, Potthoff A. Long-term changes in liver elasticity in hepatitis C virus-infected patients with sustained virologic response after treatment with direct-acting antivirals. United European Gastroenterol J 2018; 6:1188-1198. [PMID: 30288281 DOI: 10.1177/2050640618786067] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Accepted: 06/08/2018] [Indexed: 12/12/2022] Open
Abstract
Background The use of interferon-free direct-acting antiviral agents (DAAs) is associated with a rapid short-term decrease in liver stiffness in chronic hepatitis C-infected patients with sustained virologic response (SVR). Objective The objective of this article is to evaluate long-term changes in liver elasticity in hepatitis C patients with SVR using transient elastography (TE), FIB-4 and APRI. Methods A total of 143 patients were treated with DAAs and reached SVR. Patients received TE measurement (median (range)) at treatment start (baseline), follow-up week 24 (FU24) and follow-up week 96 (FU96). Laboratory data were examined at each date and FIB-4 and APRI were calculated. Results Liver elasticity showed a significant decrease from baseline to FU24 (13.1 (3.1-75) kPa to 9.3 (2.9-69.1) kPa; p < 0.0001) and declined further until FU96 (7.9 (2.4-59.3) kPa; p < 0.0001). Liver inflammation and liver function parameters normalised during long-term follow-up. Progression of liver stiffness between FU24 to FU96 despite viral clearance was observed in 24 patients (17%). Long-term liver stiffness progression was associated with aspartate aminotransferase levels and TE change from baseline to FU24. Conclusion During long-term follow-up, the majority of patients with SVR had further improved liver stiffness values. Still, a significant proportion of patients may show long-term liver stiffness progression and thus continued TE follow-up is recommended.
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Affiliation(s)
- Veronika Pietsch
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Katja Deterding
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Department of Gastroenterology and Hepatology, University of Essen, Essen, Germany
| | - Dina Attia
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Kristina Imeen Ringe
- Department of Diagnostic and Interventional Radiology, Hannover Medical School, Hannover, Germany
| | - Benjamin Heidrich
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Michael Gebel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Michael Peter Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Department of Gastroenterology and Hepatology, University of Essen, Essen, Germany
| | - Andrej Potthoff
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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Zaman B, Hassan W. Development of Stability Indicating HPLC–UV Method for Determination of Daclatasvir and Characterization of Forced Degradation Products. Chromatographia 2018. [DOI: 10.1007/s10337-018-3503-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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