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1
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Cheng Y, Cheng R, Xu T, Tan X, Bai Y. Machine Learning Techniques Applied to COVID-19 Prediction: A Systematic Literature Review. Bioengineering (Basel) 2025; 12:514. [PMID: 40428133 PMCID: PMC12109271 DOI: 10.3390/bioengineering12050514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2025] [Revised: 05/06/2025] [Accepted: 05/08/2025] [Indexed: 05/29/2025] Open
Abstract
COVID-19 was one of the most serious global public health emergencies in recent years, and its extremely fast spreading speed had a profound negative impact on society. A comprehensive analysis and prediction of COVID-19 could lay a theoretical foundation for monitoring and early warning systems. Since the outbreak of COVID-19, there has been an influx of research on predictive modelling, with artificial intelligence (AI) techniques, particularly machine learning (ML) methods, becoming the dominant research direction due to their superior capability in processing multidimensional datasets and capturing complex nonlinear transmission patterns. We systematically reviewed COVID-19 ML prediction models developed under the background of the epidemic using the PRISMA method. We used the selected keywords to screen the relevant literature of COVID-19 prediction using ML technology from 2020 to 2023 in the Web of Science, Springer and Elsevier databases. Based on predetermined inclusion and exclusion criteria, 136 eligible studies were ultimately selected from 5731 preliminarily screened publications, and the datasets, data preprocessing, ML models, and evaluation metrics used in these studies were assessed. By establishing a multi-level classification framework that included traditional statistical models (such as ARIMA), ML models (such as SVM), deep learning (DL) models (such as CNN, LSTM), ensemble learning methods (such as AdaBoost), and hybrid models (such as the fusion architecture of intelligent optimization algorithms and neural networks), it revealed that the hybrid modelling strategy effectively improved the prediction accuracy of the model through feature combination optimization and model cascade integration. In addition, we compared the performance of ML models with other models in the COVID-19 prediction task. The results showed that the propagation of COVID-19 is affected by multiple factors, including meteorological and socio-economic conditions. Compared to traditional methods, ML methods demonstrated significant advantages in COVID-19 prediction, especially hybrid modelling strategies, which showed great potential in optimizing accuracy. However, these techniques face challenges and limitations despite their strong performance. By reviewing existing research on COVID-19 prediction, this study provided systematic theoretical support for AI applications in infectious disease prediction and promoted technological innovation in public health.
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Affiliation(s)
- Yunyun Cheng
- School of Information and Communication Engineering, North University of China, Taiyuan 030051, China;
| | - Rong Cheng
- School of Mathematics, North University of China, Taiyuan 030051, China; (R.C.); (T.X.); (X.T.)
| | - Ting Xu
- School of Mathematics, North University of China, Taiyuan 030051, China; (R.C.); (T.X.); (X.T.)
| | - Xiuhui Tan
- School of Mathematics, North University of China, Taiyuan 030051, China; (R.C.); (T.X.); (X.T.)
| | - Yanping Bai
- School of Mathematics, North University of China, Taiyuan 030051, China; (R.C.); (T.X.); (X.T.)
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Di Marco L, Cannova S, Ferrigno E, Landro G, Nonni R, Mantia CL, Cartabellotta F, Calvaruso V, Di Marco V. A Comprehensive Review of Antiviral Therapy for Hepatitis C: The Long Journey from Interferon to Pan-Genotypic Direct-Acting Antivirals (DAAs). Viruses 2025; 17:163. [PMID: 40006918 PMCID: PMC11860415 DOI: 10.3390/v17020163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 01/19/2025] [Accepted: 01/20/2025] [Indexed: 02/27/2025] Open
Abstract
The treatment landscape for hepatitis C virus (HCV) infection has transformed over the past few decades, evolving from the limited efficacy of interferon (IFN) monotherapy to the highly successful pan-genotypic direct-acting antivirals (DAAs) used today. Initially, alpha-interferon monotherapy, introduced in the 1990s, was the standard treatment, yet it provided low sustained virological response (SVR) rates and caused significant adverse effects, limiting its utility. The development of pegylated interferon (peg-IFN) improved the pharmacokinetic profile of IFN, allowing for less frequent dosing and modestly improved response rates. When combined with ribavirin, peg-IFN achieved higher SVR rates, especially in non-genotype 1 HCV infections, but the combination also brought additional side effects, such as anemia and depression. The advent of the first-generation DAAs, such as telaprevir and boceprevir, marked a significant milestone. Combined with peg-IFN and ribavirin, these protease inhibitors boosted response rates in patients with genotype 1 HCV. However, high rates of adverse effects and drug resistance remained challenges. Second-generation DAAs, like sofosbuvir and ledipasvir, introduced IFN-free regimens with improved safety profiles and efficacy. The most recent advances are pan-genotypic DAAs, including glecaprevir-pibrentasvir and sofosbuvir-velpatasvir, which offer high SVR rates across all genotypes, shorter treatment durations, and fewer side effects. Current pan-genotypic regimens represent a cornerstone in HCV therapy, providing an accessible and effective solution globally.
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Affiliation(s)
- Lorenza Di Marco
- SIcilian Network for Therapy, Epidemiology and Screening In Hepatology (SINTESI), 90127 Palermo, Italy; (L.D.M.); (F.C.); (V.C.)
- Department of Oncology and Hematology, Azienda Ospedaliero-University Hospital of Mod, 41124 Modena, Italy
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41100 Modena, Italy
| | - Simona Cannova
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (S.C.); (E.F.); (G.L.); (R.N.); (C.L.M.)
| | - Emanuele Ferrigno
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (S.C.); (E.F.); (G.L.); (R.N.); (C.L.M.)
| | - Giuseppe Landro
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (S.C.); (E.F.); (G.L.); (R.N.); (C.L.M.)
| | - Rosario Nonni
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (S.C.); (E.F.); (G.L.); (R.N.); (C.L.M.)
| | - Claudia La Mantia
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (S.C.); (E.F.); (G.L.); (R.N.); (C.L.M.)
| | - Fabio Cartabellotta
- SIcilian Network for Therapy, Epidemiology and Screening In Hepatology (SINTESI), 90127 Palermo, Italy; (L.D.M.); (F.C.); (V.C.)
- Department of Medicine, Buccheri-La Ferla Hospital, 90123 Palermo, Italy
| | - Vincenza Calvaruso
- SIcilian Network for Therapy, Epidemiology and Screening In Hepatology (SINTESI), 90127 Palermo, Italy; (L.D.M.); (F.C.); (V.C.)
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (S.C.); (E.F.); (G.L.); (R.N.); (C.L.M.)
| | - Vito Di Marco
- SIcilian Network for Therapy, Epidemiology and Screening In Hepatology (SINTESI), 90127 Palermo, Italy; (L.D.M.); (F.C.); (V.C.)
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (S.C.); (E.F.); (G.L.); (R.N.); (C.L.M.)
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Das E, Samantaray M, Abrol K, Basumatari J, Pushan SS, Ramaswamy A. Development of a Multiple-Epitope-Based Vaccine for Hepatitis C Virus Genotypes 1a and 1b: an in-silico reverse vaccinology approach. In Silico Pharmacol 2024; 12:100. [PMID: 39524457 PMCID: PMC11549267 DOI: 10.1007/s40203-024-00275-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 10/15/2024] [Indexed: 11/16/2024] Open
Abstract
The Hepatitis C virus (HCV) is a blood-transmitted virus responsible for persistent inflammation, presenting a substantial worldwide health challenge. HCV, characterized by a positive-stranded ribonucleic acid genome, possesses an intricate genetic makeup encoding both structural and non-structural proteins, crucial for sustaining its life cycle. The Direct Acting Antivirals have revolutionized the treatment landscape of HCV promoting higher Sustained Virological Response rates. Despite significant advancements in treatment, no vaccines are currently available against HCV. The development of effective HCV vaccines becomes challenging as the genetic diversity of HCV virus and its complex nature of the immune response required for protection. In this work, the immunoinformatics methods were utilized to develop a multiple-epitope-based vaccine towards an effective treatment against the viral HCV polyprotein. The vaccine was constructed by T-cell epitopes extracted from the viral polyprotein of HCV genotypes 1a and 1b. The vaccine was highly antigenic, non-toxic, and non-allergenic. Effective binding of the designed vaccine construct was studied by forming complexes with the human immune Toll-Like Receptors; TLR3 and TLR8. The MD simulation of these receptor-vaccine complexes were performed for 50ns and the immunological simulation of modeled vaccine in presence of receptors for 365 days timeline validated the stability of the constructed vaccine. The in-silico vaccine construct developed from this work might be beneficial as prophylactic measures against the HCV variants, if explored further in in vivo and in vitro methods. Consequently, this research outcome is presumed to have implications in the development of safer and more efficient vaccines for lethal diseases. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s40203-024-00275-4.
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Affiliation(s)
- Enakshi Das
- Department of Bioinformatics, Pondicherry University, Kalapet, Puducherry India
| | - Mahesh Samantaray
- Department of Bioinformatics, Pondicherry University, Kalapet, Puducherry India
| | - Kajal Abrol
- Department of Bioinformatics, Pondicherry University, Kalapet, Puducherry India
| | - Jayarani Basumatari
- Department of Bioinformatics, Pondicherry University, Kalapet, Puducherry India
| | - Shilpa Sri Pushan
- Department of Bioinformatics, Pondicherry University, Kalapet, Puducherry India
| | - Amutha Ramaswamy
- Department of Bioinformatics, Pondicherry University, Kalapet, Puducherry India
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Sinclair S, Shearen S, Ghobrial Y, Trad G, Abdul Basit S, Shih D, Ryan JK. Review of the Effects of Antiviral Therapy on Hepatitis B/C-Related Mortality and the Regression of Fibrosis. Viruses 2024; 16:1531. [PMID: 39459866 PMCID: PMC11512229 DOI: 10.3390/v16101531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 09/19/2024] [Accepted: 09/23/2024] [Indexed: 10/28/2024] Open
Abstract
Hepatitis B and Hepatitis C are viral causes of Hepatitis that lead to significant worldwide mortality and morbidity through the sequelae of fibrosis and hepatocellular carcinoma. In this review, we have summarized recent studies that have examined the effects of antiviral therapy on the regression of fibrosis and the reduction in mortalities associated with the viruses. Antiviral therapy significantly decreases mortality and induces the regression of fibrosis.
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Affiliation(s)
| | | | | | | | | | | | - John K. Ryan
- Comprehensive Digestive Institute of Nevada, Las Vegas, NV 89148, USA (S.A.B.); (D.S.)
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Quirino A, Marascio N, Branda F, Ciccozzi A, Romano C, Locci C, Azzena I, Pascale N, Pavia G, Matera G, Casu M, Sanna D, Giovanetti M, Ceccarelli G, Alaimo di Loro P, Ciccozzi M, Scarpa F, Maruotti A. Viral Hepatitis: Host Immune Interaction, Pathogenesis and New Therapeutic Strategies. Pathogens 2024; 13:766. [PMID: 39338957 PMCID: PMC11435051 DOI: 10.3390/pathogens13090766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 08/30/2024] [Accepted: 09/02/2024] [Indexed: 09/30/2024] Open
Abstract
Viral hepatitis is a major cause of liver illness worldwide. Despite advances in the understanding of these infections, the pathogenesis of hepatitis remains a complex process driven by intricate interactions between hepatitis viruses and host cells at the molecular level. This paper will examine in detail the dynamics of these host-pathogen interactions, highlighting the key mechanisms that regulate virus entry into the hepatocyte, their replication, evasion of immune responses, and induction of hepatocellular damage. The unique strategies employed by different hepatitis viruses, such as hepatitis B, C, D, and E viruses, to exploit metabolic and cell signaling pathways to their advantage will be discussed. At the same time, the innate and adaptive immune responses put in place by the host to counter viral infection will be analyzed. Special attention will be paid to genetic, epigenetic, and environmental factors that modulate individual susceptibility to different forms of viral hepatitis. In addition, this work will highlight the latest findings on the mechanisms of viral persistence leading to the chronic hepatitis state and the potential implications for the development of new therapeutic strategies. Fully understanding the complex host-pathogen interactions in viral hepatitis is crucial to identifying new therapeutic targets, developing more effective approaches for treatment, and shedding light on the mechanisms underlying progression to more advanced stages of liver damage.
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Affiliation(s)
- Angela Quirino
- Unit of Clinical Microbiology, Department of Health Sciences, “Magna Græcia” University of Catanzaro “Renato Dulbecco” Teaching Hospital, 88100 Catanzaro, Italy; (A.Q.); (N.M.); (G.P.); (G.M.)
| | - Nadia Marascio
- Unit of Clinical Microbiology, Department of Health Sciences, “Magna Græcia” University of Catanzaro “Renato Dulbecco” Teaching Hospital, 88100 Catanzaro, Italy; (A.Q.); (N.M.); (G.P.); (G.M.)
| | - Francesco Branda
- Unit of Medical Statistics and Molecular Epidemiology, Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (C.R.); (M.C.)
| | - Alessandra Ciccozzi
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (A.C.); (C.L.); (D.S.); (F.S.)
| | - Chiara Romano
- Unit of Medical Statistics and Molecular Epidemiology, Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (C.R.); (M.C.)
| | - Chiara Locci
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (A.C.); (C.L.); (D.S.); (F.S.)
- Department of Veterinary Medicine, University of Sassari, 07100 Sassari, Italy; (I.A.); (N.P.); (M.C.)
| | - Ilenia Azzena
- Department of Veterinary Medicine, University of Sassari, 07100 Sassari, Italy; (I.A.); (N.P.); (M.C.)
| | - Noemi Pascale
- Department of Veterinary Medicine, University of Sassari, 07100 Sassari, Italy; (I.A.); (N.P.); (M.C.)
- Department of Chemical Physical Mathematical and Natural Sciences, University of Sassari, 07100 Sassari, Italy
| | - Grazia Pavia
- Unit of Clinical Microbiology, Department of Health Sciences, “Magna Græcia” University of Catanzaro “Renato Dulbecco” Teaching Hospital, 88100 Catanzaro, Italy; (A.Q.); (N.M.); (G.P.); (G.M.)
| | - Giovanni Matera
- Unit of Clinical Microbiology, Department of Health Sciences, “Magna Græcia” University of Catanzaro “Renato Dulbecco” Teaching Hospital, 88100 Catanzaro, Italy; (A.Q.); (N.M.); (G.P.); (G.M.)
| | - Marco Casu
- Department of Veterinary Medicine, University of Sassari, 07100 Sassari, Italy; (I.A.); (N.P.); (M.C.)
| | - Daria Sanna
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (A.C.); (C.L.); (D.S.); (F.S.)
| | - Marta Giovanetti
- Department of Sciences and Technologies for Sustainable Development and One Health, Università Campus Bio-Medico di Roma, 00128 Rome, Italy;
- Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte 30190-002, MG, Brazil
- Climate Amplified Diseases and Epidemics (CLIMADE), Brasilia 70070-130, GO, Brazil
| | - Giancarlo Ceccarelli
- Department of Public Health and Infectious Diseases, University Hospital Policlinico Umberto I, Sapienza University of Rome, 00161 Rome, Italy;
| | | | - Massimo Ciccozzi
- Unit of Medical Statistics and Molecular Epidemiology, Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (C.R.); (M.C.)
| | - Fabio Scarpa
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (A.C.); (C.L.); (D.S.); (F.S.)
| | - Antonello Maruotti
- Department GEPLI, Libera Università Maria Ss Assunta, 00193 Rome, Italy;
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Panjasawatwong N, Avihingsanon A, Menétrey C, Ribeiro I, Salvadori N, Swanson A, Gillon JY, Tan SS, Thanprasertsuk S, Thongsawat S, Cressey TR, the STORM-C-1 study team. Population pharmacokinetics of ravidasvir in adults with chronic hepatitis C virus infection and impact of antiretroviral treatment. Antimicrob Agents Chemother 2024; 68:e0000824. [PMID: 38767383 PMCID: PMC11232402 DOI: 10.1128/aac.00008-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 04/23/2024] [Indexed: 05/22/2024] Open
Abstract
Ravidasvir (RDV) is a novel NS5A inhibitor that exhibits potent pan-genotypic inhibition of hepatitis C virus (HCV) replication. Sofosbuvir (SOF) plus RDV was demonstrated to be efficacious and safe in adults with active HCV infection, including those living with HIV (LWHIV), in the STORM-C-1 trial. We assessed the population pharmacokinetics (PK) of RDV in a sub-study nested within STORM-C-1 conducted in Thailand and Malaysia. SOF (400 mg) plus RDV (200 mg) was administered orally once daily for 12 weeks to adults with chronic HCV infection, but without cirrhosis and for 24 weeks to those with compensated cirrhosis. Intensive and sparse PK samples were collected at 4, 8, and 12 weeks after treatment initiation. Population PK parameters of RDV and the impact of covariates were evaluated using nonlinear mixed-effects modeling. Five hundred ninety-four participants were included, 235 (40%) had compensated cirrhosis, and 189 (32%) were LWHIV. RDV plasma concentrations were best described by a two-compartment model with first-order elimination. Oral clearance (CL/F) and volume of distribution (Vd/F) parameters were allometrically scaled on fat-free mass. Concomitant antiretroviral treatment (ART) increased RDV CL/F by 30%-60%, with efavirenz-based ART having the largest impact. Females had 16% lower RDV CL/F than males, and higher albumin levels reduced RDV central volume of distribution. While several covariates impact RDV CL/F and Vd/F, the effect on RDV exposures was not clinically relevant based on the efficacy data reported in this diverse Asian adult population. There were no meaningful drug-drug interactions in adults LWHIV on ART.
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Affiliation(s)
- Navarat Panjasawatwong
- Department of Pharmaceutical Care, Faculty of Pharmacy, Payap University, Chiang Mai, Thailand
| | - Anchalee Avihingsanon
- The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), Thai Red Cross AIDS Research Center, Bangkok, Thailand
| | | | - Isabela Ribeiro
- Drugs for Neglected Diseases Initiative, Geneva, Switzerland
| | - Nicolas Salvadori
- AMS-PHPT Collaboration, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
| | | | | | - Soek-Siam Tan
- Department of Hepatology, Selayang Hospital, Selayang, Malaysia
| | | | | | - Tim R. Cressey
- AMS-PHPT Collaboration, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
| | - the STORM-C-1 study team
- Department of Pharmaceutical Care, Faculty of Pharmacy, Payap University, Chiang Mai, Thailand
- The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), Thai Red Cross AIDS Research Center, Bangkok, Thailand
- Drugs for Neglected Diseases Initiative, Geneva, Switzerland
- AMS-PHPT Collaboration, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
- Department of Hepatology, Selayang Hospital, Selayang, Malaysia
- Department of Disease Control, Ministry of Public Health, Bangkok, Thailand
- Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
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Nogales-Garcia M, Parraza Diez N, Vargas Axpe A, Velasco Garcia R, Larrabeiti-Etxebarria A, Roy Lopez-Cano I, Atrio Alvarez I, Lopez de Arcaute Trincado A, Fernandez Lopez de Vicuña EM, Saez de Adana Arroniz E, Martínez Martínez C, Portu Zapirain J. Elimination of hepatitis C virus in a prison: An 18-year experience. ENFERMEDADES INFECCIOSAS Y MICROBIOLOGIA CLINICA (ENGLISH ED.) 2024; 42:236-241. [PMID: 37117143 DOI: 10.1016/j.eimce.2023.04.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 01/17/2023] [Accepted: 01/19/2023] [Indexed: 04/30/2023]
Abstract
INTRODUCTION Despite the decrease of hepatitis C in Spanish prisons in the last years, it still remains a reservoir for infection. The aim of this work is to analyze the characteristics of these patients and the response to antiviral treatment over the last 18 years. METHODS Retrospective observational study in inmates of Araba penitentiary center diagnosed with HCV infection between 2002 and 2020. A descriptive analysis of patient characteristics and the response to the three antiviral treatment modalities was performed: peg-interferon and ribavirin, peg-interferon, ribavirin and a first-generation protease inhibitor and different combinations of direct-acting antivirals. RESULTS A total of 248 antiviral treatments were prescribed. Treatment response rate up to 2015 was 65% and 93,7% after that year. Interferon non-responders were the main cause of non-response to treatment in periods 1 and 2 (40%-50%). Conversely, in period 3 viral breakthrough (67%) was the main culprit. CONCLUSION After 18 years, active hepatitis C infection in prison inmates has resolved with treatment according to clinical criteria. Therefore, the stay in prison may represent an opportunity to reduce the reservoir of the disease in the community, together with continued health care for those released from prison.
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Affiliation(s)
- Maite Nogales-Garcia
- Osakidetza Servicio Vasco de Salud, Centro de Salud Zaballa, Vitoria-Gasteiz, Spain; Osakidetza Servicio Vasco de Salud, Hospital Universitario Araba, Vitoria-Gasteiz, Spain
| | - Naiara Parraza Diez
- Instituto de Investigación Sanitaria Bioaraba, Vitoria-Gasteiz, Spain; Red de Investigación en Cronicidad, Atención Primaria y Promoción de la Salud (RICAPPS).
| | - Andoni Vargas Axpe
- Osakidetza Servicio Vasco de Salud, Centro de Salud Zaballa, Vitoria-Gasteiz, Spain
| | | | | | | | | | | | - Eva María Fernandez Lopez de Vicuña
- Osakidetza Servicio Vasco de Salud, Centro de Salud Zaballa, Vitoria-Gasteiz, Spain; Osakidetza Servicio Vasco de Salud, Hospital Universitario Araba, Vitoria-Gasteiz, Spain
| | | | | | - Joseba Portu Zapirain
- Osakidetza Servicio Vasco de Salud, Hospital Universitario Araba, Vitoria-Gasteiz, Spain; Instituto de Investigación Sanitaria Bioaraba, Vitoria-Gasteiz, Spain; Universidad del País Vasco UPV/EHU, Vitoria-Gasteiz, Spain
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8
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Amancherla K, Feurer ID, Rega SA, Cluckey A, Salih M, Davis J, Pedrotty D, Ooi H, Rali AS, Siddiqi HK, Menachem J, Brinkley DM, Punnoose L, Sacks SB, Zalawadiya SK, Wigger M, Balsara K, Trahanas J, McMaster WG, Hoffman J, Pasrija C, Lindenfeld J, Shah AS, Schlendorf KH. Early Assessment of Cardiac Allograft Vasculopathy Risk Among Recipients of Hepatitis C Virus-infected Donors in the Current Era. J Card Fail 2024; 30:694-700. [PMID: 37907147 PMCID: PMC11056484 DOI: 10.1016/j.cardfail.2023.09.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Revised: 09/22/2023] [Accepted: 09/27/2023] [Indexed: 11/02/2023]
Abstract
BACKGROUND Transplantation of hearts from hepatitis C virus (HCV)-positive donors has increased substantially in recent years following development of highly effective direct-acting antiviral therapies for treatment and cure of HCV. Although historical data from the pre-direct-acting antiviral era demonstrated an association between HCV-positive donors and accelerated cardiac allograft vasculopathy (CAV) in recipients, the relationship between the use of HCV nucleic acid test-positive (NAT+) donors and the development of CAV in the direct-acting antiviral era remains unclear. METHODS AND RESULTS We performed a retrospective, single-center observational study comparing coronary angiographic CAV outcomes during the first year after transplant in 84 heart transplant recipients of HCV NAT+ donors and 231 recipients of HCV NAT- donors. Additionally, in a subsample of 149 patients (including 55 in the NAT+ cohort and 94 in the NAT- cohort) who had serial adjunctive intravascular ultrasound examination performed, we compared development of rapidly progressive CAV, defined as an increase in maximal intimal thickening of ≥0.5 mm in matched vessel segments during the first year post-transplant. In an unadjusted analysis, recipients of HCV NAT+ hearts had reduced survival free of CAV ≥1 over the first year after heart transplant compared with recipients of HCV NAT- hearts. After adjustment for known CAV risk factors, however, there was no significant difference between cohorts in the likelihood of the primary outcome, nor was there a difference in development of rapidly progressive CAV. CONCLUSIONS These findings support larger, longer-term follow-up studies to better elucidate CAV outcomes in recipients of HCV NAT+ hearts and to inform post-transplant management strategies.
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Affiliation(s)
- Kaushik Amancherla
- Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Irene D Feurer
- Departments of Surgery and Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Scott A Rega
- Vanderbilt Transplant Center, Nashville, Tennessee
| | - Andrew Cluckey
- Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Mohamed Salih
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jonathan Davis
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Dawn Pedrotty
- Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Henry Ooi
- Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Aniket S Rali
- Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Hasan K Siddiqi
- Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jonathan Menachem
- Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Douglas M Brinkley
- Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Lynn Punnoose
- Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Suzanne B Sacks
- Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Sandip K Zalawadiya
- Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Mark Wigger
- Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Keki Balsara
- Department of Cardiac Surgery, Medstar Washington Hospital Center, Washington, DC
| | - John Trahanas
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - William G McMaster
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jordan Hoffman
- Division of Cardiothoracic Surgery, University of Colorado, Aurora, Colorado
| | - Chetan Pasrija
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Joann Lindenfeld
- Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Ashish S Shah
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Kelly H Schlendorf
- Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
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9
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Nasr MS, Talaat W, Morshedy S, Kaddah MMY, Omran G, Keshk RM. A new fluorescence probe for sofosbuvir analysis in dosage form and spiked human plasma. LUMINESCENCE 2024; 39:e4742. [PMID: 38637644 DOI: 10.1002/bio.4742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 03/09/2024] [Accepted: 03/15/2024] [Indexed: 04/20/2024]
Abstract
A simple, rapid, and low-cost technique was developed to allow reliable analysis of the anti-hepatitis C drug sofosbuvir in bulk, tablet form, and spiked human plasma. This method depends on the ability of sofosbuvir to quench the fluorescence of the newly synthesized 2-amino-3-cyano-4,6-dimethylpyridine (reagent 3). Elemental analysis and spectral data were used to validate the structure of the synthesized reagent. The newly synthesized reagent exhibited a satisfactory level of fluorescence emission at 365 nm after excitation at 247 nm. All experimental variables that might affect the quenching process were analyzed and optimized. Linearity, range, accuracy, precision, limit of detection (LOD), and limit of quantitation (LOQ) were all validated in accordance with the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. The concentration range was shown to be linear between 0.1 and 1.5 μg/mL. The technique was effectively utilized for sofosbuvir analysis in both its tablet dosage form and spiked human plasma, with mean percentage recoveries of 100.13 ± 0.35 and 94.26 ± 1.69, respectively.
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Affiliation(s)
- Mohamed S Nasr
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt
| | - Wael Talaat
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt
| | - Samir Morshedy
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt
| | - Mohamed M Y Kaddah
- Pharmaceutical and Fermentation Industries Development Center, City of Scientific Research and Technological Applications, New Borg El-Arab, Alexandria, Egypt
| | - Gamal Omran
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt
| | - Reda M Keshk
- Department of Chemistry, Faculty of Science, Damanhour University, Damanhour, Egypt
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10
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Pawłowski T, Radkowski M, Perlejewski K, Laskus T, Małyszczak K. The Severity of Depressive Symptoms as an Independent Predictor of Sustained Virological Response During Treatment of Hepatitis C With Pegylated Interferon-α2a and Oral Ribavirin. Psychosom Med 2024; 86:124-128. [PMID: 38193776 DOI: 10.1097/psy.0000000000001274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2024]
Abstract
BACKGROUND Sustained virological response (SVR) is the best indicator of successful therapy for hepatitis C virus (HCV) infection. Patients with chronic HCV infection treated with pegylated interferon-α and ribavirin (PEG-IFN-α/RBV) can achieve SVR 56% of the time. OBJECTIVES This study aimed to evaluate baseline predictors of SVR in patients treated with PEG-IFN-α/RBV for HCV chronic infection. METHODS A total of 101 patients receiving PEG-IFN-α/RBV for chronic HCV infection participated in the prospective cohort study. Symptoms of depression were assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS) before the treatment. The multivariate regression analysis was applied to determine predictors of SVR. RESULTS Of a total of 101 patients included, 99 patients reached the primary end point-24 weeks after completing treatment. After the initial analysis of probable predictive variables, the logistic analysis included age, sex, HCV genetic type, and MADRS score. The HCV genotype (odds ratio = 0.22 [confidence interval = 0.073-0.68, p = .008) and MADRS score (OR = 0.88 [confidence interval = 0.80-0.98), p = .013]) predicted an SVR outcome. CONCLUSIONS The severity of depressive symptoms before treatment and HCV genotype are independent predictors of SVR.
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Affiliation(s)
- Tomasz Pawłowski
- From the Division of Psychotherapy and Psychosomatic Medicine, Department of Psychiatry (Pawłowski, Małyszczak), Wrocław Medical University, Wrocław; Departments of Immunopathology of Infectious and Parasitic Diseases (Radkowski, Perlejewski) and Adults Infectious Diseases (Laskus), Medical University of Warsaw, Warsaw, Poland
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11
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Gasmi A, Noor S, Menzel A, Khanyk N, Semenova Y, Lysiuk R, Beley N, Bolibrukh L, Gasmi Benahmed A, Storchylo O, Bjørklund G. Potential Drugs in COVID-19 Management. Curr Med Chem 2024; 31:3245-3264. [PMID: 37461346 DOI: 10.2174/0929867331666230717154101] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 05/27/2023] [Accepted: 06/05/2023] [Indexed: 11/18/2023]
Abstract
The SARS-CoV-2 virus first emerged in China in December 2019 and quickly spread worldwide. Despite the absence of a vaccination or authorized drug specifically developed to combat this infection, certain medications recommended for other diseases have shown potential effectiveness in treating COVID-19, although without definitive confirmation. This review aims to evaluate the existing literature on the efficacy of these medications against COVID-19. The review encompasses various potential treatments, including antiviral medications, anti-malaria and anti-rheumatic drugs, vaccines, corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), antipyretic and analgesic medicines, antiparasitic drugs, and statins. The analysis also addresses the potential benefits and drawbacks of these medications, as well as their effects on hypertension and diabetes. Although these therapies hold promise against COVID-19, further research, including suitable product production or clinical testing, is needed to establish their therapeutic efficacy.
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Affiliation(s)
- Amin Gasmi
- Société Francophone de Nutrithérapie et de Nutrigénétique Appliquée, Villeurbanne, France
| | - Sadaf Noor
- Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Pakistan
| | | | - Nataliia Khanyk
- Danylo Halytsky Lviv National Medical University, Lviv, Ukraine
- CONEM Ukraine Life Science Research Group, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine
| | - Yuliya Semenova
- Nazarbayev University School of Medicine, Astana, Kazakhstan
| | - Roman Lysiuk
- Danylo Halytsky Lviv National Medical University, Lviv, Ukraine
- CONEM Ukraine Life Science Research Group, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine
| | - Nataliya Beley
- I. Ya. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
| | | | | | - Olha Storchylo
- Medical Chemistry Department, Odessa National Medical University, Odesa, Ukraine
| | - Geir Bjørklund
- Council for Nutritional and Environmental Medicine (CONEM), Mo i Rana, Norway
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12
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Niazi SK. A Critical Analysis of the FDA's Omics-Driven Pharmacodynamic Biomarkers to Establish Biosimilarity. Pharmaceuticals (Basel) 2023; 16:1556. [PMID: 38004421 PMCID: PMC10675618 DOI: 10.3390/ph16111556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 09/25/2023] [Accepted: 09/29/2023] [Indexed: 11/26/2023] Open
Abstract
Demonstrating biosimilarity entails comprehensive analytical assessment, clinical pharmacology profiling, and efficacy testing in patients for at least one medical indication, as required by the U.S. Biologics Price Competition and Innovation Act (BPCIA). The efficacy testing can be waived if the drug has known pharmacodynamic (PD) markers, leaving most therapeutic proteins out of this concession. To overcome this, the FDA suggests that biosimilar developers discover PD biomarkers using omics technologies such as proteomics, glycomics, transcriptomics, genomics, epigenomics, and metabolomics. This approach is redundant since the mode-action-action biomarkers of approved therapeutic proteins are already available, as compiled in this paper for the first time. Other potential biomarkers are receptor binding and pharmacokinetic profiling, which can be made more relevant to ensure biosimilarity without requiring biosimilar developers to conduct extensive research, for which they are rarely qualified.
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Affiliation(s)
- Sarfaraz K Niazi
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, IL 60612, USA
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13
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Zhang W, Du F, Wang L, Bai T, Zhou X, Mei H. Hepatitis Virus-associated Non-hodgkin Lymphoma: Pathogenesis and Treatment Strategies. J Clin Transl Hepatol 2023; 11:1256-1266. [PMID: 37577221 PMCID: PMC10412707 DOI: 10.14218/jcth.2022.00079s] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 01/21/2023] [Accepted: 03/22/2023] [Indexed: 07/03/2023] Open
Abstract
Over the last decade, epidemiological studies have discovered a link between hepatitis C virus (HCV) and hepatitis B virus (HBV) infection and non-Hodgkin lymphoma (NHL). The regression of HCV-associated NHL after HCV eradication is the most compelling proof supporting HCV infection's role in lymphoproliferative diseases. HBV infection was found to significantly enhance the incidence of NHL, according to the epidemiological data. The exact mechanism of HCV leading to NHL has not been fully clarified, and there are mainly the following possible mechanisms: (1) Indirect mechanisms: stimulation of B lymphocytes by extracellular HCV and cytokines; (2) Direct mechanisms: oncogenic effects mediated by intracellular HCV proteins; (3) hit-and-run mechanism: permanent genetic B lymphocytes damage by the transitional entry of HCV. The specific role of HBV in the occurrence of NHL is still unclear, and the research on its mechanism is less extensively explored than HCV, and there are mainly the following possible mechanisms: (1) Indirect mechanisms: stimulation of B lymphocytes by extracellular HBV; (2) Direct mechanisms: oncogenic effects mediated by intracellular HBV DNA. In fact, it is reasonable to consider direct-acting antivirals (DAAs) as first-line therapy for indolent HCV-associated B-NHL patients who do not require immediate chemotherapy. Chemotherapy for NHL is affected by HBV infection and replication. At the same time, chemotherapy can also activate HBV replication. Following recent guidelines, all patients with HBsAg positive/HBV DNA≥2,000 IU/mL should be treated for HBV. The data on epidemiology, interventional studies, and molecular mechanisms of HCV and HBV-associated B-NHL are systematically summarized in this review.
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Affiliation(s)
- Wenjing Zhang
- Department of Hematology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Fan Du
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Li Wang
- Department of Hematology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Tao Bai
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiang Zhou
- Department of Internal Medicine II, Würzburg University Hospital, University of Würzburg, Würzburg, Germany
| | - Heng Mei
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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14
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Medina C, García AH, Crespo FI, Toro FI, Mayora SJ, De Sanctis JB. A Synopsis of Hepatitis C Virus Treatments and Future Perspectives. Curr Issues Mol Biol 2023; 45:8255-8276. [PMID: 37886964 PMCID: PMC10605161 DOI: 10.3390/cimb45100521] [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: 09/28/2023] [Revised: 10/10/2023] [Accepted: 10/10/2023] [Indexed: 10/28/2023] Open
Abstract
Hepatitis C virus (HCV) infection is a worldwide public health problem. Chronic infection with HCV can lead to liver cirrhosis or cancer. Although some immune-competent individuals can clear the virus, others develop chronic HCV disease due to viral mutations or an impaired immune response. IFNs type I and III and the signal transduction induced by them are essential for a proper antiviral effect. Research on the viral cycle and immune escape mechanisms has formed the basis of therapeutic strategies to achieve a sustained virological response (SVR). The first therapies were based on IFNα; then, IFNα plus ribavirin (IFN-RBV); and then, pegylated-IFNα-RBV (PEGIFNα-RIV) to improve cytokine pharmacokinetics. However, the maximum SVR was 60%, and several significant side effects were observed, decreasing patients' treatment adherence. The development of direct-acting antivirals (DAAs) significantly enhanced the SVR (>90%), and the compounds were able to inhibit HCV replication without significant side effects, even in paediatric populations. The management of coinfected HBV-HCV and HCV-HIV patients has also improved based on DAA and PEG-IFNα-RBV (HBV-HCV). CD4 cells are crucial for an effective antiviral response. The IFNλ3, IL28B, TNF-α, IL-10, TLR-3, and TLR-9 gene polymorphisms are involved in viral clearance, therapeutic responses, and hepatic pathologies. Future research should focus on searching for strategies to circumvent resistance-associated substitution (RAS) to DAAs, develop new therapeutic schemes for different medical conditions, including organ transplant, and develop vaccines for long-lasting cellular and humoral responses with cross-protection against different HCV genotypes. The goal is to minimise the probability of HCV infection, HCV chronicity and hepatic carcinoma.
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Affiliation(s)
- Christian Medina
- Institute of Immunology Dr. Nicolás E. Bianco C., Faculty of Medicine, Universidad Central de Venezuela, Caracas 1040, Venezuela; (C.M.); (F.I.C.); (F.I.T.); (S.J.M.)
| | - Alexis Hipólito García
- Institute of Immunology Dr. Nicolás E. Bianco C., Faculty of Medicine, Universidad Central de Venezuela, Caracas 1040, Venezuela; (C.M.); (F.I.C.); (F.I.T.); (S.J.M.)
| | - Francis Isamarg Crespo
- Institute of Immunology Dr. Nicolás E. Bianco C., Faculty of Medicine, Universidad Central de Venezuela, Caracas 1040, Venezuela; (C.M.); (F.I.C.); (F.I.T.); (S.J.M.)
| | - Félix Isidro Toro
- Institute of Immunology Dr. Nicolás E. Bianco C., Faculty of Medicine, Universidad Central de Venezuela, Caracas 1040, Venezuela; (C.M.); (F.I.C.); (F.I.T.); (S.J.M.)
| | - Soriuska José Mayora
- Institute of Immunology Dr. Nicolás E. Bianco C., Faculty of Medicine, Universidad Central de Venezuela, Caracas 1040, Venezuela; (C.M.); (F.I.C.); (F.I.T.); (S.J.M.)
| | - Juan Bautista De Sanctis
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, 779 00 Olomouc, Czech Republic
- The Czech Advanced Technology and Research Institute (Catrin), Palacky University, 779 00 Olomouc, Czech Republic
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15
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Izhari MA. Molecular Mechanisms of Resistance to Direct-Acting Antiviral (DAA) Drugs for the Treatment of Hepatitis C Virus Infections. Diagnostics (Basel) 2023; 13:3102. [PMID: 37835845 PMCID: PMC10572573 DOI: 10.3390/diagnostics13193102] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 09/23/2023] [Accepted: 09/28/2023] [Indexed: 10/15/2023] Open
Abstract
Hepatitis C virus (HCV) is a hepatotropic virus that affects millions of human lives worldwide. Direct-acting antiviral (DAA) regimens are the most effective HCV treatment option. However, amino acid substitution-dependent resistance to DAAs has been a major challenge. This study aimed to determine the increasing risk of DAA resistance due to substitutions in DAA target non-structural proteins (NS3/4A, NS5A, and NS5B). Using a Sequence Retrieval System (SRS) at the virus pathogen resource (ViPR/BV-BRC), n = 32763 target protein sequences were retrieved and analyzed for resistance-associated amino acid substitutions (RAASs) by the Sequence Feature Variant Type (SFVT) antiviral-resistance assessment modeling tool. Reference target protein sequences with 100% identity were retried from UniProt following NCBI BLAST. The types and locations of RAASs were identified and visualized by AlphaFold and PyMol. Linux-r-base/R-studio was used for the data presentation. Multi-drug-resistant variants of NS3/4A in genotype 1 (n = 9) and genotype 5 (n = 5) along with DAA-specific NS3/4A, NS5A, and NS5B variants were identified pan-genotypically. A total of 27 variants (RAASs) of all the targets were identified. Fourteen genotype 1-specific substitutions: V1196A, V1158I, D1194A/T/G, R1181K, T1080S, Q1106R, V1062A, S1148G, A1182V, Y2065N, M2000T, and L2003V were identified. The most frequent substitutions were V1062L and L2003M, followed by Q2002H. L2003V, Q2002H, M2000T, Y2065N, and NL2003M of NS5A and L2003M of NS5B conferred resistance to daclatasvir. S2702T NS5B was the sofosbuvir-resistant variant. D1194A NS3/4A was triple DAA (simeprevir, faldaprevir, and asunaprevir) resistant. The double-drug resistant variants R1181K (faldaprevir and asunaprevir), A1182V and Q1106K/R (faldaprevir and simeprevir), T1080S (faldaprevir and telaprevir), and single drug-resistant variants V1062L (telaprevir), D1194E/T (simeprevir), D1194G (asunaprevir), S1148A/G (simeprevir), and Q1106L (Boceprevir) of NS3/4A were determined. The molecular phenomenon of DAA resistance is paramount in the development of HCV drug candidates. RAASs in NS3, NS5A, and NS5B reduce the susceptibility to DAAs; therefore, continuous RAAS-dependent resistance profiling in HCV is recommended to minimize the probability of DAA therapeutic failure.
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Affiliation(s)
- Mohammad Asrar Izhari
- Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Al-Baha University, Al-Baha 65522, Saudi Arabia
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16
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Ahmed K, Jha S. Oncoviruses: How do they hijack their host and current treatment regimes. Biochim Biophys Acta Rev Cancer 2023; 1878:188960. [PMID: 37507056 DOI: 10.1016/j.bbcan.2023.188960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 07/05/2023] [Accepted: 07/20/2023] [Indexed: 07/30/2023]
Abstract
Viruses have the ability to modulate the cellular machinery of their host to ensure their survival. While humans encounter numerous viruses daily, only a select few can lead to disease progression. Some of these viruses can amplify cancer-related traits, particularly when coupled with factors like immunosuppression and co-carcinogens. The global burden of cancer development resulting from viral infections is approximately 12%, and it arises as an unfortunate consequence of persistent infections that cause chronic inflammation, genomic instability from viral genome integration, and dysregulation of tumor suppressor genes and host oncogenes involved in normal cell growth. This review provides an in-depth discussion of oncoviruses and their strategies for hijacking the host's cellular machinery to induce cancer. It delves into how viral oncogenes drive tumorigenesis by targeting key cell signaling pathways. Additionally, the review discusses current therapeutic approaches that have been approved or are undergoing clinical trials to combat malignancies induced by oncoviruses. Understanding the intricate interactions between viruses and host cells can lead to the development of more effective treatments for virus-induced cancers.
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Affiliation(s)
- Kainat Ahmed
- Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA
| | - Sudhakar Jha
- Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA.
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17
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Abstract
Clinical trials have been a central driver of change and have provided the evidence base necessary to advance new therapies for liver diseases. This review provides a perspective on the status of trials in hepatology and a vantage point into the emerging capabilities and external forces that will shape the conduct of clinical trials in the future. The adaptations to clinical trial operations in response to the disruptions by the COVID-19 pandemic and opportunities for innovation in hepatology trials are emphasized. Future trials in hepatology will be driven by unmet therapeutic needs and fueled by technological advances incorporating digital capabilities with expanded participant-derived data collection, computing, and analytics. Their design will embrace innovative trial designs adapted to these advances and that emphasize broader and more inclusive participant engagement. Their conduct will be further shaped by evolving regulatory needs and the emergence of new stakeholders in the clinical trials ecosystem. The evolution of clinical trials will offer unique opportunities to advance new therapeutics that will ultimately improve the lives of patients with liver diseases.
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Affiliation(s)
- Paul Y Kwo
- Department of Medicine, Stanford University School of Medicine, Palo Alto, California, USA
| | - Tushar Patel
- Department of Transplantation, Mayo Clinic, Jacksonville, Florida, USA
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18
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Derayea SM, Abu-Hassan AA, Hamad AA, Eltoukhi WE, Hamad AE, Mohammed BS. Mathematical processing of absorption as green smart spectrophotometric methods for concurrent assay of hepatitis C antiviral drugs, Sofosbuvir and Simeprevir: application to combined pharmaceutical dosage forms and evaluation of the method greenness. BMC Chem 2023; 17:75. [PMID: 37452429 PMCID: PMC10347804 DOI: 10.1186/s13065-023-00984-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 06/30/2023] [Indexed: 07/18/2023] Open
Abstract
The present work was developed to create three rapid, simple, eco-friendly, cheap spectrophotometric methods for concurrent assay of Sofosbuvir (SOF) and Simeprevir (SMV) in their pure, laboratory prepared mixture and pharmaceutical dosage form with high degree of accuracy and precision. Three methods were developed including iso-absorptive point, ratio subtraction and dual wavelength. The linear range of the proposed methods was 3.0-50.0 and 2.0-50.0 µg mL-1 for SMV and SOF, respectively. The proposed methods were validated according to ICH guidelines in terms of linearity, accuracy, precision, limit of detection and limit of quantitation. The proposed approach is highly simple and the procedure is environmentally green making it suitable for the drug analysis in routine works.
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Affiliation(s)
- Sayed M Derayea
- Department of Analytical Chemistry, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt
| | - Ahmed A Abu-Hassan
- Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524, Egypt
| | - Ahmed A Hamad
- Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524, Egypt
| | - Walid E Eltoukhi
- Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524, Egypt
| | - Amal E Hamad
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Menoufia University, Shebin El-Kom, Menoufia, Egypt
| | - Bassam Shaaban Mohammed
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Menoufia University, Shebin El-Kom, Menoufia, Egypt.
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19
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Sharma P, Sawtell R, Wang Q, Sise ME. Management of Hepatitis C Virus and Hepatitis B Virus Infection in the Setting of Kidney Disease. ADVANCES IN KIDNEY DISEASE AND HEALTH 2023; 30:343-355. [PMID: 37657881 PMCID: PMC10479952 DOI: 10.1053/j.akdh.2023.04.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 04/04/2023] [Accepted: 04/19/2023] [Indexed: 09/03/2023]
Abstract
Treatment of chronic hepatitis C virus (HCV) and hepatitis B virus (HBV) infection poses unique challenges in patients with kidney disease. Direct-acting antivirals have been a major breakthrough in eradicating HCV infection, and several pangenotypic regimens are available for patients with chronic kidney disease or end-stage kidney disease requiring dialysis with high cure rates and no need for dose adjustment. Direct-acting antiviral therapy alone can treat HCV-associated cryoglobulinemic glomerulonephritis; concurrent antiviral and immunosuppressive therapy is needed for cases of severe, organ-threatening manifestations of cryoglobulinemia. Immunosuppression may be needed for HBV-associated kidney disease (polyarteritis nodosa or membranous nephropathy) when there is evidence of severe immune-mediated injury while weighing the risk of potential viral activation. Most HBV antiviral agents need to be dose-adjusted in patients with chronic kidney disease or end-stage kidney disease requiring dialysis, and drug-drug interactions need to be carefully evaluated in patients with kidney transplants. Considerations for accepting HCV- and HBV-infected donors for kidney transplantation are discussed.
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Affiliation(s)
- Purva Sharma
- Department of Medicine, Division of Nephrology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell; Glomerular Disease Center at Northwell Health, Hempstead, NY
| | - Rani Sawtell
- Department of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, MA
| | - Qiyu Wang
- Department of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, MA
| | - Meghan E Sise
- Department of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, MA.
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20
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Ivashkin VT, Chulanov VP, Mamonova NA, Maevskaya MV, Zharkova MS, Tikhonov IN, Bogomolov PO, Volchkova EV, Dmitriev AS, Znojko OO, Klimova EA, Kozlov KV, Kravchenko IE, Malinnikova EY, Maslennikov RV, Mikhailov MI, Novak KE, Nikitin IG, Syutkin VE, Esaulenko EV, Sheptulin AA, Shirokova EN, Yushchuk ND. Clinical Practice Guidelines of the Russian Society for the Study of the Liver, the Russian Gastroenterological Association, the National Scientific Society of Infectious Disease Specialists for the Diagnosis and Treatment of Chronic Hepatitis C. RUSSIAN JOURNAL OF GASTROENTEROLOGY, HEPATOLOGY, COLOPROCTOLOGY 2023; 33:84-124. [DOI: 10.22416/1382-4376-2023-33-1-84-124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/26/2024]
Abstract
Аim:diagnosis and treatment algorithms in the clinical recommendations intended for general practitioners, gastroenterologists, infectious disease specialists, hepatologists on the of chronic hepatitis C are presented.Summary.Chronic viral hepatitis C is a socially significant infection, the incidence of which in the Russian Federation remains significantly high. Over the past 10 years, great progress has been made in the treatment of hepatitis C — direct acting antiviral drugs have appeared. The spectrum of their effectiveness allows to achieve a sustained virological response in more than 90 % of cases, even in groups that were not previously considered even as candidates for therapy or were difficult to treat — patients receiving renal replacement therapy, after liver transplantation (or other organs), at the stage of decompensated liver cirrhosis, HIV co-infected, etc. Interferons are excluded from the recommendations due to their low effectiveness and a wide range of adverse events. The indications for the treatment have been expanded, namely, the fact of confirmation of viral replication. The terms of dispensary observation of patients without cirrhosis of the liver have been reduced (up to 12 weeks after the end of therapy). Also, these recommendations present approaches to active screening of hepatitis in risk groups, preventive and rehabilitation measures after the end of treatment.Conclusion.Great success has been achieved in the treatment of chronic hepatitis C. In most cases, eradication of viral HCV infection is a real task even in patients at the stage of cirrhosis of the liver, with impaired renal function, HIV co-infection, after solid organs transplantation.
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Affiliation(s)
- V. T. Ivashkin
- Sechenov First Moscow State Medical University (Sechenov University)
| | - V. P. Chulanov
- Center for Epidemiologically Significant Infectious Diseases, National Medical Research Center for Phthisiopulmonology and Infectious Diseases
| | - N. A. Mamonova
- Center for Epidemiologically Significant Infectious Diseases, National Medical Research Center for Phthisiopulmonology and Infectious Diseases
| | - M. V. Maevskaya
- Sechenov First Moscow State Medical University (Sechenov University)
| | - M. S. Zharkova
- Sechenov First Moscow State Medical University (Sechenov University)
| | - I. N. Tikhonov
- Sechenov First Moscow State Medical University (Sechenov University)
| | - P. O. Bogomolov
- M.F. Vladimirsky Moscow Regional Research Clinical Institute
| | - E. V. Volchkova
- Sechenov First Moscow State Medical University (Sechenov University)
| | - A. S. Dmitriev
- Sechenov First Moscow State Medical University (Sechenov University)
| | - O. O. Znojko
- Moscow State University of Medicine and Dentistry
| | | | | | | | - E. Yu. Malinnikova
- Department of Virology, Russian Medical Academy of Continuing Professional Education
| | - R. V. Maslennikov
- Sechenov First Moscow State Medical University (Sechenov University)
| | - M. I. Mikhailov
- North-Western State Medical University named after I.I. Mechnikov
| | | | | | - V. E. Syutkin
- Sklifosovsky Clinical and Research Institute for Emergency Medicine; Russian State Research Center — Burnazyan Federal Medical Biophysical Center
| | | | - A. A. Sheptulin
- Sechenov First Moscow State Medical University (Sechenov University)
| | - E. N. Shirokova
- Sechenov First Moscow State Medical University (Sechenov University)
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21
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Gutiérrez-Rojas L, de la Gándara Martín JJ, García Buey L, Uriz Otano JI, Mena Á, Roncero C. Patients with severe mental illness and hepatitis C virus infection benefit from new pangenotypic direct-acting antivirals: Results of a literature review. GASTROENTEROLOGIA Y HEPATOLOGIA 2023; 46:382-396. [PMID: 35718017 DOI: 10.1016/j.gastrohep.2022.06.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 05/25/2022] [Accepted: 06/07/2022] [Indexed: 05/09/2023]
Abstract
INTRODUCTION Hepatitis C virus (HCV) infection is a global health problem that can results in cirrhosis, hepatocellular carcinoma and even death. HCV infection is 3-20-fold more prevalent among patients with versus without severe mental illness (SMI), such as major depressive disorder, personality disorder, bipolar disorder and schizophrenia. Treatment options for HCV were formerly based on pegylated interferon alpha, which is associated with neuropsychiatric adverse events, and this contributed to the exclusion of patients with SMI from HCV treatment, elimination programmes, and clinical trials. Moreover, the assumption of poor adherence, scant access to healthcare and the stigma and vulnerability of this population emerged as barriers and contributed to the low rates of treatment and efficacy. METHODS This paper reviews the literature published between December 2010 and December 2020 exploring the epidemiology of HCV in patients with SMI, and vice versa, the effect of HCV infection, barriers to the management of illness in these patients, and benefits of new therapeutic options with pangenotypic direct antiviral agents (DAAs). RESULTS The approval of DAAs has changed the paradigm of HCV infection treatment. DAAs have proven to be an equally efficacious and safe option that improves quality of life (QoL) in patients SMI. CONCLUSIONS Knowledge of the consequences of the HCV infection and the benefits of treatment with new pangenotypic DAAs among psychiatrists can increase screening, referral and treatment of HCV infection in patients with SMI.
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Affiliation(s)
| | | | - Luisa García Buey
- Gastroenterology Department, Liver Unit, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, Madrid, Spain
| | - Juan I Uriz Otano
- Gastroenterology Department, Liver Unit, Complejo Hospitalario de Navarra, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain
| | - Álvaro Mena
- Infectious Diseases Unit, Internal Medicine Service, Clinical Virology Group, Instituto de Investigación Biomédica de A Coruña (INIBIC)-Complejo Hospitalario Universitario de A Coruña (CHUAC), Universidade da Coruña, Coruña, Spain
| | - Carlos Roncero
- Psychiatry Service, University of Salamanca Health Care Complex and Psychiatric Unit, School of Medicine, Institute of Biomedicine, University of Salamanca, Salamanca, Spain
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22
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Qin A. An anti-cancer surveillance by the interplay between interferon-beta and retinoblastoma protein RB1. Front Oncol 2023; 13:1173467. [PMID: 37182173 PMCID: PMC10174298 DOI: 10.3389/fonc.2023.1173467] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 04/05/2023] [Indexed: 05/16/2023] Open
Abstract
Interferon-beta (IFN-β), an extracellular cytokine that initiates signaling pathways for gene regulation, has been demonstrated to function as a tumor suppressor protein through lentiviral gene transduction. In this article, I review the relevant previous works and propose a cell cycle-based, tumor suppressor protein-mediated mechanism of anti-cancer surveillance. IFN-β induces a tumor cell cycle alteration that leads to S phase accumulation, senescence entry, and a loss of tumorigenicity in solid tumor cells. IFN-β does not show a significant cell cycle effect in their normal counterparts. Retinoblastoma protein RB1, another tumor suppressor protein, tightly controls the cell cycle and differentiation of normal cells, preventing them from being significantly impacted by the IFN-β effect. The interplay between IFN-β and RB1 acts as a mechanism of cell cycle-based, tumor suppressor protein-mediated anti-cancer surveillance that can selectively suppress solid tumor or proliferating transformed cells from the loss of control leading to cancer. This mechanism has important implications for the treatment of solid tumors.
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Affiliation(s)
- Albert Qin
- Medical Research & Clinical Operations, PharmaEssentia Corporation, Taipei, Taiwan
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23
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Eliminación del virus de la hepatitis C en un centro penitenciario: una experiencia de 18 años. Enferm Infecc Microbiol Clin 2023. [DOI: 10.1016/j.eimc.2023.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/09/2023]
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24
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Brzdęk M, Zarębska-Michaluk D, Invernizzi F, Cilla M, Dobrowolska K, Flisiak R. Decade of optimizing therapy with direct-acting antiviral drugs and the changing profile of patients with chronic hepatitis C. World J Gastroenterol 2023; 29:949-966. [PMID: 36844142 PMCID: PMC9950869 DOI: 10.3748/wjg.v29.i6.949] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/22/2022] [Accepted: 01/09/2023] [Indexed: 02/10/2023] Open
Abstract
Chronic infection with the hepatitis C virus (HCV) remains a major health problem affecting approximately 58 million people worldwide. In the era of interferon (IFN)-based regimens, patients particularly infected with genotypes 1 and 4 achieved a low response rate. The implementation of direct-acting antivirals changed the landscape of HCV treatment. The increase in effectiveness provided us with the hope of eliminating HCV as a significant public threat by 2030. In the following years, there was an observed improvement in the treatment of HCV with genotype-specific regimens and highly effective pangenotypic options that are the most recent stage of the revolution. The optimization of therapy was accompanied by changes in the patient profile from the beginning of the IFN-free era over time. Patients treated with antiviral therapies were younger in successive periods, less burdened with comorbidities and comedications, more frequently treatment-naïve and had less advanced liver disease. Before the IFN-free era, specific subpopulations such as patients with HCV/HIV coinfection, those with a history of previous treatment, patients with renal impairment or with cirrhosis had lower chances for a virologic response. Currently, these populations should no longer be considered difficult to treat. Despite the high effectiveness of HCV therapy, there is a small percentage of patients with treatment failure. However, they can be effectively retreated with pangenotypic rescue regimens.
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Affiliation(s)
- Michał Brzdęk
- Collegium Medicum, Jan Kochanowski University, Kielce 25-516, Poland
| | | | - Federica Invernizzi
- Center for Liver Disease, Division of Internal Medicine and Hepatology, IRCCS Ospedale San Raffaele, Milan 20-132, Italy
| | - Marta Cilla
- Center for Liver Disease, Division of Internal Medicine and Hepatology, IRCCS Ospedale San Raffaele, Milan 20-132, Italy
| | | | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok 15-540, Poland
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25
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Hawsawi NM, Saber T, Salama HM, Fouad WS, Hagag HM, Alhuthali HM, Eed EM, Saber T, Ismail KA, Al Qurashi HH, Altowairqi S, Samaha M, El-Hossary D. Genotypes of Hepatitis C Virus and Efficacy of Direct-Acting Antiviral Drugs among Chronic Hepatitis C Patients in a Tertiary Care Hospital. Trop Med Infect Dis 2023; 8:92. [PMID: 36828508 PMCID: PMC9967136 DOI: 10.3390/tropicalmed8020092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 01/20/2023] [Accepted: 01/24/2023] [Indexed: 01/31/2023] Open
Abstract
Hepatitis C virus (HCV) chronic infection is a major causative factor for several chronic liver diseases, including liver cirrhosis, liver cell failure, and hepatocellular carcinoma. The HCV has seven major genotypes. Genotype 4 is the most prevalent genotype in the Middle East, including Saudi Arabia, followed by genotype 1. The HCV genotype affects the response to different HCV treatments and the progression of liver disease. Currently, combinations of direct-acting antiviral drugs (DAAs) approved for the treatment of HCV achieve high cure rates with minimal adverse effects. Because real-world data from Saudi Arabia about the efficacy of DAAs are still limited, this study was conducted to assess the effectiveness of DAAs in treating patients with chronic hepatitis C and to identify the variables related to a sustained virologic response (SVR) in a real-world setting in Saudi Arabia. This prospective cohort study included 200 Saudi patients with chronic HCV who were 18 years of age or older and had been treated with DAAs at King Abdul-Aziz Specialized Hospital in Taif, Saudi Arabia, between September 2018 and March 2021. The response to treatment was assessed by whether or not an SVR had been achieved at week 12 post treatment (SVR12). An SVR12 was reached in 97.5% of patients. SVR12 rates were comparable for patients of different ages, between men and women, and between patients with and without cirrhosis. In addition, the SVR12 rates did not differ according to the infecting HCV genotype. In this study, the presence of cirrhosis and the patient's gender were independent predictors of who would not reach an SVR12 (known here as the non-SVR12 group) according to the results of univariate and multivariate binary logistic regression analyses based on the determinants of SVR12. In this population of patients with chronic HCV infection, all DAA regimens achieved very high SVR12 rates. The patients' gender and the presence of cirrhosis were independent factors of a poor response.
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Affiliation(s)
- Nahed Mohammed Hawsawi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif 21944, Saudi Arabia
| | - Tamer Saber
- Departments of Internal Medicine, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Hussein M. Salama
- Departments of Internal Medicine, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Walaa S. Fouad
- Departments of Family Medicine, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Howaida M. Hagag
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif 21944, Saudi Arabia
- Department of Pathology, Faculty of Medicine, Al-Azhar University, Cairo 11884, Egypt
| | - Hayaa M. Alhuthali
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif 21944, Saudi Arabia
| | - Emad M. Eed
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif 21944, Saudi Arabia
- Medical Microbiology and Immunology Department, Faculty of Medicine, Menoufia University, Shebinel Kom 32511, Egypt
| | - Taisir Saber
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif 21944, Saudi Arabia
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Khadiga A. Ismail
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif 21944, Saudi Arabia
- Department of Parasitology, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt
| | - Hesham H. Al Qurashi
- Gastroenterology and Hepatology Department, King Abdul-Aziz Specialized Hospital, Taif 26521, Saudi Arabia
| | - Samir Altowairqi
- Gastroenterology and Hepatology Department, King Abdul-Aziz Specialized Hospital, Taif 26521, Saudi Arabia
| | - Mohmmad Samaha
- Gastroenterology and Hepatology Department, King Abdul-Aziz Specialized Hospital, Taif 26521, Saudi Arabia
| | - Dalia El-Hossary
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
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26
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Riaz M, Rehman AU, Waqas M, Khalid A, Abdalla AN, Mahmood A, Hu J, Wadood A. A Novel Approach to Develop New and Potent Inhibitors for the Simultaneous Inhibition of Protease and Helicase Activities of HCV NS3/4A Protease: A Computational Approach. Molecules 2023; 28:molecules28031300. [PMID: 36770965 PMCID: PMC9918934 DOI: 10.3390/molecules28031300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/18/2023] [Accepted: 01/19/2023] [Indexed: 02/03/2023] Open
Abstract
Infection of hepatitis C (HCV) is a major threat to human health throughout the world. The current therapy program suffers from restricted efficiency and low tolerance, and there is serious demand frr novel medication. NS3/4A protease is observed to be very effective target for the treatment of HCV. A data set of the already reported HCV NS3/4A protease inhibitors was first docked into the NS3/4A protease (PDB ID: 4A92A) active sites of both protease and helicase sites for calculating the docking score, binding affinity, binding mode, and solvation energy. Then the data set of these reported inhibitors was used in a computer-based program "RECAP Analyses" implemented in MOE to fragment every molecule in the subset according to simple retrosynthetic analysis rules. The RECAP analysis fragments were then used in another computer-based program "RECAP Synthesis" to randomly recombine and generate synthetically reasonable novel chemical structures. The novel chemical structures thus produced were then docked against HCV NS3/4A. After a thorough validation of all undertaken steps, based on Lipinski's rule of five, docking score, binding affinity, solvation energy, and Van der Waal's interactions with HCV NS3/4A, 12 novel chemical structures were identified as inhibitors of HCV NS3/4A. The novel structures thus designed are hoped to play a key role in the development of new effective inhibitors of HCV.
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Affiliation(s)
- Muhammad Riaz
- Computational Medicinal Chemistry Laboratory, Department of Biochemistry, Abdul Wali Khan University Mardan, Mardan 23200, Pakistan
| | - Ashfaq Ur Rehman
- School of Biological Science, University of California, Irvine, CA 92697, USA
| | - Muhammad Waqas
- Natural and Medical Sciences Research Center, University of Nizwa, Birkat Al Mauz, P.O. Box 33, Nizwa 616, Oman
| | - Asaad Khalid
- Substance Abuse and Toxicology Research Center, Jazan University, P.O. Box 114, Jazan 45142, Saudi Arabia
- Medicinal and Aromatic Plants and Traditional Medicine Research Institute, National Center for Research, Khartoum P.O. Box 2404, Sudan
| | - Ashraf N. Abdalla
- Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia
| | - Arif Mahmood
- Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
| | - Junjian Hu
- Department of Central Laboratory, SSL, Central Hospital of Dongguan City, Affiliated Dongguan Shilong People’s Hospital of Southern Medical University, Dongguan 523000, China
- Correspondence: (J.H.); (A.W.)
| | - Abdul Wadood
- Computational Medicinal Chemistry Laboratory, Department of Biochemistry, Abdul Wali Khan University Mardan, Mardan 23200, Pakistan
- Correspondence: (J.H.); (A.W.)
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27
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Zhang K, Chen L, Zhu C, Zhang M, Liang C. Current Knowledge of Th22 Cell and IL-22 Functions in Infectious Diseases. Pathogens 2023; 12:pathogens12020176. [PMID: 36839448 PMCID: PMC9965464 DOI: 10.3390/pathogens12020176] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 01/19/2023] [Accepted: 01/19/2023] [Indexed: 01/24/2023] Open
Abstract
T helper 22 (Th22) cells, a newly defined CD4+ T-cell lineage, are characterized by their distinct cytokine profile, which primarily consists of IL-13, IL-22 and TNF-α. Th22 cells express a wide spectrum of chemokine receptors, such as CCR4, CCR6 and CCR10. The main effector molecule secreted by Th22 cells is IL-22, a member of the IL-10 family, which acts by binding to IL-22R and triggering a complex downstream signaling system. Th22 cells and IL-22 have been found to play variable roles in human immunity. In preventing the progression of infections such as HIV and influenza, Th22/IL-22 exhibited protective anti-inflammatory characteristics, and their deleterious proinflammatory activities have been demonstrated to exacerbate other illnesses, including hepatitis B and Helicobacter pylori infection. Herein, we review the current understanding of Th22 cells, including their definition, differentiation and mechanisms, and the effect of Th22/IL-22 on human infectious diseases. According to studies on Th22 cells, Th22/IL-22 may be a promising therapeutic target and an effective treatment strategy for various infections.
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Affiliation(s)
- Kunyu Zhang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
- Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei 230022, China
- Institute of Urology, Anhui Medical University, Hefei 230022, China
- The Second Clinical Medical College, Anhui Medical University, Hefei 230032, China
| | - Lei Chen
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
- Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei 230022, China
- Institute of Urology, Anhui Medical University, Hefei 230022, China
| | - Chenyu Zhu
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
- Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei 230022, China
- Institute of Urology, Anhui Medical University, Hefei 230022, China
- The Second Clinical Medical College, Anhui Medical University, Hefei 230032, China
| | - Meng Zhang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
- Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei 230022, China
- Institute of Urology, Anhui Medical University, Hefei 230022, China
- Correspondence: (M.Z.); (C.L.); Tel./Fax: +86-55162922034 (M.Z.); +86-55162922034 (C.L.)
| | - Chaozhao Liang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
- Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei 230022, China
- Institute of Urology, Anhui Medical University, Hefei 230022, China
- Correspondence: (M.Z.); (C.L.); Tel./Fax: +86-55162922034 (M.Z.); +86-55162922034 (C.L.)
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28
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Brzdęk M, Dobrowolska K, Flisiak R, Zarębska-Michaluk D. Genotype 4 hepatitis C virus-a review of a diverse genotype. Adv Med Sci 2023; 68:54-59. [PMID: 36640687 DOI: 10.1016/j.advms.2022.12.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 12/02/2022] [Accepted: 12/21/2022] [Indexed: 01/15/2023]
Abstract
PURPOSE Hepatitis C virus (HCV) infection remains a major health problem and one of the leading causes of chronic liver disease worldwide. The purpose of this paper was to summarize knowledge about the epidemiology of HCV genotype (GT) 4 infection, similarities and differences with other genotypes, specific problems associated with this genotype, and treatment regimens used to treat GT4-infected patients. METHODS We performed an accurate search for literature using the PubMed database to select high-quality reviews and original articles concerning this topic. RESULTS GT4 with a global prevalence of 8% takes third place, closing the global HCV podium in terms of frequency. However, there are regions where GT4 infections are dominant, such as sub-Saharan and North Africa, and the Middle East. The disease course and complications are generally similar to those of chronic hepatitis C caused by other genotypes, although the faster progression of fibrosis was demonstrated in patients with coexisting schistosomiasis. In the era of interferon-based therapy, GT4-infected patients were described as difficult to treat due to suboptimal response. A breakthrough in the treatment of HCV-infected patients, including those with GT4 infection, was the introduction of direct-acting antiviral drugs. CONCLUSIONS The availability of safe and effective therapy has created a real opportunity for HCV eradication in line with the goal set by the World Health Organization. An example of a country where this is happening is Egypt, where GT4 accounts for more than 90% of HCV infections. There, broad access to therapy has been effectively supported by population-based screening.
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Affiliation(s)
- Michał Brzdęk
- Collegium Medicum, Jan Kochanowski University, Kielce, Poland.
| | | | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Bialystok, Poland
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29
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Su CM, Du Y, Rowland RRR, Wang Q, Yoo D. Reprogramming viral immune evasion for a rational design of next-generation vaccines for RNA viruses. Front Immunol 2023; 14:1172000. [PMID: 37138878 PMCID: PMC10149994 DOI: 10.3389/fimmu.2023.1172000] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 04/03/2023] [Indexed: 05/05/2023] Open
Abstract
Type I interferons (IFNs-α/β) are antiviral cytokines that constitute the innate immunity of hosts to fight against viral infections. Recent studies, however, have revealed the pleiotropic functions of IFNs, in addition to their antiviral activities, for the priming of activation and maturation of adaptive immunity. In turn, many viruses have developed various strategies to counteract the IFN response and to evade the host immune system for their benefits. The inefficient innate immunity and delayed adaptive response fail to clear of invading viruses and negatively affect the efficacy of vaccines. A better understanding of evasion strategies will provide opportunities to revert the viral IFN antagonism. Furthermore, IFN antagonism-deficient viruses can be generated by reverse genetics technology. Such viruses can potentially serve as next-generation vaccines that can induce effective and broad-spectrum responses for both innate and adaptive immunities for various pathogens. This review describes the recent advances in developing IFN antagonism-deficient viruses, their immune evasion and attenuated phenotypes in natural host animal species, and future potential as veterinary vaccines.
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Affiliation(s)
- Chia-Ming Su
- Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, United States
| | - Yijun Du
- Shandong Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, Shandong, China
| | - Raymond R. R. Rowland
- Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, United States
| | - Qiuhong Wang
- Center for Food Animal Health, Department of Animal Sciences, College of Food, Agricultural, and Environmental Sciences, The Ohio State University, Wooster, OH, United States
- Department of Veterinary Preventive Medicine, College of Veterinary Medicine, The Ohio State University, Columbus, OH, United States
| | - Dongwan Yoo
- Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, United States
- *Correspondence: Dongwan Yoo,
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30
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Hsiao CY, Meng JL, Hong JZ, Ly XH, Lin MH, Chang CY, Nguyen MTT, Cheng TL, Lin WW, Burnouf PA, Al-Qaisi TS, Liu ES, Su YC. Engineering a High-Affinity Anti-Methoxy Poly(ethylene glycol) (mPEG) Antibody for Sensitive Immunosensing of mPEGylated Therapeutics and mPEG Molecules. Bioconjug Chem 2022; 33:2180-2188. [DOI: 10.1021/acs.bioconjchem.2c00416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Chiao-Yu Hsiao
- Department of Biological Science and Technology, Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu 300193, Taiwan
| | - Jun-Lun Meng
- Department of Biological Science and Technology, Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu 300193, Taiwan
| | - Jung-Zhe Hong
- Department of Biological Science and Technology, Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu 300193, Taiwan
| | - Xuan-Huong Ly
- Department of Biological Science and Technology, Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu 300193, Taiwan
| | - Meng-Hsuan Lin
- Department of Biological Science and Technology, Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu 300193, Taiwan
| | - Chin-Yuan Chang
- Department of Biological Science and Technology, Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu 300193, Taiwan
- Department of Biomedical Science and Environmental Biology, Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
| | - Minh-Tram T. Nguyen
- Department of Biological Science and Technology, Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu 300193, Taiwan
| | - Tian-Lu Cheng
- Department of Biomedical Science and Environmental Biology, Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
| | - Wen-Wei Lin
- School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
| | - Pierre-Alain Burnouf
- International Center for Wound Repair and Regeneration (iWRR), National Cheng-Kung University, Tainan 701401, Taiwan
| | - Talal Salem Al-Qaisi
- Department of Medical Laboratory Sciences, Pharmacological and Diagnostic Research Centre, Faculty of Allied Medical Sciences, Al-Ahliyya Amman University, Amman 19328, Jordan
| | - En-Shuo Liu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
| | - Yu-Cheng Su
- Department of Biological Science and Technology, Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu 300193, Taiwan
- Department of Biomedical Science and Environmental Biology, Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
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31
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Marascio N, De Caro C, Quirino A, Mazzitelli M, Russo E, Torti C, Matera G. The Role of the Microbiota Gut-Liver Axis during HCV Chronic Infection: A Schematic Overview. J Clin Med 2022; 11:5936. [PMID: 36233804 PMCID: PMC9572099 DOI: 10.3390/jcm11195936] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 10/03/2022] [Accepted: 10/04/2022] [Indexed: 11/30/2022] Open
Abstract
Hepatitis C virus (HCV) still represents one of the most important worldwide health care problems. Since 2011, direct-acting antiviral (DAA) drugs have increased the number of people who have achieved a sustained virological response (SVR). Even if the program to eradicate HCV by 2030 is still ongoing, the SARS-CoV-2 pandemic has created a delay due to the reallocation of public health resources. HCV is characterized by high genetic variability and is responsible for hepatic and extra-hepatic diseases. Depending on the HCV genotype/subtype and comorbidities of patients, tailored treatment is necessary. Recently, it has been shown that liver damage impacts gut microbiota, altering the microbial community (dysbiosis) during persistent viral replication. An increasing number of studies are trying to clarify the role of the gut-liver axis during HCV chronic infection. DAA therapy, by restoring the gut microbiota equilibrium, seems to improve liver disease progression in both naïve and treated HCV-positive patients. In this review, we aim to discuss a snapshot of selected peer-reviewed papers concerning the interplay between HCV and the gut-liver axis.
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Affiliation(s)
- Nadia Marascio
- Clinical Microbiology Unit, Department of Health Science, “Magna Graecia” University, 88100 Catanzaro, Italy
| | - Carmen De Caro
- System and Applied Pharmacology, Department of Health Science, “Magna Graecia” University, 88100 Catanzaro, Italy
| | - Angela Quirino
- Clinical Microbiology Unit, Department of Health Science, “Magna Graecia” University, 88100 Catanzaro, Italy
| | - Maria Mazzitelli
- Infectious and Tropical Diseases Unit, University Hospital of Padua, 35128 Padua, Italy
| | - Emilio Russo
- System and Applied Pharmacology, Department of Health Science, “Magna Graecia” University, 88100 Catanzaro, Italy
| | - Carlo Torti
- Infectious and Tropical Diseases Unit, Department of Medical and Surgical Sciences, “Magna Graecia” University, 88100 Catanzaro, Italy
| | - Giovanni Matera
- Clinical Microbiology Unit, Department of Health Science, “Magna Graecia” University, 88100 Catanzaro, Italy
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Kiattanaphon A, Vipsoongnern Y, Kunthalert D, Sistayanarain A. Partial nonstructural 3 region analysis of hepatitis C virus genotype 3a. Mol Biol Rep 2022; 49:9437-9443. [PMID: 36002650 DOI: 10.1007/s11033-022-07803-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 07/07/2022] [Accepted: 07/08/2022] [Indexed: 02/08/2023]
Abstract
BACKGROUND The hepatitis C virus (HCV) is a major cause of illness around the world. HCV genotype 3a is the most prevalent genotype in Thailand. Direct-acting antiviral (DAA) drugs are available for treatment, and these drugs target the NS3, NS5A, and NS5b proteins of HCV. However, HCV variants that are resistant to NS3 protease inhibitors have been found during treatment. This resistance can be naturally occurring or in response to treatment. The purpose of this study is to analyze the codon positions of the main mutation of the partial NS3 gene region of HCV genotype 3a. METHODS In order to detect mutations and confirm the genotype of HCV genotype 3a, the nucleotide sequencing and amino acid portion of NS3 were analyzed. RESULTS Twenty-six samples were successfully sequenced and clustered within two sub-clades defined as 3a-1 and 3a-2. Through amino acid mutation analysis, the variations were detected at codon positions 122 (3.8%), 132 (84.6%), 168 (100%), 170 (92.3%), 174 (100%), and 175 (100%). CONCLUSIONS In conclusion, mutations at positions 168, 170, 174, and 175 of the NS3 region are common within the HCV genotype 3a. This information should be useful in the development of effective anti-viral drugs that can successfully treat HCV infection.
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Affiliation(s)
- Anusorn Kiattanaphon
- Department of Microbiology and Parasitology, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand
| | | | - Duangkamol Kunthalert
- Department of Microbiology and Parasitology, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand
| | - Anchalee Sistayanarain
- Department of Microbiology and Parasitology, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand.
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Panigrahi M, Palmer MA, Wilson JA. MicroRNA-122 Regulation of HCV Infections: Insights from Studies of miR-122-Independent Replication. Pathogens 2022; 11:1005. [PMID: 36145436 PMCID: PMC9504723 DOI: 10.3390/pathogens11091005] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 08/26/2022] [Accepted: 08/29/2022] [Indexed: 11/18/2022] Open
Abstract
Despite the advancement in antiviral therapy, Hepatitis C remains a global health challenge and one of the leading causes of hepatitis related deaths worldwide. Hepatitis C virus, the causative agent, is a positive strand RNA virus that requires a liver specific microRNA called miR-122 for its replication. Unconventional to the canonical role of miRNAs in translation suppression by binding to 3'Untranslated Region (UTR) of messenger RNAs, miR-122 binds to two sites on the 5'UTR of viral genome and promotes viral propagation. In this review, we describe the unique relationship between the liver specific microRNA and HCV, the current knowledge on the mechanisms by which the virus uses miR-122 to promote the virus life cycle, and how miR-122 impacts viral tropism and pathogenesis. We will also discuss the use of anti-miR-122 therapy and its impact on viral evolution of miR-122-independent replication. This review further provides insight into how viruses manipulate host factors at the initial stage of infection to establish a successful infection.
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Affiliation(s)
| | | | - Joyce A. Wilson
- Department of Biochemistry, Microbiology, and Immunology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
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Ahn YH, Lee H, Han JE, Cho HJ, Cheong JY, Park B, Kim SS. Effect of direct-acting antivirals for hepatitis C virus-related hepatocellular carcinoma recurrence and death after curative treatment. JOURNAL OF LIVER CANCER 2022; 22:125-135. [PMID: 37383412 PMCID: PMC10035739 DOI: 10.17998/jlc.2022.05.24] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 05/13/2022] [Accepted: 05/24/2022] [Indexed: 06/30/2023]
Abstract
Background/Aim There has been a long-standing debate about the association of directacting antiviral (DAA) therapy and hepatocellular carcinoma (HCC) recurrence. This study aimed to investigate the association between DAA therapy and HCC recurrence after curative therapy. Methods We retrospectively enrolled 1,021 patients with HCV-related (hepatitis C virus) HCC who underwent radiofrequency ablation (RFA), liver resection, or both as the first treatment modality from January 2007 to December 2016 and without a history of HCV therapy before HCC treatment from a nationwide database. The effect of HCV treatment on HCC recurrence and all-cause mortality was also investigated. Results Among the 1,021 patients, 77 (7.5%) were treated with DAA, 14 (1.4%) were treated with interferon-based therapy, and 930 (91.1%) did not receive HCV therapy. DAA therapy was an independent prognostic factor for lower HCC recurrence rate (hazard ratio [HR], 0.04; 95% confidence interval [CI], 0.006-0.289; P=0.001 for landmarks at 6 months after HCC treatment and HR, 0.05; 95% CI, 0.007-0.354; P=0.003 for landmarks at 1 year). Furthermore, DAA therapy was associated with lower all-cause mortality (HR, 0.049; 95% CI, 0.007-0.349; P=0.003 for landmarks at 6 months and HR, 0.063; 95% CI, 0.009-0.451; P=0.006 for landmarks at 1 year). Conclusions DAA therapy after curative HCC treatment can decrease HCC recurrence and all-cause mortality compared to interferon-based therapy or no antiviral therapy. Therefore, clinicians should consider administering DAA therapy after curative HCC treatment in patients with HCV-related HCC.
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Affiliation(s)
- Young-Hwan Ahn
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Heirim Lee
- Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Korea
- Office of Biostatistics, Medical Research Collaborating Center, Ajou Research Institute for Innovative Medicine, Ajou University Medical Center, Suwon, Korea
| | - Ji Eun Han
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Hyo Jung Cho
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Jae Youn Cheong
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Bumhee Park
- Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Korea
- Office of Biostatistics, Medical Research Collaborating Center, Ajou Research Institute for Innovative Medicine, Ajou University Medical Center, Suwon, Korea
| | - Soon Sun Kim
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
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Nguyen MTT, Shih YC, Lin MH, Roffler SR, Hsiao CY, Cheng TL, Lin WW, Lin EC, Jong YJ, Chang CY, Su YC. Structural determination of an antibody that specifically recognizes polyethylene glycol with a terminal methoxy group. Commun Chem 2022; 5:88. [PMID: 35936993 PMCID: PMC9340711 DOI: 10.1038/s42004-022-00709-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 07/19/2022] [Indexed: 01/27/2023] Open
Abstract
Covalent attachment of methoxy poly(ethylene) glycol (mPEG) to therapeutic molecules is widely employed to improve their systemic circulation time and therapeutic efficacy. mPEG, however, can induce anti-PEG antibodies that negatively impact drug therapeutic effects. However, the underlying mechanism for specific binding of antibodies to mPEG remains unclear. Here, we determined the first co-crystal structure of the humanized 15-2b anti-mPEG antibody in complex with mPEG, which possesses a deep pocket in the antigen-binding site to accommodate the mPEG polymer. Structural and mutational analyses revealed that mPEG binds to h15-2b via Van der Waals and hydrogen bond interactions, whereas the methoxy group of mPEG is stabilized in a hydrophobic environment between the VH:VL interface. Replacement of the heavy chain hydrophobic V37 residue with a neutral polar serine or threonine residue offers additional hydrogen bond interactions with methoxyl and hydroxyl groups, resulting in cross-reactivity to mPEG and OH-PEG. Our findings provide insights into understanding mPEG-binding specificity and antigenicity of anti-mPEG antibodies.
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Affiliation(s)
- Minh-Tram T. Nguyen
- Department of Biological Science and Technology, Center for Intelligent Drug Systems and Smart Bio-devices (IDS²B), National Yang Ming Chiao Tung University, Hsinchu, Taiwan
| | - Yu-Chien Shih
- Department of Biological Science and Technology, Center for Intelligent Drug Systems and Smart Bio-devices (IDS²B), National Yang Ming Chiao Tung University, Hsinchu, Taiwan
| | - Meng-Hsuan Lin
- Department of Biological Science and Technology, Center for Intelligent Drug Systems and Smart Bio-devices (IDS²B), National Yang Ming Chiao Tung University, Hsinchu, Taiwan
| | - Steve R. Roffler
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chiao-Yu Hsiao
- Department of Biological Science and Technology, Center for Intelligent Drug Systems and Smart Bio-devices (IDS²B), National Yang Ming Chiao Tung University, Hsinchu, Taiwan
| | - Tian-Lu Cheng
- Department of Biomedical Science and Environmental Biology, Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wen-Wei Lin
- School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - En-Chi Lin
- Department of Biological Science and Technology, Center for Intelligent Drug Systems and Smart Bio-devices (IDS²B), National Yang Ming Chiao Tung University, Hsinchu, Taiwan
| | - Yuh-Jyh Jong
- Department of Biological Science and Technology, Center for Intelligent Drug Systems and Smart Bio-devices (IDS²B), National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Departments of Pediatrics and Laboratory Medicine, and Translational Research Center of Neuromuscular Diseases, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Chin-Yuan Chang
- Department of Biological Science and Technology, Center for Intelligent Drug Systems and Smart Bio-devices (IDS²B), National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Department of Biomedical Science and Environmental Biology, Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yu-Cheng Su
- Department of Biological Science and Technology, Center for Intelligent Drug Systems and Smart Bio-devices (IDS²B), National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Department of Biomedical Science and Environmental Biology, Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
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Kuwano A, Yada M, Nagasawa S, Tanaka K, Morita Y, Masumoto A, Motomura K. Hepatitis C virus eradication ameliorates the prognosis of advanced hepatocellular carcinoma treated with sorafenib. J Viral Hepat 2022; 29:543-550. [PMID: 35499194 DOI: 10.1111/jvh.13681] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/16/2022] [Accepted: 03/22/2022] [Indexed: 01/27/2023]
Abstract
The risk of hepatocellular carcinoma (HCC) occurrence following hepatitis C virus (HCV) eradication has been previously reported, but the impact of HCV eradication on advanced HCC patient survival remains unclear. Therefore, the present study aimed to evaluate the effect of HCV eradication on the survival outcome of patients with advanced HCC treated with sorafenib. One hundred and three HCV-related advanced HCC patients who were treated with sorafenib were enrolled in this study. Of these, 43 patients were administered antiviral therapy before sorafenib treatment (HCV eradication group), while 60 patients remained HCV-infected (HCV non-eradication group). We analysed the impact of HCV eradication on survival in advanced HCC treated with sorafenib. Median overall survival (OS) was significantly longer in the HCV eradication group than in the HCV non-eradication group (24.0 months vs. 14.1 months; p = 0.001). Although there was no significant difference in the albumin-bilirubin (ALBI) score at the start of treatment between the HCV eradication group and the non-eradication group (p = 0.065), the ALBI score at 2 months after initiation of sorafenib treatment was significantly decreased in the HCV non-eradication group (p < 0.001), but not in the HCV eradication group (p = 0.121). Multivariate logistic analysis revealed HCV eradication (hazard ratio [HR], 0.5; p = 0.006) and ALBI score at the start of treatment (HR, 2.47; p = 0.002) as factors that may contribute to OS. HCV eradication may serve an important role in the survival outcome of advanced HCC patients treated with sorafenib.
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Affiliation(s)
- Akifumi Kuwano
- Department of Hepatology, Aso Iizuka Hospital, Fukuoka, Japan
| | - Masayoshi Yada
- Department of Hepatology, Aso Iizuka Hospital, Fukuoka, Japan
| | | | - Kosuke Tanaka
- Department of Hepatology, Aso Iizuka Hospital, Fukuoka, Japan
| | - Yusuke Morita
- Department of Hepatology, Aso Iizuka Hospital, Fukuoka, Japan
| | | | - Kenta Motomura
- Department of Hepatology, Aso Iizuka Hospital, Fukuoka, Japan
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37
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Khan A, Nawaz M, Ullah S, Rehman IU, Khan A, Saleem S, Zaman N, Shinwari ZK, Ali M, Wei DQ. Core amino acid substitutions in HCV-3a isolates from Pakistan and opportunities for multi-epitopic vaccines. J Biomol Struct Dyn 2022; 40:3753-3768. [PMID: 33246391 DOI: 10.1080/07391102.2020.1850353] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatitis C virus (HCV), which infected 71 million worldwide and about 5%-6% are from Pakistan, is an ssRNA virus, responsible for end-stage liver disease. To date, no effective therapy is available to cure this disease. Hence, it is important to study the most prevalent genotypes infecting human population and design novel vaccine or small molecule inhibitors to control the infections associated with HCV. Therefore, in this study clinical samples (n = 35; HCV-3a) from HCV patients were subjected to Sanger sequencing method. The sequencing of the core gene, which is generally considered as conserved, involved in the detection, quantitation and genotyping of HCV was performed. Multiple mutations, that is, R46C, R70Q, L91C, G60E, N/S105A, P108A, N110I, S116V, G90S, A77G and G145R that could be linked with response to antiviral therapies were detected. Phylogenetic analysis suggests emerging viral isolates are circulating in Pakistan. Using ab initio modelling technique, we predicted the 3D structure of core protein and subjected to molecular dynamics simulation to extract the most stable conformation of the structure for further analysis. Immunoinformatic approaches were used to propose a multi-epitopes vaccine against HCV by using core protein. The vaccine constructs consist of nine CTL and three HTL epitopes joined by different linkers were docked against the two reported Toll-like receptors (TLR-3 and TLR-8). Docking of vaccine construct with TLR-3 and TLR-8 shows proper binding and in silico expression of the vaccine resulted in a CAI value of 0.93. These analyses suggest that specific immune responses may be produced by the proposed vaccine.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Ayyaz Khan
- Department of Biotechnology, Quaid-i-Azam University Islamabad, Islamabad, Pakistan
| | - Mehboob Nawaz
- Department of Biotechnology, Quaid-i-Azam University Islamabad, Islamabad, Pakistan
| | - Saeed Ullah
- Saidu Group of Teaching Hospital, Swat, Pakistan
| | - Irshad Ur Rehman
- Center of Biotechnology and Microbiology, University of Peshawar, Peshawar, Pakistan
| | - Abbas Khan
- Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiaotong University, Shanghai, China
| | - Shoaib Saleem
- National Center for Bioinformatics, Quaid-i-Azam University Islamabad, Islamabad, Pakistan
| | - Nasib Zaman
- Center of Biotechnology and Microbiology, University of Swat, Swat, Pakistan
| | - Zabta Khan Shinwari
- Department of Biotechnology, Quaid-i-Azam University Islamabad, Islamabad, Pakistan.,Pakistan Academy of Sciences, Islamabad, Pakistan
| | - Muhammad Ali
- Department of Biotechnology, Quaid-i-Azam University Islamabad, Islamabad, Pakistan
| | - Dong-Qing Wei
- Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiaotong University, Shanghai, China.,State Key Laboratory of Microbial Metabolism, Shanghai-Islamabad-Belgrade Joint Innovation Center on Antibacterial Resistances, Joint Laboratory of International Cooperation in Metabolic and Developmental Sciences, Ministry of Education and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, P.R. China.,Peng Cheng Laboratory, Shenzhen, Guangdong, P.R China
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Khan M, Rauf W, Habib FE, Rahman M, Iqbal S, Shehzad A, Iqbal M. Hesperidin identified from Citrus extracts potently inhibits HCV genotype 3a NS3 protease. BMC Complement Med Ther 2022; 22:98. [PMID: 35366855 PMCID: PMC8976278 DOI: 10.1186/s12906-022-03578-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 03/25/2022] [Indexed: 11/29/2022] Open
Abstract
Background Hepatitis C virus infection is the main cause of liver ailments across the globe. Several HCV genotypes have been identified in different parts of the world. Effective drugs for combating HCV infections are available but not affordable, particularly to infected individuals from resource-limited countries. Hence, cost-effective drugs need to be developed against important HCV drug targets. As Citrus fruits naturally contain bioactive compounds with antiviral activities, the current study was designed to identify antiviral inhibitors from Citrus fruit extracts against an important drug target, NS3 protease, of HCV genotype 3a which is found predominantly in South Asian countries. Methods The full-length NS3 protease alone and the NS3 protease domain in fusion with the cognate NS4A cofactor were expressed in Escherichia coli, and purified by chromatographic techniques. Using the purified protein as a drug target, Citrus extracts were evaluated in a FRET assay, and active ingredients, identified using ESI–MS/MS, were docked to observe the interaction with active site residues of NS3. The best interacting compound was further confirmed through the FRET assay as the inhibitor of NS3 protease. Results Fusion of the NS3 protease domain to the NS4A cofactor significantly improved the purification yield, and NS3-NS4A was functionally more active than the full-length NS3 alone. The purified protein (NS3-NS4A) was successfully employed in a validated FRET assay to evaluate 14 Citrus fruit extracts, revealing that the mesocarp extract of Citrus paradisi, and whole fruit extracts of C. sinesis, C. aurantinum, and C. reticulata significantly inhibited the protease activity of HCV NS3 protease (IC50 values of 5.79 ± 1.44 µg/mL, 37.19 ± 5.92 µg/mL, 42.62 ± 6.89 µg/mL, and 57.65 ± 3.81 µg/mL, respectively). Subsequent ESI-MSn analysis identified a flavonoid, hesperidin, abundantly present in all the afore-mentioned Citrus extracts. Importantly, docking studies suggested that hesperidin interacts with active site residues, and acts as a potent inhibitor of NS3 protease, exhibiting an IC50 value of 11.34 ± 3.83 µg/mL. Conclusions A FRET assay was developed using NS3-NS4A protease, which was successfully utilized for the evaluation of Citrus fruit extracts. Hesperidin, a compound present in the Citrus extracts, was identified as the main flavonoid, which can serve as a cost-effective potent inhibitor of NS3 protease, and could be developed as a drug for antiviral therapy against HCV genotype 3a. Supplementary Information The online version contains supplementary material available at 10.1186/s12906-022-03578-1.
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Oe N, Takeda H, Eso Y, Takai A, Marusawa H. Clinical and Molecular Basis of Hepatocellular Carcinoma after Hepatitis C Virus Eradication. Pathogens 2022; 11:pathogens11040430. [PMID: 35456105 PMCID: PMC9028726 DOI: 10.3390/pathogens11040430] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 03/28/2022] [Accepted: 03/30/2022] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) arises in the background of chronic liver diseases, including hepatitis and liver cirrhosis caused by hepatitis C virus (HCV) infection. It is well known that HCV eradication using antiviral drugs can efficiently inhibit hepatocarcinogenesis. Recent advances in and development of direct-acting antiviral (DAA) drugs has revolutionized the treatment of HCV infection, and the vast majority of HCV patients can achieve HCV eradication using DAAs. However, mounting evidence clearly indicates that HCC inevitably occurs in a subset of patients after successful viral eradication using DAA therapy. Cancer is a genetic disease, and the accumulation of genetic and epigenetic aberrations may cause hepatocarcinogenesis in chronically damaged liver, even after virus elimination. In this review, we highlight HCC development after HCV eradication and discuss the current understanding of the molecular mechanisms of tumorigenesis after virus elimination, focusing on the genetic and epigenetic background of chronically damaged liver tissues.
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Affiliation(s)
- Natsumi Oe
- Department of Gastroenterology, Red Cross Osaka Hospital, Osaka 5438555, Japan;
| | - Haruhiko Takeda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 6068501, Japan; (H.T.); (Y.E.); (A.T.)
| | - Yuji Eso
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 6068501, Japan; (H.T.); (Y.E.); (A.T.)
| | - Atsushi Takai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 6068501, Japan; (H.T.); (Y.E.); (A.T.)
| | - Hiroyuki Marusawa
- Department of Gastroenterology, Red Cross Osaka Hospital, Osaka 5438555, Japan;
- Correspondence: ; Tel.: +81-6-6774-5111; Fax: +81-6-6774-5131
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Nakajima T, Karino Y, Hige S, Suii H, Tatsumi R, Yamaguchi M, Arakawa T, Kuwata Y, Toyota J. Aging impairs fibrosis-4 index after sustained virologic response by direct-acting antivirals in chronic hepatitis C infection. Ann Hepatol 2022; 27:100566. [PMID: 34688887 DOI: 10.1016/j.aohep.2021.100566] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 09/18/2021] [Accepted: 09/27/2021] [Indexed: 02/08/2023]
Abstract
INTRODUCTION AND OBJECTIVES Sustained virologic response (SVR) is achieved in most cases of C-type liver disease after direct-acting antiviral (DAA) therapy. Although liver fibrosis improves, the degree of improvement is different. This study aimed to analyze the factors involved in improving liver fibrosis using the fibrosis 4 (FIB-4) index. MATERIAL AND METHODS Patients were monitored for >3 years after SVR. At the start of therapy (SOT), liver fibrosis was categorized as either mild (<1.45 n = 28), moderate (1.45-3.25 n = 139), or advanced (>3.25 n = 236) based on the FIB-4 index. The FIB-4 index in the advanced group decreased significantly compared to that of the other two, so we selected the advanced group as the analysis target. SOT and end of therapy (EOT) factors that contributed to the FIB-4 index ≤3.25 at 3 years after therapy were examined using a multivariate analysis. RESULTS Among the SOT factors, age (<72 years old), absence of liver cirrhosis (LC), alanine transferase (ALT) (≥50 U/L), platelet (PLT) (≥10.2 × 104/mm3), and total bilirubin (T.Bil) (<0.8 mg/dl) were the significant factors contributing to the improvement of the FIB-4 index. Among the EOT factors, age (<72 years), PLT (≥12.0 × 104/mm3), and hemoglobin (Hb) (≥12.1 g/dl) were the significant factors contributing to the improvement of FIB-4 index. CONCLUSIONS Factors involved in the improvement of liver fibrosis after SVR were young age, absence of LC, low T.Bil., high ALT, high PLT, and high Hb levels. The levels of T.Bil, PLT, and Hb were considered to be related to portal hypertension. Aging strongly impaired the improvement in liver fibrosis.
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Affiliation(s)
- Tomoaki Nakajima
- Department of Hepatology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Yoshiyasu Karino
- Department of Hepatology, Sapporo Kosei General Hospital, Sapporo, Japan; Department of Gastroenterology, Keiyukai Sapporo Hospital, Sapporo, Japan.
| | - Shuhei Hige
- Department of Hepatology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Hirokazu Suii
- Department of Hepatology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Ryoji Tatsumi
- Department of Hepatology, Sapporo Kosei General Hospital, Sapporo, Japan
| | | | - Tomohiro Arakawa
- Department of Hepatology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Yasuaki Kuwata
- Department of Hepatology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Joji Toyota
- Department of Hepatology, Sapporo Kosei General Hospital, Sapporo, Japan
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Kim IJ, Yoo SH, Kim S, Cho YY, Yoo KY, Kim HJ, Lee HW. Low Incidence of Hepatocellular Carcinoma after Antiviral Therapy in Patients with Chronic Hepatitis C and Hemophilia. J Clin Med 2022; 11:jcm11051451. [PMID: 35268541 PMCID: PMC8911386 DOI: 10.3390/jcm11051451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 03/05/2022] [Accepted: 03/06/2022] [Indexed: 11/16/2022] Open
Abstract
Background: Hepatocellular carcinoma (HCC) rarely develops in patients with chronic hepatitis C (CHC) who achieve sustained virological response (SVR). We assessed the incidence of HCC in CHC patients with hemophilia after treatment with pegylated interferon plus ribavirin (PegIFN/RBV) and direct-acting antivirals (DAAs). Methods: Patients (n = 202) were enrolled between March 2007 and July 2019. A total of 139 patients were treated with PegIFN/RBV (genotype 1, n = 98; genotype 2, n = 41). Sixty-three patients were treated with DAAs (genotype 1, n = 44; genotype 2, n = 19). The cumulative incidence rates of HCC were estimated using the Kaplan−Meier method and compared using the log-rank test. Results: For genotype 1, SVR was achieved in 78.6% (77/98) and 90.9% (40/44) of patients in the PegIFN/RBV and DAAs groups, respectively. For genotype 2, SVR was achieved in 95.1% (39/41) and 94.7% (18/19) of patients in the PegIFN/RBV and DAAs groups, respectively. Six HCC cases were identified. The cumulative incidence of HCC was 4.1% at 14 years in PegIFN/RBV and 1.7% at 5 years in DAAs. The 14-year cumulative incidence of HCC was 1.9% in the SVR group and 21.7% in the no-SVR group in the PegIFN/RBV group (p < 0.001). Conclusions: Treatment with PegIFN/RBV led to stable SVR and a low incidence of HCC. Although the follow-up period was short, DAAs led to more stable SVR than PegIFN/RBV and a low incidence of HCC in CHC patients with hemophilia.
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Affiliation(s)
- In Jung Kim
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Korea; (I.J.K.); (S.H.Y.); (S.K.)
| | - Sung Hwan Yoo
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Korea; (I.J.K.); (S.H.Y.); (S.K.)
| | - Sora Kim
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Korea; (I.J.K.); (S.H.Y.); (S.K.)
| | - Young Youn Cho
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul 06973, Korea;
| | - Ki Young Yoo
- Department of Pediatrics, Korea Hemophilia Foundation Hospital, Seoul 06641, Korea;
| | - Hyung Joon Kim
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul 06973, Korea;
- Correspondence: (H.J.K.); (H.W.L.); Tel.: +82-2-6299-1417 (H.J.K.); +82-2-2019-3315 (H.W.L.); Fax: +82-2-6299-1137 (H.J.K.); +82-2-3463-3882 (H.W.L.)
| | - Hyun Woong Lee
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Korea; (I.J.K.); (S.H.Y.); (S.K.)
- Correspondence: (H.J.K.); (H.W.L.); Tel.: +82-2-6299-1417 (H.J.K.); +82-2-2019-3315 (H.W.L.); Fax: +82-2-6299-1137 (H.J.K.); +82-2-3463-3882 (H.W.L.)
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Patil VS, Harish DR, Vetrivel U, Roy S, Deshpande SH, Hegde HV. Hepatitis C Virus NS3/4A Inhibition and Host Immunomodulation by Tannins from Terminalia chebula: A Structural Perspective. Molecules 2022; 27:molecules27031076. [PMID: 35164341 PMCID: PMC8839135 DOI: 10.3390/molecules27031076] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 01/15/2022] [Accepted: 01/22/2022] [Indexed: 01/27/2023] Open
Abstract
Terminalia chebula Retz. forms a key component of traditional folk medicine and is also reported to possess antihepatitis C virus (HCV) and immunomodulatory activities. However, information on the intermolecular interactions of phytochemicals from this plant with HCV and human proteins are yet to be established. Thus, by this current study, we investigated the HCV NS3/4A inhibitory and host immune-modulatory activity of phytocompounds from T. chebula through in silico strategies involving network pharmacology and structural bioinformatics techniques. To start with, the phytochemical dataset of T. chebula was curated from biological databases and the published literature. Further, the target ability of the phytocompounds was predicted using BindingDB for both HCV NS3/4A and other probable host targets involved in the immune system. Further, the identified targets were docked to the phytochemical dataset using AutoDock Vina executed through the POAP pipeline. The resultant docked complexes with significant binding energy were subjected to 50 ns molecular dynamics (MD) simulation in order to infer the stability of complex formation. During network pharmacology analysis, the gene set pathway enrichment of host targets was performed using the STRING and Reactome pathway databases. Further, the biological network among compounds, proteins, and pathways was constructed using Cytoscape 3.6.1. Furthermore, the druglikeness, side effects, and toxicity of the phytocompounds were also predicted using the MolSoft, ADVERpred, and PreADMET methods, respectively. Out of 41 selected compounds, 10 were predicted to target HCV NS3/4A and also to possess druglike and nontoxic properties. Among these 10 molecules, Chebulagic acid and 1,2,3,4,6-Pentagalloyl glucose exhibited potent HCV NS3/4A inhibitory activity, as these scored a lowest binding energy (BE) of −8.6 kcal/mol and −7.7 kcal/mol with 11 and 20 intermolecular interactions with active site residues, respectively. These findings are highly comparable with Asunaprevir (known inhibitor of HCV NS3/4A), which scored a BE of −7.4 kcal/mol with 20 key intermolecular interactions. MD studies also strongly suggest that chebulagic acid and 1,2,3,4,6-Pentagalloyl glucose as promising leads, as these molecules showed stable binding during 50 ns of production run. Further, the gene set enrichment and network analysis of 18 protein targets prioritized 10 compounds and were predicted to potentially modulate the host immune system, hemostasis, cytokine levels, interleukins signaling pathways, and platelet aggregation. On overall analysis, this present study predicts that tannins from T. chebula have a potential HCV NS3/4A inhibitory and host immune-modulatory activity. However, further experimental studies are required to confirm the efficacies.
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Affiliation(s)
- Vishal S. Patil
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India; (V.S.P.); (U.V.); (S.H.D.); (H.V.H.)
| | - Darasaguppe R. Harish
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India; (V.S.P.); (U.V.); (S.H.D.); (H.V.H.)
- Correspondence: (D.R.H.); (S.R.)
| | - Umashankar Vetrivel
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India; (V.S.P.); (U.V.); (S.H.D.); (H.V.H.)
- ICMR-National Institute for Research in Tuberculosis, Chetpet, Chennai 600031, India
| | - Subarna Roy
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India; (V.S.P.); (U.V.); (S.H.D.); (H.V.H.)
- Correspondence: (D.R.H.); (S.R.)
| | - Sanjay H. Deshpande
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India; (V.S.P.); (U.V.); (S.H.D.); (H.V.H.)
- Regional Centre for Biotechnology, NCR-Biotech Science Cluster, Faridabad 121001, India
| | - Harsha V. Hegde
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India; (V.S.P.); (U.V.); (S.H.D.); (H.V.H.)
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Abstract
The development of direct-acting antivirals (DAA) has revolutionized the treatment of chronic hepatitis C, enabling cure of hepatitis C virus (HCV) infection in more than 95% of cases. There are essentially no contraindications, so almost any patient can now be successfully treated. The result is the prevention or amelioration of cirrhosis, hepatocellular carcinoma (HCC), and extrahepatic manifestations. Consequently, the 2020 Nobel Prize in Medicine and Physiology was awarded for the discovery of HCV. Due to the high efficacy of therapy, even global HCV elimination is conceivable even without a vaccine. Here, we would like to venture a SWOT analysis of current HCV therapies aimed at HCV elimination.
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Affiliation(s)
- Markus Cornberg
- Department of Gastroenterology, Hepatology, and Endocrinology, 9177Hannover Medical School Hannover, Hannover, Germany.,Centre for Individualised Infection Medicine (CiiM), a joint venture of Helmholtz Centre for Infection Research and Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner-Site Hannover-Braunschweig, Hannover, Germany
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44
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Kouroumalis E, Voumvouraki A. Hepatitis C virus: A critical approach to who really needs treatment. World J Hepatol 2022; 14:1-44. [PMID: 35126838 PMCID: PMC8790391 DOI: 10.4254/wjh.v14.i1.1] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/14/2021] [Accepted: 12/31/2021] [Indexed: 02/06/2023] Open
Abstract
Introduction of effective drugs in the treatment of hepatitis C virus (HCV) infection has prompted the World Health Organization to declare a global eradication target by 2030. Propositions have been made to screen the general population and treat all HCV carriers irrespective of the disease status. A year ago the new severe acute respiratory syndrome coronavirus 2 virus appeared causing a worldwide pandemic of coronavirus disease 2019 disease. Huge financial resources were redirected, and the pandemic became the first priority in every country. In this review, we examined the feasibility of the World Health Organization elimination program and the actual natural course of HCV infection. We also identified and analyzed certain comorbidity factors that may aggravate the progress of HCV and some marginalized subpopulations with characteristics favoring HCV dissemination. Alcohol consumption, HIV coinfection and the presence of components of metabolic syndrome including obesity, hyperuricemia and overt diabetes were comorbidities mostly responsible for increased liver-related morbidity and mortality of HCV. We also examined the significance of special subpopulations like people who inject drugs and males having sex with males. Finally, we proposed a different micro-elimination screening and treatment program that can be implemented in all countries irrespective of income. We suggest that screening and treatment of HCV carriers should be limited only in these particular groups.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, University of Crete Medical School, Heraklion 71500, Crete, Greece
| | - Argyro Voumvouraki
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
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45
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Dale CH, Smith E, Biondi MJ. Nurse practitioners as primary care site champions for the screening and treatment of hepatitis C virus. J Am Assoc Nurse Pract 2022; 34:688-695. [PMID: 35066534 DOI: 10.1097/jxx.0000000000000689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 12/06/2021] [Indexed: 11/26/2022]
Abstract
BACKGROUND Primary care providers are often the first point of contact for hepatitis C virus (HCV) care, yet treatment initiation in primary care continues to be low. Nurse practitioners (NPs) are autonomous providers who, in Ontario, currently prescribe HCV therapy; however, methods to engage primary care NPs in HCV care have not occurred. PURPOSE To assess the feasibility of a systematic approach to train and support NPs in HCV testing, care, and treatment. METHODOLOGY Nurse practitioners from Canada's largest family health team (FHT) were recruited. Nurse practitioners received six hours of training and develop approaches to screen and treat at FHT sites. Treatment algorithms were given, and the number and types of inquiries from NPs were recorded. RESULTS Over 1 year, 9 NPs screened 1,026 patients; 87.4% were screened based on the identification of a risk factor. A mail-out approach for birth cohort screening occurred at a single site, resulting in rapid uptake in screening. Antibody prevalence was 1.66%, with 76.5% RNA positivity. All RNA-positive treatment-eligible individuals were treated by an NP and completed treatment. Thirty-eight consults occurred over 1 year, the majority related to HCV or liver disease staging. CONCLUSIONS Formalized initiatives to engage and educate NPs lead to innovative strategies to test for HCV. Nurse practitioners can safely and effectively treat HCV in primary care with minimal support. IMPLICATIONS This work could be extrapolated to NPs in other primary care settings. Implementing formalized strategies has the potential to create NP leaders in the treatment and elimination of HCV in Ontario, Canada, and globally.
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Affiliation(s)
- Cheryl H Dale
- Arthur Labatt Family School of Nursing, Western University, London, Ontario, Canada
| | - Elizabeth Smith
- Arthur Labatt Family School of Nursing, Western University, London, Ontario, Canada
- Thames Valley Family Health Team, London, Ontario, Canada
| | - Mia J Biondi
- Arthur Labatt Family School of Nursing, Western University, London, Ontario, Canada
- Viral Hepatitis Care Network (VIRCAN) Study Group, Toronto Centre for Liver Disease, Toronto, Ontario, Canada
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46
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Manrai M, Dawra S, Kapoor R, Srivastava S, Singh A. Anemia in cirrhosis: An underestimated entity. World J Clin Cases 2022; 10:777-789. [PMID: 35127894 PMCID: PMC8790443 DOI: 10.12998/wjcc.v10.i3.777] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 07/18/2021] [Accepted: 12/25/2021] [Indexed: 02/06/2023] Open
Abstract
Anemia in a patient with cirrhosis is a clinically pertinent but often overlooked clinical entity. Relevant guidelines highlight the algorithmic approach of managing a patient of cirrhosis presenting with acute variceal hemorrhage but day-to-day management in hospital and out-patient raises multiple dilemmas: Whether anemia is a disease complication or a part of the disease spectrum? Should iron, folic acid, and vitamin B complex supplementation and nutritional advice, suffice in those who can perform tasks of daily living but have persistently low hemoglobin. How does one investigate and manage anemia due to multifactorial etiologies in the same patient: Acute or chronic blood loss because of portal hypertension and bone marrow aplasia secondary to hepatitis B or C viremia? To add to the clinician's woes the prevalence of anemia increases with increasing disease severity. We thus aim to critically analyze the various pathophysiological mechanisms complicating anemia in a patient with cirrhosis with an emphasis on the diagnostic flowchart in such patients and proposed management protocols thereafter.
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Affiliation(s)
- Manish Manrai
- Department of Internal Medicine, Armed Forces Medical College, Pune 411040, India
| | - Saurabh Dawra
- Department of Medicine and Gastroenterology, Command Hospital, Pune 411040, India
| | - Rajan Kapoor
- Department of Medicine, Command Hospital, Kolkata 70027, India
| | - Sharad Srivastava
- Department of Medicine and Gastroenterology, Command Hospital, Pune 411040, India
| | - Anupam Singh
- Department of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
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47
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Targeting the Virus Capsid as a Tool to Fight RNA Viruses. Viruses 2022; 14:v14020174. [PMID: 35215767 PMCID: PMC8879806 DOI: 10.3390/v14020174] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/14/2022] [Accepted: 01/16/2022] [Indexed: 12/10/2022] Open
Abstract
Several strategies have been developed to fight viral infections, not only in humans but also in animals and plants. Some of them are based on the development of efficient vaccines, to target the virus by developed antibodies, others focus on finding antiviral compounds with activities that inhibit selected virus replication steps. Currently, there is an increasing number of antiviral drugs on the market; however, some have unpleasant side effects, are toxic to cells, or the viruses quickly develop resistance to them. As the current situation shows, the combination of multiple antiviral strategies or the combination of the use of various compounds within one strategy is very important. The most desirable are combinations of drugs that inhibit different steps in the virus life cycle. This is an important issue especially for RNA viruses, which replicate their genomes using error-prone RNA polymerases and rapidly develop mutants resistant to applied antiviral compounds. Here, we focus on compounds targeting viral structural capsid proteins, thereby inhibiting virus assembly or disassembly, virus binding to cellular receptors, or acting by inhibiting other virus replication mechanisms. This review is an update of existing papers on a similar topic, by focusing on the most recent advances in the rapidly evolving research of compounds targeting capsid proteins of RNA viruses.
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Pabjan P, Brzdęk M, Chrapek M, Dziedzic K, Dobrowolska K, Paluch K, Garbat A, Błoniarczyk P, Reczko K, Stępień P, Zarębska-Michaluk D. Are There Still Difficult-to-Treat Patients with Chronic Hepatitis C in the Era of Direct-Acting Antivirals? Viruses 2022; 14:96. [PMID: 35062302 PMCID: PMC8779728 DOI: 10.3390/v14010096] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 12/29/2021] [Accepted: 01/04/2022] [Indexed: 12/17/2022] Open
Abstract
Difficult-to-treat populations with chronic hepatitis C (CHC), in the era of interferon treatment, included patients with liver cirrhosis, kidney impairment, treatment-experienced individuals, and those coinfected with the human immunodeficiency virus. The current study aimed to determine whether, in the era of direct-acting antivirals (DAA), there are still patients that are difficult-to-treat. The study included all consecutive patients chronically infected with hepatitis C virus (HCV) who started interferon-free therapy between July 2015 and December 2020 in the Department of Infectious Diseases in Kielce. The analyzed real-world population consisted of 963 patients, and most of them were infected with genotype 1 (87.6%) with the predominance of subtype 1b and were treatment-naïve (78.8%). Liver cirrhosis was determined in 207 individuals (21.5%), of whom 82.6% were compensated. The overall sustained virologic response, after exclusion of non-virologic failures, was achieved in 98.4%. The univariable analysis demonstrated the significantly lower response rates in males, patients with liver cirrhosis, decompensation of hepatic function at baseline, documented esophageal varices, concomitant diabetes, body mass index ≥25, and previous ineffective antiviral treatment. Despite an overall very high effectiveness, some unfavorable factors, including male gender, genotype 3 infection, liver cirrhosis, and treatment experience, significantly reduce the chances for a virologic response were identified.
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Affiliation(s)
- Paweł Pabjan
- Department of Infectious Diseases, Voivodship Hospital, Jan Kochanowski University, 25-317 Kielce, Poland; (P.P.); (K.P.); (A.G.); (P.B.); (K.R.); (P.S.)
| | - Michał Brzdęk
- Collegium Medicum, Jan Kochanowski University, 25-369 Kielce, Poland; (M.B.); (K.D.); (K.D.)
| | - Magdalena Chrapek
- Faculty of Natural Sciences, Jan Kochanowski University, 25-369 Kielce, Poland;
| | - Kacper Dziedzic
- Collegium Medicum, Jan Kochanowski University, 25-369 Kielce, Poland; (M.B.); (K.D.); (K.D.)
| | - Krystyna Dobrowolska
- Collegium Medicum, Jan Kochanowski University, 25-369 Kielce, Poland; (M.B.); (K.D.); (K.D.)
| | - Katarzyna Paluch
- Department of Infectious Diseases, Voivodship Hospital, Jan Kochanowski University, 25-317 Kielce, Poland; (P.P.); (K.P.); (A.G.); (P.B.); (K.R.); (P.S.)
| | - Anna Garbat
- Department of Infectious Diseases, Voivodship Hospital, Jan Kochanowski University, 25-317 Kielce, Poland; (P.P.); (K.P.); (A.G.); (P.B.); (K.R.); (P.S.)
| | - Piotr Błoniarczyk
- Department of Infectious Diseases, Voivodship Hospital, Jan Kochanowski University, 25-317 Kielce, Poland; (P.P.); (K.P.); (A.G.); (P.B.); (K.R.); (P.S.)
| | - Katarzyna Reczko
- Department of Infectious Diseases, Voivodship Hospital, Jan Kochanowski University, 25-317 Kielce, Poland; (P.P.); (K.P.); (A.G.); (P.B.); (K.R.); (P.S.)
| | - Piotr Stępień
- Department of Infectious Diseases, Voivodship Hospital, Jan Kochanowski University, 25-317 Kielce, Poland; (P.P.); (K.P.); (A.G.); (P.B.); (K.R.); (P.S.)
| | - Dorota Zarębska-Michaluk
- Department of Infectious Diseases, Voivodship Hospital, Jan Kochanowski University, 25-317 Kielce, Poland; (P.P.); (K.P.); (A.G.); (P.B.); (K.R.); (P.S.)
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Kuwano A, Yada M, Nagasawa S, Tanaka K, Morita Y, Masumoto A, Motomura K. Serum α-fetoprotein level at treatment completion is a useful predictor of hepatocellular carcinoma occurrence more than one year after hepatitis C virus eradication by direct-acting antiviral treatment. J Viral Hepat 2022; 29:35-42. [PMID: 34661320 DOI: 10.1111/jvh.13625] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/14/2021] [Accepted: 09/21/2021] [Indexed: 01/15/2023]
Abstract
Direct-acting antivirals (DAAs) have recently been developed to treat hepatitis C virus (HCV) infection, and interferon-free DAA treatment has improved liver function of HCV patients. The risk of hepatocellular carcinoma (HCC) occurrence following HCV eradication has been previously reported, but HCC may have been missed following imaging diagnosis before DAA administration in previous studies. Therefore, the present study aimed to identify definite predictors of HCC occurrence ≥1 year after DAA treatment. Among 956 patients receiving DAAs for HCV infection, 567 patients who achieved sustained virologic response with no history of HCC treatment were enrolled in this study between September 2014 and July 2021. The incidence of HCC in HCV-infected patients ≥1 year following DAA treatment, and the predictors contributing to HCC occurrence were identified using clinical characteristics and blood test results. In the present study, 25 patients developed HCC. The incidence of HCC was 1.4%, 3.2%, 4.9% and 6.8% at 2, 3, 4 and 5 years, respectively, from the end of treatment with DAAs. Multivariate logistic analysis revealed serum α-fetoprotein level at end of treatment (EOT-AFP) >3.8 ng/ml ≥1 year following treatment with DAAs (HR, 9.7; p < .0001) as an independent factor that may contribute to HCC occurrence following DAA treatment. In conclusion, serum EOT-AFP level may serve an important role in determining the risk of HCC occurrence ≥1 year after DAA treatment. Regular examinations are required even if serum EOT-AFP level is low at treatment completion.
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Affiliation(s)
- Akifumi Kuwano
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Fukuoka, Japan.,Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan
| | - Masayoshi Yada
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Fukuoka, Japan
| | | | - Kosuke Tanaka
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Fukuoka, Japan
| | - Yusuke Morita
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Fukuoka, Japan
| | - Akihide Masumoto
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Fukuoka, Japan
| | - Kenta Motomura
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Fukuoka, Japan
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Villamil FG, Massenzio NE, Baré PC, Cocco PA, Cairo FM, Picchio GR. Twenty-year follow-up of an outbreak of hepatitis C in a small rural town of Argentina: The O'Brien Project. Ann Hepatol 2022; 27 Suppl 1:100577. [PMID: 34740846 DOI: 10.1016/j.aohep.2021.100577] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 04/08/2021] [Accepted: 04/08/2021] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES In 1999, a population-based survey showed a 5.6 % (102/1832) prevalence of HCV infection in O'Brien, a small rural town of Argentina. The aim of this study was to assess the impact of screening, clinical evaluation and antiviral therapy on elimination of HCV after 20 years of follow-up. PATIENTS AND METHODS HCV+ subjects (n=102) underwent clinical, biochemical and histological evaluation to assess the presence and severity of liver disease. Antiviral therapy included pegylated interferon + ribavirin in 2005 and direct antiviral agents from 2017. RESULTS All viremic subjects (n=84) had genotype 1b with 90%-97.5% sequence homology scores, suggesting the existence of a common source of infection (use of unsafe injections administered by the same health professional). Liver biopsy (n=55) showed chronic hepatitis in all patients. The prevalence of cirrhosis was 28% overall (29/102) and 34.5% among viremic patients. Sustained virological response (SVR) was obtained in 20/34 (59%) patients treated with interferon. From 2005 to 2017, when oral antivirals became available 37/50 untreated patients died. Median age of this group in 2005 was 67 years. Six interferon non-responders and five naive subjects received direct antiviral agents and all developed SVR. Only 1/31 patient (3.2%) with SVR died and none developed decompensated cirrhosis or HCC. In 2019, a new population-based study showed that the prevalence of HCV in O'Brien decreased 20-fold, from 5.6% to 0.28% (3/1070). CONCLUSIONS Despite the high mortality rate precluding timely access to direct antiviral agents, the O'Brien Project is a good example of HCV micro-elimination studies.
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Affiliation(s)
- Federico Guillermo Villamil
- Liver Transplantation Unit, British Hospital, Ciudad Autónoma de Buenos Aires, Argentina; Hepatology and Liver Transplantation Unit, Hospital El Cruce, Florencio Varela, Provincia Buenos Aires, Argentina.
| | | | - Patricia Cristina Baré
- Instituto de Investigaciones Hematológicas, Instituto de Medicina Experimental CONICET, Academia Nacional de Medicina, Ciudad Autónoma de Buenos Aires, Argentina
| | - Paula Andrea Cocco
- Unidad Sanitaria "Martín Espinel Bavio", O'Brien, Provincia Buenos Aires, Argentina
| | - Fernando Mario Cairo
- Liver Transplantation Unit, British Hospital, Ciudad Autónoma de Buenos Aires, Argentina; Hepatology and Liver Transplantation Unit, Hospital El Cruce, Florencio Varela, Provincia Buenos Aires, Argentina
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