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AbdelMagid AM, Abbassi MM, Ebeid FS, Farid SF, El-Sayed MH. Ledipasvir/Sofosbuvir in Hepatitis C Virus-Infected Children With Hematological Malignancies: A Pharmacokinetic Study. Clin Ther 2024; 46:e12-e22. [PMID: 37925363 DOI: 10.1016/j.clinthera.2023.10.007] [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: 08/22/2023] [Revised: 10/08/2023] [Accepted: 10/09/2023] [Indexed: 11/06/2023]
Abstract
PURPOSE Children with hematological malignancies and chronic hepatitis C virus (HCV) infection are at a higher risk for rapid progression of liver disease and malignancy relapse due to multiple hepatitis flares and chemotherapy interruption. They are therefore potential candidates for microelimination of HCV infection. This study aimed to assess the effect of acute lymphoblastic leukemia (ALL) on the pharmacokinetic (PK) profile of direct-acting antivirals, namely ledipasvir/sofosbuvir (LDV/SOF) and the SOF major metabolite GS-331007. METHODS This was a 24-week, prospective, controlled, open-label, 2-arm PK study of patients receiving 45/200 mg once-daily LDV/SOF orally for 12 weeks. Eligible patients were HCV-RNA-positive, treatment-naive children aged 6 to <12 years and/or weighing 17 to <35 kg with genotype 4 chronic HCV infection without cirrhosis. The primary efficacy and safety end points were the achievement of sustained virologic response for all patients with absence of any adverse events leading to permanent discontinuation of the study drug. Steady-state noncompartmental analysis was performed to determine the PK parameters of SOF, GS-331007, and LDV as the primary PK outcome. Dose suitability was based on the 90% CI of exposure geometric mean ratio percentage within 50% to 200% compared with adults. FINDINGS Ten HCV-infected children with ALL (chemotherapy treatment group) and 12 eligible children with no malignancy (control group) were enrolled and completed the study period. All 22 patients achieved the sustained virologic response with no adverse events leading to interruption or permanent discontinuation of the study drug. Compared with the control group, the ALL group patients had similar SOF, GS-331007, and LDV exposure. Compared with adults, the AUCτ of GS-331007 was lower and the AUCτ and Cmax,ss of SOF and the Cmax,ss of LDV were modestly higher in the ALL group (acceptance limit, 50%-200%). However, the observed efficacy and favorable safety profile made these changes not clinically significant. IMPLICATIONS Weight-based dosing of LDV/SOF (45/200 mg) is highly effective and safe among genotype 4 HCV-infected children weighing 17 to <35 kg and diagnosed with ALL undergoing maintenance chemotherapy. The similarity in the drug exposure, efficacy, and safety clinical end points between patients with and without hematological malignancy support their therapeutic equivalence. Further studies with a larger sample size may be required to confirm the safety of LDV/SOF in patients with ALL and to recommend appropriate dosing in children with hematological malignancies, if needed. CLINICALTRIALS gov identifier: NCT03903185.
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Affiliation(s)
- Aya M AbdelMagid
- Clinical Pharmacy Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
| | - Maggie M Abbassi
- Clinical Pharmacy Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Fatma S Ebeid
- Pediatric Hematology, Oncology and BMT Department, Ain Shams University, Cairo, Egypt; Faculty of Medicine, Ain Shams University Research Institute-Clinical Research Center (MASRI-CRC), Cairo, Egypt
| | - Samar F Farid
- Clinical Pharmacy Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Manal H El-Sayed
- Pediatric Hematology, Oncology and BMT Department, Ain Shams University, Cairo, Egypt; Faculty of Medicine, Ain Shams University Research Institute-Clinical Research Center (MASRI-CRC), Cairo, Egypt
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Di Stefano M, Ismail MH, Leitner T, Faleo G, Alwazzeh MJ, Mbisa JL, Fiore JR, Santantonio TA. A novel candidate hepatitis C virus genotype 4 subtype identified by next generation sequencing full-genome characterization in a patient from Saudi Arabia. Front Microbiol 2023; 14:1285367. [PMID: 38029191 PMCID: PMC10653324 DOI: 10.3389/fmicb.2023.1285367] [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: 08/29/2023] [Accepted: 10/03/2023] [Indexed: 12/01/2023] Open
Abstract
Background and aim Hepatitis C virus (HCV) infection is a major global public health concern, being a leading cause of chronic liver diseases such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma. The virus is classified into 8 genotypes and 93 subtypes, each displaying distinct geographic distributions. Genotype 4 is the most predominant in the Middle East and Eastern Mediterranean and is associated with high rates of hepatitis C infection worldwide. This study used next-generation sequencing to fully characterize the HCV genome and identify a novel subtype within genotype 4 isolated from a 64-year-old Saudi man diagnosed with hepatitis C. Methods We analyzed the complete genome of the 141-HCV isolate using whole-genome sequencing. Results Our phylogenetic reconstructions, based on the entire genome of HCV-4 strains, revealed that the 141-HCV isolate formed a distinct group within the genotype 4 classification, providing valuable new insights into the variability of HCV. Conclusion This discovery of a previously unclassified HCV subtype within genotype 4 sheds light on the ongoing evolution and diversity of the virus. Such knowledge has significant implications for diagnostic and therapeutic approaches, as different subtypes may exhibit varying drug sensitivities and resistance profiles.
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Affiliation(s)
- Mariantonietta Di Stefano
- Section of Infectious Diseases, Department of Clinical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Mona H. Ismail
- Division of Gastroenterology, King Fahd Hospital of the University, Al-Khobar, Saudi Arabia
- College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Thomas Leitner
- Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM, United States
| | - Giuseppina Faleo
- Section of Infectious Diseases, Department of Clinical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Marwan Jabr Alwazzeh
- College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
- Infectious Disease Division, King Fahd Hospital of the University, Al-Khobar, Saudi Arabia
| | - Jean Lutamyo Mbisa
- Antiviral Unit, Blood Safety, Hepatitis, Sexually Transmitted Infections, and HIV (BSHSH) Service, UK Health Security Agency, London, United Kingdom
| | - Josè Ramon Fiore
- Section of Infectious Diseases, Department of Clinical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Teresa Antonia Santantonio
- Section of Infectious Diseases, Department of Clinical and Surgical Sciences, University of Foggia, Foggia, Italy
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Tandan M, Dunlea S, Bury G. Hepatitis C Infection and Treatment among Injecting Drug Users Attending General Practice: A Systematic Review and Meta-Analysis. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2023; 20:5569. [PMID: 37107851 PMCID: PMC10138322 DOI: 10.3390/ijerph20085569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 03/28/2023] [Accepted: 04/03/2023] [Indexed: 05/11/2023]
Abstract
BACKGROUND The care provided in general practice to intravenous drug users (IDUs) with hepatitis C (HCV) extends beyond opioid substitution therapy. An aggregated analysis of HCV service utilization within general practice specifically related to diagnosis and treatment outcomes remains unknown from previous literature. AIMS This study aims to estimate the prevalence of HCV and analyze data related to the diagnosis and treatment-related outcomes of HCV patients with a history of intravenous drug use in the general practice setting. DESIGN AND SETTING A systematic review and meta-analysis in general practice. METHODS This review included studies published in the following databases: EMBASE, PubMed, and Cochrane Central Register of Controlled Trials. Two reviewers independently extracted data in standard forms in Covidence. A meta-analysis was done using a DerSimonian and Laird random-effects model with inverse variance weighting. RESULTS A total of 20,956 patients from 440 general practices participated in the 18 selected studies. A meta-analysis of 15 studies showed a 46% (95% confidence interval (CI), 26-67%) prevalence rate of hepatitis C amongst IDUs. Genotype information was available in four studies and treatment-related outcomes in 11 studies. Overall, treatment uptake was 9%, with a cure rate of 64% (95% CI, 43-83%). However, relevant information, such as specific treatment regimens, treatment duration and doses, and patient comorbidities, was poorly documented in these studies. CONCLUSION The prevalence of HCV in IDUs is 46% in general practice. Only ten studies reported HCV-related treatment outcomes; however, the overall uptake rate was below 10%, with a cure rate of 64%. Likewise, the genotypic variants of HCV diagnoses, medication types, and doses were poorly reported, suggesting a need for further research into this aspect of care within this patient group to ensure optimal treatment outcomes.
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Affiliation(s)
- Meera Tandan
- General Practice, School of Medicine, University College Dublin, D04 N2E5 Dublin, Ireland
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Liu D, Ndongwe TP, Ji J, Huber AD, Michailidis E, Rice CM, Ralston R, Tedbury PR, Sarafianos SG. Mechanisms of Action of the Host-Targeting Agent Cyclosporin A and Direct-Acting Antiviral Agents against Hepatitis C Virus. Viruses 2023; 15:981. [PMID: 37112961 PMCID: PMC10143304 DOI: 10.3390/v15040981] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/30/2023] [Accepted: 04/04/2023] [Indexed: 04/29/2023] Open
Abstract
Several direct-acting antivirals (DAAs) are available, providing interferon-free strategies for a hepatitis C cure. In contrast to DAAs, host-targeting agents (HTAs) interfere with host cellular factors that are essential in the viral replication cycle; as host genes, they are less likely to rapidly mutate under drug pressure, thus potentially exhibiting a high barrier to resistance, in addition to distinct mechanisms of action. We compared the effects of cyclosporin A (CsA), a HTA that targets cyclophilin A (CypA), to DAAs, including inhibitors of nonstructural protein 5A (NS5A), NS3/4A, and NS5B, in Huh7.5.1 cells. Our data show that CsA suppressed HCV infection as rapidly as the fastest-acting DAAs. CsA and inhibitors of NS5A and NS3/4A, but not of NS5B, suppressed the production and release of infectious HCV particles. Intriguingly, while CsA rapidly suppressed infectious extracellular virus levels, it had no significant effect on the intracellular infectious virus, suggesting that, unlike the DAAs tested here, it may block a post-assembly step in the viral replication cycle. Hence, our findings shed light on the biological processes involved in HCV replication and the role of CypA.
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Affiliation(s)
- Dandan Liu
- CS Bond Life Sciences Center, Department of Molecular Microbiology & Immunology, University of Missouri, Columbia, MO 65201, USA
| | - Tanya P. Ndongwe
- CS Bond Life Sciences Center, Department of Molecular Microbiology & Immunology, University of Missouri, Columbia, MO 65201, USA
| | - Juan Ji
- CS Bond Life Sciences Center, Department of Molecular Microbiology & Immunology, University of Missouri, Columbia, MO 65201, USA
| | - Andrew D. Huber
- CS Bond Life Sciences Center, Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65201, USA
| | - Eleftherios Michailidis
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
- Laboratory of Biochemical Pharmacology, Center for ViroScience and Cure, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, GA 30322, USA
| | - Charles M. Rice
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
| | - Robert Ralston
- CS Bond Life Sciences Center, Department of Molecular Microbiology & Immunology, University of Missouri, Columbia, MO 65201, USA
| | - Philip R. Tedbury
- CS Bond Life Sciences Center, Department of Molecular Microbiology & Immunology, University of Missouri, Columbia, MO 65201, USA
- Laboratory of Biochemical Pharmacology, Center for ViroScience and Cure, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, GA 30322, USA
| | - Stefan G. Sarafianos
- CS Bond Life Sciences Center, Department of Molecular Microbiology & Immunology, University of Missouri, Columbia, MO 65201, USA
- Laboratory of Biochemical Pharmacology, Center for ViroScience and Cure, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, GA 30322, USA
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Cao Y, Wu X, Wang Z, Huang Y, Wu J, Cao G, Yu J, Wang J, Yang H, Zhang W, Zhang J. Single-Ascending-Dose, Food-Effect, and Multiple-Dose Study of the Safety, Tolerability, and Pharmacokinetics of the Pangenotypic Anti-Hepatitis C Virus Drug Holybuvir in Healthy Chinese Subjects. Antimicrob Agents Chemother 2023; 67:e0129522. [PMID: 36809048 PMCID: PMC10019294 DOI: 10.1128/aac.01295-22] [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: 09/24/2022] [Accepted: 12/25/2022] [Indexed: 02/23/2023] Open
Abstract
Holybuvir is a novel pangenotypic hepatitis C virus NS5B inhibitor. This first in-human study aimed to evaluate the pharmacokinetics (PK), safety, and tolerability of holybuvir and its metabolites and the effect of food on the PK of holybuvir and its metabolites in healthy Chinese subjects. A total of 96 subjects were enrolled in this study which included (i) a single-ascending-dose (SAD) study (100 to 1,200 mg), (ii) a food-effect (FE) study (600 mg), and (iii) a multiple-dose (MD) study (400 and 600 mg once daily for 14 days). The results showed that single oral administration of holybuvir at doses up to 1,200 mg was well tolerated. Holybuvir was rapidly absorbed and metabolized in the human body, which was consistent with the characteristics of holybuvir as a prodrug. PK analysis showed that Cmax and area under the curve (AUC) increased with dose in no dose-proportional manner after a single-dose administration (100 to 1,200 mg). Although high-fat meals did change the PK of holybuvir and its metabolites, clinical significance of changes in PK parameters induced by eating a high-fat diet would be further confirmed. Following multiple-dose administration, accumulation of metabolites SH229M4 and SH229M5-sul was observed. The favorable PK and safety results support the further development of holybuvir for patients with HCV. (This study was registered at Chinadrugtrials.org under identifier CTR20170859.).
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Affiliation(s)
- Yuran Cao
- Phase I Clinical Research Center, Huashan Hospital, Fudan University, Shanghai, China
| | - Xiaojie Wu
- Phase I Clinical Research Center, Huashan Hospital, Fudan University, Shanghai, China
| | - Zhiqiang Wang
- Nanjing Sanhome Pharmaceutical Co., Ltd., Nanjing, Jiangsu, China
| | - Yuxian Huang
- Infectious Disease Department, Huashan Hospital, Fudan University, Shanghai, China
| | - Junzhen Wu
- Phase I Clinical Research Center, Huashan Hospital, Fudan University, Shanghai, China
| | - Guoying Cao
- Phase I Clinical Research Center, Huashan Hospital, Fudan University, Shanghai, China
| | - Jicheng Yu
- Phase I Clinical Research Center, Huashan Hospital, Fudan University, Shanghai, China
| | - Jingjing Wang
- Phase I Clinical Research Center, Huashan Hospital, Fudan University, Shanghai, China
| | - Haijing Yang
- Phase I Clinical Research Center, Huashan Hospital, Fudan University, Shanghai, China
| | - Wenhong Zhang
- Infectious Disease Department, Huashan Hospital, Fudan University, Shanghai, China
| | - Jing Zhang
- Phase I Clinical Research Center, Huashan Hospital, Fudan University, Shanghai, China
- Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China
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Emanuelson C, Ankenbruck N, Kumbhare R, Thomas M, Connelly C, Baktash Y, Randall G, Deiters A. Transcriptional Inhibition of MicroRNA miR-122 by Small Molecules Reduces Hepatitis C Virus Replication in Liver Cells. J Med Chem 2022; 65:16338-16352. [PMID: 36449366 PMCID: PMC9942140 DOI: 10.1021/acs.jmedchem.2c01141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022]
Abstract
MicroRNAs (miRNAs) are noncoding RNA molecules of 22-24 nucleotides that are estimated to regulate thousands of genes in humans, and their dysregulation has been implicated in many diseases. MicroRNA-122 (miR-122) is the most abundant miRNA in the liver and has been linked to the development of hepatocellular carcinoma and hepatitis C virus (HCV) infection. Its role in these diseases renders miR-122 a potential target for small-molecule therapeutics. Here, we report the discovery of a new sulfonamide class of small-molecule miR-122 inhibitors from a high-throughput screen using a luciferase-based reporter assay. Structure-activity relationship (SAR) studies and secondary assays led to the development of potent and selective miR-122 inhibitors. Preliminary mechanism-of-action studies suggest a role in the promoter-specific transcriptional inhibition of miR-122 expression through direct binding to the liver-enriched transcription factor hepatocyte nuclear factor 4α. Importantly, the developed inhibitors significantly reduce HCV replication in human liver cells.
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Affiliation(s)
- Cole Emanuelson
- Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
| | - Nicholas Ankenbruck
- Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
| | - Rohan Kumbhare
- Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
| | - Meryl Thomas
- Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
| | - Colleen Connelly
- Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695, United States
| | - Yasmine Baktash
- Department of Microbiology, The University of Chicago, Chicago, Illinois 60637, United States
| | - Glenn Randall
- Department of Microbiology, The University of Chicago, Chicago, Illinois 60637, United States
| | - Alexander Deiters
- Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
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Hassuna NA, Gamil AN, Mahmoud MS, Mohamed WK, Khairy R. Circulating microRNAs as predictors of response to sofosbuvir + daclatasvir + ribavirin in in HCV genotype-4 Egyptian patients. BMC Gastroenterol 2022; 22:499. [PMID: 36463118 PMCID: PMC9719120 DOI: 10.1186/s12876-022-02485-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Accepted: 08/09/2022] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) play an important role in various diseases, including HCV infection, the aim of the current study was to evaluate the potential use of serum miRNAs as biomarkers for diagnosis, prognosis, and prediction of responses to direct acting antivirals (sofosbuvir + daclatasvir + ribavirin) in HCV-4 patients. METHODS The serum expression profiles of four liver-associated miRNAs (miRNA-122, 155, 196 and 29) were assessed in 160 HCV-4 patients and 50 healthy controls using real-time PCR prior to therapy. RESULTS miR-122 and miR-155 showed upregulation in HCV-4 patients compared to healthy controls while miR-196 and miR-29 showed downregulation in HCV-4 patients. ROC curve analyses revealed that the four-studied miRNAs could be valuable biomarkers for predicting response to DAAs with AUC 0.973 for miR-122, 0.878 for miR-155, 0.808 for miR-29 and 0.874 for miR-196 respectively. Univariate logistic regression analysis revealed that miR-196 level is positive predictor for SVR, whereas miR-122,155 levels are negative predictors of response. Multivariate logistic regression analysis revealed that miR-196 is the most significant in predicting response to treatment (p value = 0.011). CONCLUSION To the best of our knowledge, the current study provided the first clinical evidence of the potential use of circulating miRNAs (miR; 122, 155, 196 and 29) as biomarkers of CHC in HCV-4 patients receiving the new DAA regimen (SOF/DAV + RIB), which is a strong motivator for further studies.
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Affiliation(s)
- Noha Anwar Hassuna
- grid.411806.a0000 0000 8999 4945Department of Medical Microbiology and Immunology, Faculty of Medicine, Minia University, Minia, Egypt
| | - Aya Nabil Gamil
- grid.411806.a0000 0000 8999 4945Department of Medical Microbiology and Immunology, Faculty of Medicine, Minia University, Minia, Egypt
| | - Mahmoud Shokry Mahmoud
- grid.411806.a0000 0000 8999 4945Department of Medical Microbiology and Immunology, Faculty of Medicine, Minia University, Minia, Egypt
| | - Wafaa Khairy Mohamed
- grid.411806.a0000 0000 8999 4945Department of Medical Microbiology and Immunology, Faculty of Medicine, Minia University, Minia, Egypt
| | - Rasha Khairy
- grid.411806.a0000 0000 8999 4945Department of Medical Microbiology and Immunology, Faculty of Medicine, Minia University, Minia, Egypt
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van Vliet VJE, Huynh N, Palà J, Patel A, Singer A, Slater C, Chung J, van Huizen M, Teyra J, Miersch S, Luu GK, Ye W, Sharma N, Ganaie SS, Russell R, Chen C, Maynard M, Amarasinghe GK, Mark BL, Kikkert M, Sidhu SS. Ubiquitin variants potently inhibit SARS-CoV-2 PLpro and viral replication via a novel site distal to the protease active site. PLoS Pathog 2022; 18:e1011065. [PMID: 36548304 PMCID: PMC9822107 DOI: 10.1371/journal.ppat.1011065] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 01/06/2023] [Accepted: 12/13/2022] [Indexed: 12/24/2022] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has made it clear that combating coronavirus outbreaks benefits from a combination of vaccines and therapeutics. A promising drug target common to all coronaviruses-including SARS-CoV, MERS-CoV, and SARS-CoV-2-is the papain-like protease (PLpro). PLpro cleaves part of the viral replicase polyproteins into non-structural protein subunits, which are essential to the viral replication cycle. Additionally, PLpro can cleave both ubiquitin and the ubiquitin-like protein ISG15 from host cell substrates as a mechanism to evade innate immune responses during infection. These roles make PLpro an attractive antiviral drug target. Here we demonstrate that ubiquitin variants (UbVs) can be selected from a phage-displayed library and used to specifically and potently block SARS-CoV-2 PLpro activity. A crystal structure of SARS-CoV-2 PLpro in complex with a representative UbV reveals a dimeric UbV bound to PLpro at a site distal to the catalytic site. Yet, the UbV inhibits the essential cleavage activities of the protease in vitro and in cells, and it reduces viral replication in cell culture by almost five orders of magnitude.
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Affiliation(s)
- Vera J. E. van Vliet
- Department of Medical Microbiology, Leiden University Center of Infectious Diseases (LU-CID), Leiden University Medical Center, Leiden, South Holland, The Netherlands
- The Roslin Institute, University of Edinburgh, Midlothian, Scotland, United Kingdom
| | - Nhan Huynh
- The Anvil Institute, Kitchener, Ontario, Canada
- School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada
| | - Judith Palà
- The Anvil Institute, Kitchener, Ontario, Canada
- School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada
| | - Ankoor Patel
- Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Alex Singer
- The Anvil Institute, Kitchener, Ontario, Canada
- School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada
| | - Cole Slater
- Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Jacky Chung
- The Anvil Institute, Kitchener, Ontario, Canada
- School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada
| | - Mariska van Huizen
- Department of Medical Microbiology, Leiden University Center of Infectious Diseases (LU-CID), Leiden University Medical Center, Leiden, South Holland, The Netherlands
| | - Joan Teyra
- The Anvil Institute, Kitchener, Ontario, Canada
- School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada
| | - Shane Miersch
- The Anvil Institute, Kitchener, Ontario, Canada
- School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada
| | - Gia-Khanh Luu
- The Anvil Institute, Kitchener, Ontario, Canada
- School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada
| | - Wei Ye
- The Anvil Institute, Kitchener, Ontario, Canada
- School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada
| | - Nitin Sharma
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Safder S. Ganaie
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Raquel Russell
- Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Chao Chen
- The Anvil Institute, Kitchener, Ontario, Canada
- School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada
| | - Mindy Maynard
- The Anvil Institute, Kitchener, Ontario, Canada
- School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada
| | - Gaya K. Amarasinghe
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Brian L. Mark
- Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Marjolein Kikkert
- Department of Medical Microbiology, Leiden University Center of Infectious Diseases (LU-CID), Leiden University Medical Center, Leiden, South Holland, The Netherlands
| | - Sachdev S. Sidhu
- The Anvil Institute, Kitchener, Ontario, Canada
- School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada
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Kartashov MY, Svirin KA, Krivosheina EI, Chub EV, Ternovoi VA, Kochneva GV. [Prevalence and molecular genetic characteristics of parenteral hepatitis B, C and D viruses in HIV positive persons in the Novosibirsk region]. Vopr Virusol 2022; 67:423-438. [PMID: 36515288 DOI: 10.36233/0507-4088-133] [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: 07/27/2022] [Indexed: 12/05/2022]
Abstract
INTRODUCTION Parenteral viral hepatitis (B, C, D) and HIV share modes of transmission and risk groups, in which the probability of infection with two or more of these viruses simultaneously is increased. Mutual worsening of the course of viral infections is important issue that occurs when HIV positive patients are coinfected with parenteral viral hepatitis. The aim of the study was to determine the prevalence of HCV, HBV and HDV in HIV positive patients in the Novosibirsk region and to give molecular genetic characteristics of their isolates. MATERIALS AND METHODS Total 185 blood samples were tested for the presence of total antibodies to HCV, HCV RNA, HBV DNA and HDV RNA. The identified isolates were genotyped by amplification of the NS5B gene fragment for HCV, the polymerase gene for HBV and whole genome for HDV. RESULTS The total antibodies to HCV were detected in 51.9% (95% CI: 44.758.9), HCV RNA was detected in 32.9% (95% CI: 26.639.5) of 185 studied samples. The distribution of HCV RNA positive cases completely repeated the distribution of HCV serological markers in different sex and age groups. The number of HCV infected among HIV positive patients increases with age. HCV subgenotypes distribution was as follows: 1b (52.5%), 3а (34.5%), 1а (11.5%), 2а (1.5%). 84.3% of detected HCV 1b isolates had C316N mutation associated with resistance to sofosbuvir and dasabuvir. The prevalence of HBV DNA in the studied samples was 15.2% (95% CI: 10.721.0). M204I mutation associated with resistance to lamivudine and telbivudine was identified in one HBV isolate. Two HDV isolates that belonged to genotype 1 were detected in HIV/HBV coinfected patients. CONCLUSION The data obtained confirm the higher prevalence of infection with parenteral viral hepatitis among people living with HIV in the Novosibirsk region compared to the general population of that region. The genetic diversity of these viruses among HIV infected individuals is similar to that observed in the general population.
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Affiliation(s)
- M Y Kartashov
- State Scientific Center of Virology and Biotechnology "Vector" of the Federal Service for Surveillance of Consumer Rights Protection and Human Welfare (Rospotrebnadzor).,Novosibirsk National Research State University
| | - K A Svirin
- State Scientific Center of Virology and Biotechnology "Vector" of the Federal Service for Surveillance of Consumer Rights Protection and Human Welfare (Rospotrebnadzor)
| | - E I Krivosheina
- State Scientific Center of Virology and Biotechnology "Vector" of the Federal Service for Surveillance of Consumer Rights Protection and Human Welfare (Rospotrebnadzor)
| | - E V Chub
- State Scientific Center of Virology and Biotechnology "Vector" of the Federal Service for Surveillance of Consumer Rights Protection and Human Welfare (Rospotrebnadzor)
| | - V A Ternovoi
- State Scientific Center of Virology and Biotechnology "Vector" of the Federal Service for Surveillance of Consumer Rights Protection and Human Welfare (Rospotrebnadzor)
| | - G V Kochneva
- State Scientific Center of Virology and Biotechnology "Vector" of the Federal Service for Surveillance of Consumer Rights Protection and Human Welfare (Rospotrebnadzor)
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10
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Efficacy and safety of direct-acting antivirals for HCV in patients with extrahepatic malignancies: real-life experience. EGYPTIAN LIVER JOURNAL 2022. [DOI: 10.1186/s43066-022-00213-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Outcome of HCV treatment with direct antiviral agents in malignant patients is questionable. The aim is to assess the safety and efficacy of DAAs in treatment of chronic HCV patients who received chemotherapy for malignancies.
Materials
Retrospective cohort study of 83 patients with HCV post chemotherapy receiving DAAs treatment compared to a matched group of 88 chronic HCV patients without cancer. Demographic, laboratory and abdominal ultrasound data, and SVR were taken for all patients.
Results
Patients’ data revealed mean age (52 years) and BMI (29). A total of 52% of HCV patients were females, and 83.6% were treatment naïve. Patients with cancer had higher FIB4 values and more cirrhosis (20.5% vs. 13.6%) with no statistical significance. Total bilirubin and HbA1C levels were significantly higher in HCV patients without cancer. All patients in either groups received SOF-based DAAs except 2 cases received PAR/OMP/RBV. SVR rate was very high and comparable between the two groups (100% and 97.7% in post chemotherapy and control groups) with no statistical difference. Mortality was represented in 23% in patients post chemotherapy with FIB4 score considered the only predictor for mortality.
Conclusion
DAAs have excellent efficacy in patients post chemotherapy. Further studies should be conducted for their concomitant use with chemotherapy.
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11
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Patel D, Ono SK, Bassit L, Verma K, Amblard F, Schinazi RF. Assessment of a Computational Approach to Predict Drug Resistance Mutations for HIV, HBV and SARS-CoV-2. Molecules 2022; 27:molecules27175413. [PMID: 36080181 PMCID: PMC9457688 DOI: 10.3390/molecules27175413] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/18/2022] [Accepted: 08/22/2022] [Indexed: 11/28/2022] Open
Abstract
Viral resistance is a worldwide problem mitigating the effectiveness of antiviral drugs. Mutations in the drug-targeting proteins are the primary mechanism for the emergence of drug resistance. It is essential to identify the drug resistance mutations to elucidate the mechanism of resistance and to suggest promising treatment strategies to counter the drug resistance. However, experimental identification of drug resistance mutations is challenging, laborious and time-consuming. Hence, effective and time-saving computational structure-based approaches for predicting drug resistance mutations are essential and are of high interest in drug discovery research. However, these approaches are dependent on accurate estimation of binding free energies which indirectly correlate to the computational cost. Towards this goal, we developed a computational workflow to predict drug resistance mutations for any viral proteins where the structure is known. This approach can qualitatively predict the change in binding free energies due to mutations through residue scanning and Prime MM-GBSA calculations. To test the approach, we predicted resistance mutations in HIV-RT selected by (-)-FTC and demonstrated accurate identification of the clinical mutations. Furthermore, we predicted resistance mutations in HBV core protein for GLP-26 and in SARS-CoV-2 3CLpro for nirmatrelvir. Mutagenesis experiments were performed on two predicted resistance and three predicted sensitivity mutations in HBV core protein for GLP-26, corroborating the accuracy of the predictions.
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Affiliation(s)
- Dharmeshkumar Patel
- Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Dr., Atlanta, GA 30322, USA
| | - Suzane K. Ono
- Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Dr., Atlanta, GA 30322, USA
- Department of Gastroenterology, University of São Paulo School of Medicine, Av. Dr. Arnaldo, 455, São Paulo 05403-000, SP, Brazil
| | - Leda Bassit
- Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Dr., Atlanta, GA 30322, USA
| | - Kiran Verma
- Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Dr., Atlanta, GA 30322, USA
| | - Franck Amblard
- Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Dr., Atlanta, GA 30322, USA
| | - Raymond F. Schinazi
- Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Dr., Atlanta, GA 30322, USA
- Correspondence:
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12
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Freitas ED, Bataglioli RA, Oshodi J, Beppu MM. Antimicrobial peptides and their potential application in antiviral coating agents. Colloids Surf B Biointerfaces 2022; 217:112693. [PMID: 35853393 PMCID: PMC9262651 DOI: 10.1016/j.colsurfb.2022.112693] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 06/29/2022] [Accepted: 07/05/2022] [Indexed: 11/24/2022]
Abstract
Coronavirus pandemic has evidenced the importance of creating bioactive materials to mitigate viral infections, especially in healthcare settings and public places. Advances in antiviral coatings have led to materials with impressive antiviral performance; however, their application may face health and environmental challenges. Bio-inspired antimicrobial peptides (AMPs) are suitable building blocks for antimicrobial coatings due to their versatile design, scalability, and environmentally friendly features. This review presents the advances and opportunities on the AMPs to create virucidal coatings. The review first describes the fundamental characteristics of peptide structure and synthesis, highlighting the recent findings on AMPs and the role of peptide structure (α-helix, β-sheet, random, and cyclic peptides) on the virucidal mechanism. The following section presents the advances in AMPs coating on medical devices with a detailed description of the materials coated and the targeted pathogens. The use of peptides in vaccine formulations is also reported, emphasizing the molecular interaction of peptides with different viruses and the current clinical stage of each formulation. The role of several materials (metallic particles, inorganic materials, and synthetic polymers) in the design of antiviral coatings is also presented, discussing the advantages and the drawbacks of each material. The final section offers future directions and opportunities for using AMPs on antiviral coatings to prevent viral outbreaks.
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Affiliation(s)
- Emanuelle D Freitas
- School of Chemical Engineering, Department of Materials and Bioprocess Engineering, University of Campinas, Campinas, São Paulo 13083-852, Brazil
| | - Rogério A Bataglioli
- School of Chemical Engineering, Department of Materials and Bioprocess Engineering, University of Campinas, Campinas, São Paulo 13083-852, Brazil
| | - Josephine Oshodi
- Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, United States
| | - Marisa M Beppu
- School of Chemical Engineering, Department of Materials and Bioprocess Engineering, University of Campinas, Campinas, São Paulo 13083-852, Brazil.
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13
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Patel D, Cox BD, Kasthuri M, Mengshetti S, Bassit L, Verma K, Ollinger-Russell O, Amblard F, Schinazi RF. In silico design of a novel nucleotide antiviral agent by free energy perturbation. Chem Biol Drug Des 2022; 99:801-815. [PMID: 35313085 PMCID: PMC9175506 DOI: 10.1111/cbdd.14042] [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: 11/16/2021] [Revised: 02/03/2022] [Accepted: 03/05/2022] [Indexed: 11/30/2022]
Abstract
Nucleoside analogs are the backbone of antiviral therapies. Drugs from this class undergo processing by host or viral kinases to form the active nucleoside triphosphate species that selectively inhibits the viral polymerase. It is the central hypothesis that the nucleoside triphosphate analog must be a favorable substrate for the viral polymerase and the nucleoside precursor must be a satisfactory substrate for the host kinases to inhibit viral replication. Herein, free energy perturbation (FEP) was used to predict substrate affinity for both host and viral enzymes. Several uridine 5'-monophosphate prodrug analogs known to inhibit hepatitis C virus (HCV) were utilized in this study to validate the use of FEP. Binding free energies to the host monophosphate kinase and viral RNA-dependent RNA polymerase (RdRp) were calculated for methyl-substituted uridine analogs. The 2'-C-methyl-uridine and 4'-C-methyl-uridine scaffolds delivered favorable substrate binding to the host kinase and HCV RdRp that were consistent with results from cellular antiviral activity in support of our new approach. In a prospective evaluation, FEP results suggest that 2'-C-dimethyl-uridine scaffold delivered favorable monophosphate and triphosphate substrates for both host kinase and HCV RdRp, respectively. Novel 2'-C-dimethyl-uridine monophosphate prodrug was synthesized and exhibited sub-micromolar inhibition of HCV replication. Using this novel approach, we demonstrated for the first time that nucleoside analogs can be rationally designed that meet the multi-target requirements for antiviral activity.
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Affiliation(s)
- Dharmeshkumar Patel
- Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Dr., Atlanta, GA, 30322, USA
| | - Bryan D. Cox
- Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Dr., Atlanta, GA, 30322, USA
| | - Mahesh Kasthuri
- Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Dr., Atlanta, GA, 30322, USA
| | - Seema Mengshetti
- Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Dr., Atlanta, GA, 30322, USA
| | - Leda Bassit
- Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Dr., Atlanta, GA, 30322, USA
| | - Kiran Verma
- Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Dr., Atlanta, GA, 30322, USA
| | - Olivia Ollinger-Russell
- Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Dr., Atlanta, GA, 30322, USA
| | - Franck Amblard
- Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Dr., Atlanta, GA, 30322, USA
| | - Raymond F. Schinazi
- Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Dr., Atlanta, GA, 30322, USA
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14
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Allam AS, Elmeged MLA, Ghaly SM, Ahmed OA, Naguib GG, Abohalima AS. Impact of direct-acting antiviral therapy on metabolic profiles and adiponectin serum level in different categories of patients with chronic hepatitis C infection. EGYPTIAN LIVER JOURNAL 2022. [DOI: 10.1186/s43066-022-00194-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Infection with the hepatitis C virus (HCV) is a worldwide health problem. HCV infection is linked to a variety of metabolic abnormalities as it interferes with lipid metabolism, causing steatosis and a wide range of adipocytokine alterations, as well as impairing glucose metabolism, resulting in a rising prevalence of insulin resistance (IR) and type 2 diabetes. Over the last few years, numerous oral anti-HCV medicines (direct-acting antivirals; DAAs) have been introduced. With DAA therapy, HCV can now be eradicated from the infected host within 12 weeks. There is a need for more research because there is minimal information on the effects of DAA therapy on metabolic profiles, lipid profiles, and adiponectin levels. Thus, the purpose of this study was to see how direct-acting antivirals (DAAs) affected metabolic profiles and serum adiponectin levels in 2 different categories of Egyptian patients with chronic hepatitis C infection. This study included 100 patients with chronic HCV who were separated into two groups. Group I consisted of 50 patients who were treated for 12 weeks with sofosbuvir, daclatasvir, and ribavirin). Group II consisted of 50 patients who were treated for 12 weeks with ombitasvir, paritaprevir, and ritonavir/ribavirin. This regimen was chosen because these patients had an eGFR of 30 ml/min. Fasting lipid profiles (total cholesterol, triglyceride, HDL, and LDL), metabolic profiles (fasting blood sugar, fasting insulin, HOMA-IR, and HbA1C), and serum adiponectin levels were measured before and after the end of treatment.
Results
Statistical analysis of the data showed a significant difference in the lipid profile in group I before and after treatment, as we found a significant reduction in serum triglycerides after treatment (113.2 ± 22.9 mg/dL vs 105.6 ± 23.2 mg/dL, P < 0.001) and a significant elevation of serum total cholesterol, LDL, and HDL after treatment (TC: 153.2 ± 20.1 mg/dL vs 174.1 ± 19 mg/dL, P < 0.001; LDL: 74.7 ± 9.9 mg/dL vs 93.3 ± 12 mg/dL, P < 0.001; HDL: 54.6 ± 10.1 mg/dL vs 57.2 ± 10.3 mg/dL, P 0.010). But in group II, there was no significant difference in the lipid profile before and after treatment. We also found a significant reduction in fasting insulin, HOMA-IR, and HBA1C after treatment in group I (fasting insulin: 11.4 ± 3.3 (µU/L)/ml vs 9.7 ± 2.2 (µU/L)/ml, P < 0.001; HOMA-IR: 2.7 ± 0.9 vs 2.2 ± 0.6, P < 0.001; HBA1C: 5.6 ± 0.4 vs 5.4 ± 0.3, P 0.003). But in group II, there was no significant difference in fasting insulin, HOMA-IR, and HBA1C before and after treatment. Also, we found that there were no significant changes in the serum adiponectin level in either group before or after treatment.
Conclusion
HCV clearance with DAAs had an impact on the lipid and metabolic profiles of the patients at the end of treatment. This could depend on the type of DAAs used in the treatment, the stage of the liver disease, and the associated conditions of patients. However, serum adiponectin levels are unaffected.
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15
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Cusato J, Boglione L, De Nicolò A, Caviglia GP, Mornese Pinna S, Ciancio A, Troshina G, Smedile A, Antonucci M, Avataneo V, Palermiti A, Mula J, Manca A, Cariti G, Cantù M, Saracco GM, Di Perri G, D’Avolio A. Factors Influencing the Intracellular Concentrations of the Sofosbuvir Metabolite GS-331007 (in PBMCs) at 30 Days of Therapy. Pharmaceuticals (Basel) 2022; 15:355. [PMID: 35337152 PMCID: PMC8953593 DOI: 10.3390/ph15030355] [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: 02/07/2022] [Revised: 03/09/2022] [Accepted: 03/10/2022] [Indexed: 01/27/2023] Open
Abstract
Sofosbuvir (SOF) is an HCV NS5B polymerase inhibitor, and GS-331007 is its major metabolite. The aim of this study was to investigate whether clinical and pharmacological factors could influence GS-331007 intracellular (IC) concentrations in peripheral blood mononuclear cells (PBMCs) associated with a sustained virological response in patients treated with SOF and ribavirin (RBV). Drug levels were analyzed using liquid chromatography at different days of therapy, whereas variants in genes encoding transporters and nuclear factors were investigated using real-time PCR. This study enrolled 245 patients treated with SOF; 245 samples were analyzed for pharmacogenetics and 50 were analyzed for IC pharmacokinetics. The GS-331007 IC concentration at 30 days was associated with its plasma concentration determinate at 30, 60 and 90 days of SOF-therapy and with daclatasvir concentrations at 7 days of therapy. No genetic polymorphism affected IC exposure. In linear multivariate analysis, ledipasvir treatment, baseline albumin and estimated glomerular filtration rate were significant predictors of IC exposure. This study presents data on an IC evaluation in a cohort of patients treated with SOF, also considering pharmacogenetics. These results could be useful for regions where SOF-RBV treatment is considered the standard of care; moreover, they could further deepen the knowledge of IC exposure for similar drugs in the future.
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Affiliation(s)
- Jessica Cusato
- Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, 10149 Turin, Italy; (A.D.N.); (G.P.C.); (S.M.P.); (A.C.); (G.T.); (A.S.); (M.A.); (V.A.); (A.P.); (J.M.); (A.M.); (G.C.); (G.M.S.); (G.D.P.); (A.D.)
| | - Lucio Boglione
- Department of Traslational Medicine, University of Eastern Piedmont, 28100 Novara, Italy;
| | - Amedeo De Nicolò
- Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, 10149 Turin, Italy; (A.D.N.); (G.P.C.); (S.M.P.); (A.C.); (G.T.); (A.S.); (M.A.); (V.A.); (A.P.); (J.M.); (A.M.); (G.C.); (G.M.S.); (G.D.P.); (A.D.)
| | - Gian Paolo Caviglia
- Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, 10149 Turin, Italy; (A.D.N.); (G.P.C.); (S.M.P.); (A.C.); (G.T.); (A.S.); (M.A.); (V.A.); (A.P.); (J.M.); (A.M.); (G.C.); (G.M.S.); (G.D.P.); (A.D.)
| | - Simone Mornese Pinna
- Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, 10149 Turin, Italy; (A.D.N.); (G.P.C.); (S.M.P.); (A.C.); (G.T.); (A.S.); (M.A.); (V.A.); (A.P.); (J.M.); (A.M.); (G.C.); (G.M.S.); (G.D.P.); (A.D.)
| | - Alessia Ciancio
- Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, 10149 Turin, Italy; (A.D.N.); (G.P.C.); (S.M.P.); (A.C.); (G.T.); (A.S.); (M.A.); (V.A.); (A.P.); (J.M.); (A.M.); (G.C.); (G.M.S.); (G.D.P.); (A.D.)
| | - Giulia Troshina
- Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, 10149 Turin, Italy; (A.D.N.); (G.P.C.); (S.M.P.); (A.C.); (G.T.); (A.S.); (M.A.); (V.A.); (A.P.); (J.M.); (A.M.); (G.C.); (G.M.S.); (G.D.P.); (A.D.)
| | - Antonina Smedile
- Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, 10149 Turin, Italy; (A.D.N.); (G.P.C.); (S.M.P.); (A.C.); (G.T.); (A.S.); (M.A.); (V.A.); (A.P.); (J.M.); (A.M.); (G.C.); (G.M.S.); (G.D.P.); (A.D.)
| | - Miriam Antonucci
- Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, 10149 Turin, Italy; (A.D.N.); (G.P.C.); (S.M.P.); (A.C.); (G.T.); (A.S.); (M.A.); (V.A.); (A.P.); (J.M.); (A.M.); (G.C.); (G.M.S.); (G.D.P.); (A.D.)
| | - Valeria Avataneo
- Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, 10149 Turin, Italy; (A.D.N.); (G.P.C.); (S.M.P.); (A.C.); (G.T.); (A.S.); (M.A.); (V.A.); (A.P.); (J.M.); (A.M.); (G.C.); (G.M.S.); (G.D.P.); (A.D.)
| | - Alice Palermiti
- Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, 10149 Turin, Italy; (A.D.N.); (G.P.C.); (S.M.P.); (A.C.); (G.T.); (A.S.); (M.A.); (V.A.); (A.P.); (J.M.); (A.M.); (G.C.); (G.M.S.); (G.D.P.); (A.D.)
| | - Jacopo Mula
- Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, 10149 Turin, Italy; (A.D.N.); (G.P.C.); (S.M.P.); (A.C.); (G.T.); (A.S.); (M.A.); (V.A.); (A.P.); (J.M.); (A.M.); (G.C.); (G.M.S.); (G.D.P.); (A.D.)
| | - Alessandra Manca
- Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, 10149 Turin, Italy; (A.D.N.); (G.P.C.); (S.M.P.); (A.C.); (G.T.); (A.S.); (M.A.); (V.A.); (A.P.); (J.M.); (A.M.); (G.C.); (G.M.S.); (G.D.P.); (A.D.)
| | - Giuseppe Cariti
- Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, 10149 Turin, Italy; (A.D.N.); (G.P.C.); (S.M.P.); (A.C.); (G.T.); (A.S.); (M.A.); (V.A.); (A.P.); (J.M.); (A.M.); (G.C.); (G.M.S.); (G.D.P.); (A.D.)
| | - Marco Cantù
- Laboratory of Clinical Biochemistry and Pharmacology, Department of Laboratory Medicine EOLAB, Ente Ospedaliero Cantonale, CH-6500 Bellinzona, Switzerland;
| | - Giorgio Maria Saracco
- Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, 10149 Turin, Italy; (A.D.N.); (G.P.C.); (S.M.P.); (A.C.); (G.T.); (A.S.); (M.A.); (V.A.); (A.P.); (J.M.); (A.M.); (G.C.); (G.M.S.); (G.D.P.); (A.D.)
| | - Giovanni Di Perri
- Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, 10149 Turin, Italy; (A.D.N.); (G.P.C.); (S.M.P.); (A.C.); (G.T.); (A.S.); (M.A.); (V.A.); (A.P.); (J.M.); (A.M.); (G.C.); (G.M.S.); (G.D.P.); (A.D.)
| | - Antonio D’Avolio
- Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, 10149 Turin, Italy; (A.D.N.); (G.P.C.); (S.M.P.); (A.C.); (G.T.); (A.S.); (M.A.); (V.A.); (A.P.); (J.M.); (A.M.); (G.C.); (G.M.S.); (G.D.P.); (A.D.)
- Interdepartmental Center for Clinical and Experimental Pharmacology (CIFACS), University of Turin, 10149 Turin, Italy
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16
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Hagag RY, Selim AF, Darrag OM, Zied H, Aboelnasr MS. Does Hepatitis C Virus Treatment by Directly Acting Antivirals Obligate Shifting Patients with Type 2 Diabetes from Oral Hypoglycemic Drugs to Insulin Therapy? Diabetes Metab Syndr Obes 2022; 15:1261-1268. [PMID: 35502409 PMCID: PMC9056022 DOI: 10.2147/dmso.s354023] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Accepted: 04/06/2022] [Indexed: 12/15/2022] Open
Abstract
PURPOSE The aim of the present work was to investigate whether hepatitis C virus treatment by directly acting antivirals obligate shifting patients with type 2 diabetes from oral hypoglycemic drugs to insulin therapy. METHODS This was a prospective study including 92 treatment-naïve patients with chronic hepatitis C virus infection and type 2 diabetes who were eligible for treatment with directly acting antivirals (sofosbuvir + daclatasvir ± ribavirin). Patients in the study were divided into two groups; group 1 included 22 patients on insulin therapy and group 2 included 70 patients on oral antidiabetic medications. Patients were advised to keep on their anti-diabetic treatment. RESULTS All our patients achieved sustained virologic response with significantly lower HbA1c 12 weeks after the end of therapy (p. values 0.001 for group 1 and group 2). There was no statistically significant difference in HbA1c level post-treatment between both groups (p. value 0.352). CONCLUSION Achievement of sustained virologic response using interferon free, directly acting antivirals-based regimen was associated with significantly lower HbA1c 12 weeks after the end of therapy. The type of treatment used for type 2 diabetes (oral drugs or insulin) did not affect improved glycemic control observed after achieving sustained virologic response.
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Affiliation(s)
- Rasha Youssef Hagag
- Department of internal medicine, Faculty of medicine, Tanta University, Tanta, Egypt
| | - Ahmed Fawzy Selim
- Department of internal medicine, Faculty of medicine, Tanta University, Tanta, Egypt
| | - Omneya Mohamed Darrag
- Department of internal medicine, Faculty of medicine, Tanta University, Tanta, Egypt
| | - Hassan Zied
- Kafr-Elsheikh Liver Institute, Kafr-Elsheikh, Egypt
| | - Mohamed Sabry Aboelnasr
- Department of internal medicine, Faculty of medicine, Tanta University, Tanta, Egypt
- Correspondence: Mohamed Sabry Aboelnasr, Elgeish Street, Aboelelasorour Building, Floor 6, Kafrelzayat, Gharbia Governorate, 31611, Egypt, Tel +20 1066276267, Email ;
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17
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Wang Y, Cheng G, Lau G. Achieving WHO target of HCV control in Hong Kong: challenges and strategies. Glob Health Med 2021; 3:276-282. [PMID: 34782869 DOI: 10.35772/ghm.2021.01075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 07/26/2021] [Accepted: 08/03/2021] [Indexed: 11/08/2022]
Abstract
With the introduction of effective directly acting antiviral agents (DAAs) therapy, control and elimination of hepatitis C virus (HCV) infection is becoming a feasible goal. In Hong Kong, HCV prevalence in general population is 0.3%-0.5% over the past decades. However, like other high-income areas/countries, high prevalence of HCV infection has been found in several population groups, such as people who inject drugs (PWID), patients undergoing dialysis, and human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/ AIDS) patients. Based on the epidemiological study using data retrieved from the Hong Kong HCV Registry from January 2005 to March 2017, the estimated territory-wide diagnosis rate and treatment rate of HCV infection were only 50.9% and 12.4%, respectively. Although these rates was comparable to many developed countries/areas, the performances remained substantially below 90% and 80%, the 2030 targets proposed by World Health Organization (WHO). In recognition of the challenges, the Hong Kong Government set up the Steering Committee on Prevention and Control of Viral Hepatitis (SCVH) which formulated the Hong Kong Viral Hepatitis Action Plan 2020-2024. The Action Plan adopts four key strategies, as described in the WHO framework for global action, namely, awareness, surveillance, prevention and treatment. With the effective implementation of the Action Plan, especially in targeted screening of high-risk populations and more generalized use of the highly efficacious DAAs for all diagnosed HCV subjects, the goals of reducing HCV transmission and HCV-related morbidity and mortality can be achieved in Hong Kong by 2030.
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Affiliation(s)
- Yudong Wang
- Humanity and Health Clinical Trial Center, Humanity & Health Medical Group, Hong Kong SAR, China
| | - Gregory Cheng
- Humanity and Health Clinical Trial Center, Humanity & Health Medical Group, Hong Kong SAR, China.,Faculty of Health Science, University of Macau, Macau SAR, China
| | - George Lau
- Humanity and Health Clinical Trial Center, Humanity & Health Medical Group, Hong Kong SAR, China.,The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
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18
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Lapumnuaypol K, Pisarcik D, Putthapiban P, Sukhumthammarat W, Wijarnpreecha K, Thongprayoon C, Ungprasert P. Direct-acting antiviral agents decrease haemoglobin A1c level in patients with diabetes infected with hepatitis C virus: A systematic review & meta-analysis. Indian J Med Res 2021; 152:562-567. [PMID: 34145095 PMCID: PMC8224154 DOI: 10.4103/ijmr.ijmr_1088_18] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022] Open
Abstract
Background & objectives: Several epidemiologic studies have demonstrated that type 2 diabetes mellitus (T2DM) is more prevalent in patients infected with hepatitis C virus (HCV), and the eradication of HCV has been shown to decrease the risk of T2DM. This meta-analysis was undertaken to see if treatment with direct-acting antiviral (DAA) agents would improve glycaemic control among HCV-infected patients with T2DM . Methods: A systematic review was conducted using MEDLINE and EMBASE databases since inception to February 2018. Eligible studies must be cohort studies that recruited HCV-infected patients with T2DM and received DAA therapy. The studies must report the change of haemoglobin A1c (HbA1c) level (before vs. after DAA therapy). Patients who achieved sustained virologic response (SVR) were included in the meta-analysis. The mean HbA1c level and standard deviation of participants were extracted from each study to calculate the mean difference (MD). Pooled MD was then calculated using the random effects model. Results: Four cohort studies with 2648 patients were included. Among HCV-infected T2DM patients who achieved SVR with DAA agents, the mean HbA1c level after treatment was significantly lower than the mean HbA1c level before treatment, with the pooled MD of −0.50 per cent (95% confidence interval, −0.66 to −0.34, I2 = 77%). The main limitation of this study was the lack of comparison groups. Therefore, it could not be concluded that the observed decreased HbA1c level was a direct result of DAA therapy. Interpretation & conclusions: Treatment with DAA agents was found to be associated with a significant reduction of post-treatment HbA1c level compared with pre-treatment HbA1c level among T2DM patients who achieved SVR.
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Affiliation(s)
| | - David Pisarcik
- Department of Internal Medicine, Philadelphia College of Osteopathic Medicine, PA, USA
| | | | | | - Karn Wijarnpreecha
- Department of Gastroenterology, Mayo Clinic Hospital, Gastroenterology - Jacksonville, FL, USA
| | - Charat Thongprayoon
- Department of Nephrology, Mayo Clinic, Nephrology & Hypertension Rochester, MN, USA
| | - Patompong Ungprasert
- Department of Research & Development, Division of Clinical Epidemiology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
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19
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Ahmed NAF, Ali ASH, El Baz RA, El-Zayyadi IAEH. IL-28B single nucleotide polymorphism as a predictor of hepatocellular carcinoma after treatment of chronic hepatitis C patients with direct acting antivirals. EGYPTIAN LIVER JOURNAL 2021. [DOI: 10.1186/s43066-021-00102-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Abstract
Background
Hepatitis C virus (HCV) infection is considered one of the main causes of chronic liver diseases. HCV is responsible for 25% of HCC cases worldwide. DAAs represent an important step for HCV eradication. The aim was to study the role of IL-28B single nucleotide polymorphism in the prediction of HCC in patients with HCV-related cirrhosis after DAAs.
Results
This study was done at Mansoura Specialized Hospital: 50 cases HCC after DAAs, 50 cases without HCC after DAAs, and 100 controls. SNPs of the IL-28B gene were genotyped. There was an insignificant difference between HCC patients and the cirrhotic group as regards genotypes (p value = 0.26) and alleles (p value = 0.77). A significant association in SNP of IL-28B between healthy individuals and the cirrhotic group was detected. C C genotype (28%) and C T (64%) genotype were more prevalent in the healthy group than in the cirrhotic group 20% and 52% respectively while T T genotype was more prevalent in cirrhotic patients (28%) than controls (8%). C allele was protective against cirrhosis with 60% distribution in healthy individuals and 46% in the cirrhotic group. T allele was more prevalent in cirrhotic (54%) than the normal group (40%)
Conclusion
Although IL-28B SNP had a role in HCV-related cirrhosis progression, it did not predict the probability for HCC development following DAAs.
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20
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A Lay-User Assessment of Hepatitis C Virus Self-Testing Device Usability and Interpretation in Johannesburg, South Africa. Diagnostics (Basel) 2021; 11:diagnostics11030463. [PMID: 33800060 PMCID: PMC8000311 DOI: 10.3390/diagnostics11030463] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 03/03/2021] [Accepted: 03/05/2021] [Indexed: 01/14/2023] Open
Abstract
Only 20% of people with hepatitis C virus (HCV) know their status. In low-income countries diagnosis is under 10%. Self-testing for HCV antibodies (HCVST) could expand the coverage of HCV testing services. Currently, there are no stringent regulatory authority (SRA) approved HCVSTs, therefore lay-user usability of three prototype kits was assessed. This was a cross-sectional observational study conducted with 171 (CareStart n = 60, Bioline n = 52, First Response n = 59) participants. Participants were given one of the three HCVST kits with only instructions for use (IFU) and asked to perform the test in front of a professional trained in rapid diagnostic tests (RDT). Usability indices were calculated based on the correctness of performing each step of the product-specific process followed by contrived results interpretation and a post-test interview. The usability index was 93.9% for CareStart, 90.7% for Bioline and 94.9% for First Response. Most errors were on incorrect handwashing, sample collection and transfer to the test device. An average of 93.1% of contrived results were correctly interpreted, with most errors related to interpreting invalid results. Most participants (n = 167) stated they would visit a clinic after a positive result. With negative results, nearly half (28/60 (46.7%)) stated they should condomize, while just over two-thirds of participants that used Bioline (35/52 (67.3%)) and First Response (38/59 (64.4%)) said they should re-test. Most participants (n = 162) found the devices easy to use. Participants liked that self-testing was fast, private and convenient, however there were some confusion with IFU steps and pictures, finger-pricking with the lancet, collecting blood after the finger-prick, and transferring the sample/buffer. Prototype HCVST kits exhibit high usability and result interpretation by lay-users, and should be considered for SRA approval.
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21
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Ma Y, Frutos-Beltrán E, Kang D, Pannecouque C, De Clercq E, Menéndez-Arias L, Liu X, Zhan P. Medicinal chemistry strategies for discovering antivirals effective against drug-resistant viruses. Chem Soc Rev 2021; 50:4514-4540. [PMID: 33595031 DOI: 10.1039/d0cs01084g] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
During the last forty years we have witnessed impressive advances in the field of antiviral drug discovery culminating with the introduction of therapies able to stop human immunodeficiency virus (HIV) replication, or cure hepatitis C virus infections in people suffering from liver disease. However, there are important viral diseases without effective treatments, and the emergence of drug resistance threatens the efficacy of successful therapies used today. In this review, we discuss strategies to discover antiviral compounds specifically designed to combat drug resistance. Currently, efforts in this field are focused on targeted proteins (e.g. multi-target drug design strategies), but also on drug conformation (either improving drug positioning in the binding pocket or introducing conformational constraints), in the introduction or exploitation of new binding sites, or in strengthening interaction forces through the introduction of multiple hydrogen bonds, covalent binding, halogen bonds, additional van der Waals forces or multivalent binding. Among the new developments, proteolysis targeting chimeras (PROTACs) have emerged as a valid approach taking advantage of intracellular mechanisms involving protein degradation by the ubiquitin-proteasome system. Finally, several molecules targeting host factors (e.g. human dihydroorotate dehydrogenase and DEAD-box polypeptide 3) have been identified as broad-spectrum antiviral compounds. Implementation of herein described medicinal chemistry strategies are expected to contribute to the discovery of new drugs effective against current and future threats due to emerging and re-emerging viral pandemics.
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Affiliation(s)
- Yue Ma
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012, Shandong Province, P. R. China.
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22
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Kakizoe Y, Koizumi Y, Ikoma Y, Ohashi H, Wakita T, Iwami S, Watashi K. Required concentration index quantifies effective drug combinations against hepatitis C virus infection. Theor Biol Med Model 2021; 18:4. [PMID: 33422060 PMCID: PMC7796629 DOI: 10.1186/s12976-020-00135-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 12/10/2020] [Indexed: 01/27/2023] Open
Abstract
Successful clinical drug development requires rational design of combination treatments based on preclinical data. Anti-hepatitis C virus (HCV) drugs exhibit significant diversity in antiviral effect. Dose-response assessments can be used to determine parameters profiling the diverse antiviral effect during combination treatment. In the current study, a combined experimental and mathematical approaches were used to compare and score different combinations of anti-HCV treatments. A “required concentration index” was generated and used to rank the antiviral profile of possible double- and triple-drug combinations against HCV genotype 1b and 2a. Rankings varied based on target HCV genotype. Interestingly, multidrug (double and triple) treatment not only augmented antiviral activity, but also reduced genotype-specific efficacy, suggesting another advantage of multidrug treatment. The current study provides a quantitative method for profiling drug combinations against viral genotypes, to better inform clinical drug development.
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Affiliation(s)
- Yusuke Kakizoe
- Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka, 812-8581, Japan.,Present address: Data Science Group, Advanced Technology Division, INTAGE Inc, Tokyo, 101-8201, Japan
| | - Yoshiki Koizumi
- National Center for Global Health and Medicine, Tokyo, 162-8655, Japan
| | - Yukino Ikoma
- Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka, 812-8581, Japan
| | - Hirofumi Ohashi
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, 162-8640, Japan.,Department of Applied Biological Science, Tokyo University of Science, Noda, 278-8510, Japan
| | - Takaji Wakita
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, 162-8640, Japan
| | - Shingo Iwami
- Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka, 812-8581, Japan. .,Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto, 606-8501, Japan. .,NEXT-Ganken Program, Japanese Foundation for Cancer Research (JFCR), Tokyo, 135-8550, Japan. .,Science Groove Inc, Fukuoka, Japan.
| | - Koichi Watashi
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, 162-8640, Japan. .,Department of Applied Biological Science, Tokyo University of Science, Noda, 278-8510, Japan. .,Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto, 606-8501, Japan. .,NEXT-Ganken Program, Japanese Foundation for Cancer Research (JFCR), Tokyo, 135-8550, Japan. .,Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.
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23
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Kochneva GV, Kartashov MY, Krivosheina EI, Kuznetsov AI, Chub EV, Sivolobova GF, Netesov SV. On the Possibility of Eradicating Hepatitis C in Russia. MOLECULAR GENETICS, MICROBIOLOGY AND VIROLOGY 2021; 36:27-38. [DOI: 10.3103/s0891416821010043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 10/05/2020] [Accepted: 10/11/2020] [Indexed: 01/05/2025]
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24
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Ogawa E, Toyoda H, Iio E, Jun DW, Huang CF, Enomoto M, Hsu YC, Haga H, Iwane S, Wong G, Lee DH, Tada T, Liu CH, Chuang WL, Hayashi J, Cheung R, Yasuda S, Tseng CH, Takahashi H, Tran S, Yeo YH, Henry L, Barnett SD, Nomura H, Nakamuta M, Dai CY, Huang JF, Yang HI, Lee MH, Jun MJ, Kao JH, Eguchi Y, Ueno Y, Tamori A, Furusyo N, Yu ML, Tanaka Y, Nguyen MH. Hepatitis C Virus Cure Rates Are Reduced in Patients With Active but Not Inactive Hepatocellular Carcinoma: A Practice Implication. Clin Infect Dis 2020; 71:2840-2848. [PMID: 31777940 DOI: 10.1093/cid/ciz1160] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 11/27/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Cure rates of hepatitis C virus (HCV) treatment with direct-acting antivirals (DAAs) for patients with active and inactive hepatocellular carcinoma (HCC) may differ, but well-controlled studies are limited. We aimed to evaluate DAA outcomes in a large East Asian HCV/HCC population compared with HCV/non-HCC patients. METHODS Using data from the Real-World Evidence from the Asia Liver Consortium (REAL-C) registry (Hong Kong, Japan, South Korea, and Taiwan), we used propensity score matching (PSM) to match HCC and non-HCC (1:1) groups for age, sex, cirrhosis, prior treatment, HCV genotype, treatment regimen, baseline platelet count, HCV RNA, total bilirubin, alanine aminotransferase, and albumin levels to evaluate DAA treatment outcomes in a large population of HCV/HCC compared with HCV/non-HCC patients. RESULTS We included 6081 patients (HCC, n = 465; non-HCC, n = 5 616) treated with interferon-free DAAs. PSM of the entire study population yielded 436 matched pairs with similar baseline characteristics. There was no statistically significant difference in the overall SVR rate of HCC (92.7%) and non-HCC (95.0%) groups. Rates of treatment discontinuation, adverse effects, and death were also similar between HCC and non-HCC groups. Among patients with HCC, those with active HCC had a lower SVR than inactive HCC cases (85.5% vs 93.7%; P = .03). On multivariable analysis, active HCC, but not inactive HCC, was significantly associated with lower SVR (OR, 0.28; P = .01) when compared with non-HCC. CONCLUSIONS Active HCC but not inactive HCC was independently associated with lower SVR compared with non-HCC patients undergoing DAA therapy, although cure rate was still relatively high (85%) in active HCC patients.
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Affiliation(s)
- Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Etsuko Iio
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Dae Won Jun
- Department of Gastroenterology, Hanyang University, Seoul, South Korea
| | - Chung-Feng Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Masaru Enomoto
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yao-Chun Hsu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan
| | - Hiroaki Haga
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Shinji Iwane
- Liver Center, Saga University Hospital, Saga, Japan
| | - Grace Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - Dong Hyun Lee
- Department of Gastroenterology, Good Gang-An Hospital, Busan, Korea
| | - Toshifumi Tada
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Chen-Hua Liu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jun Hayashi
- Kyushu General Internal Medicine Center, Haradoi Hospital, Fukuoka, Japan
| | - Ramsey Cheung
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, California, USA
- Division of Gastroenterology and Hepatology, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA
| | - Satoshi Yasuda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Cheng-Hao Tseng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan
| | - Hirokazu Takahashi
- Liver Center, Saga University Hospital, Saga, Japan
- Division of Metabolism and Endocrinology, Saga University Faculty of Medicine, Saga, Japan
| | - Sally Tran
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, California, USA
| | - Yee Hui Yeo
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, California, USA
| | - Linda Henry
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, California, USA
| | - Scott D Barnett
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, California, USA
| | - Hideyuki Nomura
- The Center for Liver Disease, Shin-Kokura Hospital, Kitakyushu, Japan
| | - Makoto Nakamuta
- Department of Gastroenterology, Kyushu Medical Center, National Hospital Organization, Fukuoka, Japan
| | - Chia-Yen Dai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hwai-I Yang
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Mei-Hsuan Lee
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Mi Jung Jun
- Department of Gastroenterology, Good Gang-An Hospital, Busan, Korea
| | - Jia-Horng Kao
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | | | - Yoshiyuki Ueno
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Akihiro Tamori
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Norihiro Furusyo
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, California, USA
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Xiao L, Wu X, Zhang F, Wang J, Xu X, Li L. Changes of inflammatory cytokines/chemokines during ravidasvir plus ritonavir-boosted danoprevir and ribavirin therapy for patients with genotype 1b hepatitis C infection. J Med Virol 2020; 92:3516-3524. [PMID: 32525562 DOI: 10.1002/jmv.26161] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 05/05/2020] [Accepted: 06/07/2020] [Indexed: 01/02/2023]
Abstract
This study investigated the safety and efficacy of ravidasvir (RDV) plus ritonavir-boosted danoprevir (DNVr) and ribavirin (RBV) regimens for treatment-naïve non-cirrhotic patients with hepatitis C virus (HCV) genotype 1b in mainland China. We also gained insight into HCV-host interactions during anti-HCV treatment. 16 patients with HCV and 10 healthy people enrolled the study. Three of 16 patients received 12-weeks' placebo treatment first and served as the placebo controls. All (n = 16) patients received 12-weeks' RDV plus DNVr and RBV treatment. The adverse effects (AEs), viral loads, alanine transaminase, and aspartate aminotransferase were recorded during study. We also performed multianalyte profiling of 48 cytokines/chemokines in 16 patients with HCV and 10 normal controls. Seventy-five percent patients treated with RDV plus DNVr and RBV experienced AEs. No death, treatment-related serious AEs or AEs leading to discontinuation were reported. The serum HCV-RNA levels remained extremely high in 3 placebo controls after treated with placebo. After RDV plus DNVr and RBV treatment, all patients achieved sustained virologic response (SVR) at posttreatment week 12, but 1 patient experienced viral relapse at SVR 24. The cytokine/chemokine expression pattern was markedly altered in patients with HCV as compared with healthy controls. The interferon-inducible protein-10 (IP-10) decreased after anti-HCV treatment, and dramatically increased in one patient with viral relapse. The regimen of RDV and DNVr plus RBV represents a highly safe and effective treatment option for HCV patients in mainland China. The IP-10 has the potential to be an indicator of innate immune viral recognition.
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Affiliation(s)
- Lanlan Xiao
- Infections Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaoxin Wu
- Infections Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Fen Zhang
- Infections Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jie Wang
- Infections Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaowei Xu
- Infections Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lanjuan Li
- Infections Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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26
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Chan PPY, Levy MT, Shackel N, Davison SA, Prakoso E. Hepatocellular carcinoma incidence post direct-acting antivirals in hepatitis C-related advanced fibrosis/cirrhosis patients in Australia. Hepatobiliary Pancreat Dis Int 2020; 19:541-546. [PMID: 32660841 DOI: 10.1016/j.hbpd.2020.06.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 06/22/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Despite efficacy in HCV eradication, direct-acting antiviral (DAA) therapy has raised controversies around their impact on hepatocellular carcinoma (HCC) incidence. Herein we reported the first Australian data on HCC incidence in DAA-treated HCV patients with advanced fibrosis/cirrhosis. METHODS We conducted a retrospective single center study of DAA-treated HCV patients with advanced fibrosis/cirrhosis from April 2015 to December 2017. Patients with prior HCC were included if they had complete response to HCC treatment. RESULTS Among 138 patients who completed DAA therapy, 133 (96.4%) achieved sustained virologic response (median follow-up 23.8 months). Ten had prior HCC and 5/10 (50.0%) developed recurrence, while de novo HCC developed in 7/128 (5.5%). Median time from DAA to HCC diagnosis was 34 weeks in recurrent HCC vs. de novo 52 weeks (P = 0.159). In patients with prior HCC, those with recurrence (vs. without) had shorter median time between last HCC treatment and DAA (12 vs. 164 weeks, P < 0.001). On bivariate analysis, failed sustained virologic response at 12 weeks (SVR12) (P = 0.011), platelets (P = 0.005), model for end-stage liver disease (MELD) score (P = 0.029), alpha fetoprotein (AFP) (P = 0.013), and prior HCC (P < 0.001) were associated with HCC post-DAA. On multivariate analysis, significant factors were prior HCC (OR = 4.80; 95% CI: 1.47-48.50; P = 0.010), failed SVR12 (OR = 2.83; 95% CI: 1.71-16.30; P = 0.016) and platelets (OR = 0.97; 95% CI: 0.95-0.99; P = 0.009). CONCLUSIONS Our study demonstrates a high incidence of recurrent HCC in HCV patients with advanced fibrosis/cirrhosis treated with DAA. Factors associated with HCC development post-DAA were more advanced liver disease, failed SVR12 and prior HCC, with higher rates of recurrence in those who started DAA earlier.
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Affiliation(s)
- Patrick P Y Chan
- Department of Gastroenterology and Hepatology, Liverpool Hospital, Elizabeth Street, Liverpool, NSW 2170, Australia; South Western Clinical School, University of New South Wales, Liverpool, NSW 2170, Australia
| | - Miriam T Levy
- Department of Gastroenterology and Hepatology, Liverpool Hospital, Elizabeth Street, Liverpool, NSW 2170, Australia; South Western Clinical School, University of New South Wales, Liverpool, NSW 2170, Australia
| | - Nicholas Shackel
- Department of Gastroenterology and Hepatology, Liverpool Hospital, Elizabeth Street, Liverpool, NSW 2170, Australia; South Western Clinical School, University of New South Wales, Liverpool, NSW 2170, Australia
| | - Scott A Davison
- Department of Gastroenterology and Hepatology, Liverpool Hospital, Elizabeth Street, Liverpool, NSW 2170, Australia; South Western Clinical School, University of New South Wales, Liverpool, NSW 2170, Australia
| | - Emilia Prakoso
- Department of Gastroenterology and Hepatology, Liverpool Hospital, Elizabeth Street, Liverpool, NSW 2170, Australia; Central Clinical School - The Faculty of Medicine and Health, University of Sydney, NSW 2050, Australia.
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27
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Javanbakht M, Archer R, Klausner J. Will prior health insurance authorization for medications continue to hinder hepatitis C treatment delivery in the United States? Perspectives from hepatitis C treatment providers in a large urban healthcare system. PLoS One 2020; 15:e0241615. [PMID: 33147293 PMCID: PMC7641373 DOI: 10.1371/journal.pone.0241615] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 10/16/2020] [Indexed: 12/13/2022] Open
Abstract
Background The recent introduction of direct acting antivirals for the treatment of hepatitis C virus (HCV) has dramatically improved treatment options for HCV infected patients. However, in the United States (US) treatment uptake has been low and time to initiation of therapy has been long. We sought to examine provider perspectives of facilitators and barriers to HCV treatment delivery. Methods From June to August 2019, we conducted in-depth, semi-structured interviews with medical staff providing HCV care as part of a university medical center in Los Angeles, CA. In order to understand the HCV treatment process, we interviewed key staff members providing care to the majority of HCV patients seeking care at the university medical center, including hepatologists and infectious disease specialists as well as key nursing and pharmacy staff. The interviews focused on workload and activities required for HCV treatment initiation for non-cirrhotic, treatment naïve patients. Results Providers noted that successful HCV treatment delivery was reliant on a care model involving close collaboration between a team of providers, in particular requiring a highly coordinated effort between dedicated nursing and pharmacy staff. The HCV care team overwhelmingly reported that the process of insurance authorization was the greatest obstacle delaying treatment initiation and noted that very few patient level factors served as a barrier to treatment uptake. Conclusions In the US, prior authorization for HCV treatment is a requirement for most public and private insurance plans. In an era with access to therapies that allow for a cure—and until revocation of prior authorization for HCV treatment is a reality—implementing strategies that can expedite authorization to accelerate treatment access are critical. Not only will this benefit patients, but it has the potential to help expand treatment to settings that are otherwise too resource strained to successfully deliver HCV care.
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Affiliation(s)
- Marjan Javanbakht
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, California, United States of America
- * E-mail:
| | - Roxanne Archer
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, California, United States of America
| | - Jeffrey Klausner
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, California, United States of America
- Division of Infectious Diseases, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, California, United States of America
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Yao BB, Fredrick LM, Schnell G, Kowdley KV, Kwo PY, Poordad F, Nguyen K, Lee SS, George C, Wong F, Gane E, Abergel A, Spearman CW, Nguyen T, Hung Le M, Pham TTT, Mensa F, Asselah T. Efficacy and safety of glecaprevir/pibrentasvir in patients with HCV genotype 5/6: An integrated analysis of phase 2/3 studies. Liver Int 2020; 40:2385-2393. [PMID: 32445613 PMCID: PMC7539968 DOI: 10.1111/liv.14535] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 04/17/2020] [Accepted: 05/17/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS Hepatitis C virus (HCV) has high genetic diversity with six major genotypes (GT) GT1-6 and global distribution. HCV GT5 and 6 are rare with < 10 million people infected worldwide. Data on direct-acting antiviral use in these rare HCV genotypes are limited. The study aimed to evaluate the efficacy and safety of glecaprevir/pibrentasvir (G/P) in a pooled analysis of phase 2/3 trials in HCV GT5 or 6-infected patients without cirrhosis or with compensated cirrhosis. METHODS Patients with chronic HCV GT5 or 6 infection received oral G/P (300 mg/120 mg) once daily for 8 or 12 weeks. The primary efficacy endpoint was sustained virological response at post-treatment week 12 (SVR12) in the intention-to-treat population. RESULTS One hundred eighty-one patients were evaluated; 56 with HCV GT5 and 125 with HCV GT6. The majority were treatment-naïve (88%) and non-cirrhotic (85%). Overall SVR12 rate with 8- or 12-week G/P treatment was 98% (178/181). Eight-week treatment with G/P yielded SVR12 rates of 95% (21/22) in HCV GT5- and 99% (69/70) in HCV GT6-infected non-cirrhotic patients. Eight- and 12-week treatment of patients with compensated cirrhosis achieved SVR12 rates of 100% (10/10) and 94% (17/18) respectively. The G/P regimen was well-tolerated; 3% (6/181) Grade 3 or higher adverse events, and no serious adverse events were attributed to G/P or led to study drug discontinuation. CONCLUSIONS This integrated dataset demonstrates a high SVR12 rate following 8-week G/P treatment in patients with HCV GT5 (96%) or GT6 (99%) infection without cirrhosis or with compensated cirrhosis.
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Affiliation(s)
| | | | | | - Kris V. Kowdley
- Elson S. Floyd College of MedicineWashington State UniversitySpokaneWAUSA
| | - Paul Y. Kwo
- Stanford University School of MedicinePalo AltoCAUSA
| | - Fred Poordad
- The Texas Liver InstituteUniversity of Texas HealthSan AntonioTXUSA
| | - Kinh Nguyen
- National Hospital for Tropical DiseasesHanoiVietnam
| | | | | | - Florence Wong
- Toronto General HospitalUniversity of TorontoTorontoONCanada
| | - Edward Gane
- Auckland Clinical StudiesAucklandNew Zealand
| | - Armand Abergel
- Centre Hospitalier Universitaire EstaingClermont FerrandFrance
| | - Catherine W. Spearman
- Division of HepatologyDepartment of MedicineFaculty of Health SciencesUniversity of Cape Town and Groote Schuur HospitalCape TownSouth Africa
| | - Tuan Nguyen
- Alvarado Hospital Medical CenterSan DiegoCAUSA
| | - Manh Hung Le
- Hospital for Tropical DiseasesHo Chi MinhVietnam
| | | | | | - Tarik Asselah
- Department of HepatologyCentre de Recherche sur l’InflammationINSERM UMR 1149Université Paris DiderotAP‐HP Hôpital BeaujonClichyFrance
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Farouk F, Wahba D, Mogawer S, Elkholy S, Elmeligui A, Abdelghani R, Ibahim S. Development and Validation of a New LC-MS/MS Analytical Method for Direct-Acting Antivirals and Its Application in End-Stage Renal Disease Patients. Eur J Drug Metab Pharmacokinet 2020; 45:89-99. [PMID: 31667795 DOI: 10.1007/s13318-019-00584-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND OBJECTIVE The effectiveness of direct-acting antivirals (DAAs) is not well established in end-stage renal disease (ESRD) patients. Assessment of the plasma concentrations may support understanding of their therapeutic outcomes in this population. The aim of this study is to develop a direct, yet matrix-effect tolerant, analytical method for determining DAAs in the plasma of ESRD patients while maintaining a moderate cost per sample and with an improved analyte extraction recovery. METHODS In this study, a liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed for the analysis of ombitasvir (OMB), paritaprevir (PRT) and ritonavir (RIT) in plasma. Sample preparation was performed using the liquid-liquid extraction (LLE) method. Isocratic separation was performed using a mixture of methanol and 10 mM ammonium acetate (79:21, v/v) followed by MS/MS detection. The method was validated and applied to determine DAAs in the plasma of ESRD patients (n = 7). RESULTS The developed method was linear (r2 > 0.995), accurate (89.4 ± 7.8 to 108.3 ± 3.0) and precise (% CV 0.9-15.0) and showed improved recovery (> 80) over previously published ones in the range 5-250, 30-1,500, 20-1,000 ng/mL for OMB, PRT and RIT, respectively. Relative matrix effect was absent, and the method accurately determined the three DAAs in real-life samples (n = 7). CONCLUSIONS An efficient analytical method for the determination of DAAs is presented. The method overcomes the potential analytical response fluctuation in ESRD. The developed method show improved extraction recoveries and is suitable for routine application in developing economies where hepatitis C virus is most prevalent.
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Affiliation(s)
- Faten Farouk
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6th October City, Egypt.
| | - Dina Wahba
- National Organization of Drug Quality Control and Research, Giza, Egypt
| | - Sherif Mogawer
- Internal Medicine Department, Hepato-gastroenterology Unit, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Shaimaa Elkholy
- Internal Medicine Department, Hepato-gastroenterology Unit, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Ahmed Elmeligui
- Internal Medicine Department, Hepato-gastroenterology Unit, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Reham Abdelghani
- Internal Medicine Department, Nephrology Unit, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Salwa Ibahim
- Internal Medicine Department, Nephrology Unit, Faculty of Medicine, Cairo University, Giza, Egypt
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30
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Yang X, Ding T, Huang H, Xu Y, Yu J, Chen Z. Development and validation of a simple and rapid method for hepatitis C virus genotyping based on one-step RT-qPCR. Exp Ther Med 2020; 20:2284-2290. [PMID: 32765706 DOI: 10.3892/etm.2020.8912] [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: 08/08/2019] [Accepted: 01/22/2020] [Indexed: 11/06/2022] Open
Abstract
Hepatitis C virus (HCV) infections caused by different subtypes require different treatments; therefore, rapid and cost-effective genotyping methods for the diagnosis of HCV are greatly needed. In the present study, a new method to diagnose HCV subtypes that depends on a one-step quantitative reverse transcription PCR (RT-qPCR) and TaqMan fluorescence probe technique is described. Five pairs of primers and five probes were designed, which were able to detect five genotypes in three reaction tubes. One reaction was used to detect the 1b subtype, one was used to detect the 2a and 6a subtypes, and the other was used to detect the 3a and 3b subtypes. Rigorous performance validation was implemented for five aspects: Precision, sensitivity, accuracy, specificity and anti-interference. The HCV subtype that infected 289 patients was evaluated in the present study via RT-qPCR and verified by sequencing. The results revealed that the 1b subtype accounted for 45% of infections, the 2a subtype accounted for 9% of infections, the 3a subtype accounted for 13% of infections, the 3b subtype accounted for 18% of infections, and the 6a subtype accounted for 15% of infections. The analytical sensitivity for the detection of each of the five HCV subtypes was 1,000 IU/ml. The new method performed well in the performance validation mentioned above, indicating its effectiveness as a HCV genotyping method. RT-qPCR has mitigated some of the former challenges of existing HCV genotyping methods, including the time commitment, expense, and inaccuracy of such methods. The performance validation of this new method showed that RT-qPCR is reliable enough to be widely applied in China for HCV genotyping.
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Affiliation(s)
- Xinyun Yang
- Department of Laboratory Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.,The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Ting Ding
- Department of Laboratory Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.,The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Haifeng Huang
- Triplex International Biosciences (China) Co., Ltd., Xiamen, Fujian 361000, P.R. China
| | - Yang Xu
- Department of First Generation Sequencing, Hangzhou DiAn Medical Laboratory, Hangzhou, Zhejiang 310030, P.R. China
| | - Jian Yu
- Department of Laboratory Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Zhanguo Chen
- Department of Laboratory Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
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31
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Musa NI, Mohamed IE, Abohalima AS. Impact of treating chronic hepatitis C infection with direct-acting antivirals on the risk of hepatocellular carcinoma recurrence. EGYPTIAN LIVER JOURNAL 2020. [DOI: 10.1186/s43066-020-00035-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Abstract
Background
The impact of direct-acting antivirals (DAAs) remains a debate, whether they accelerate the recurrence rate of hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) after curative therapy. We evaluated the impact of direct-acting antiviral therapy on the rate of recurrence of HCV-related hepatocellular carcinoma following intervention in Egyptian patients.
Results
The results of the study represented an HCC recurrence rate of 38% in patients who received direct-acting antiviral therapy after HCC intervention versus 62% in those who did not receive antiviral therapy. In group I, according to the Barcelona Clinic of Liver Cancer (BCLC) staging, a higher recurrence rate was observed (57.9%) among patients who were classified as BCLC stage B.
Conclusions
HCC patients who did not receive direct-acting antiviral therapy after HCC intervention had a greater risk of HCC recurrence. DAAs did not increase the risk of HCC recurrence following HCC treatment; however, it did not abolish it. Close monitoring of patients after antiviral therapy is recommended.
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Donnison T, von Delft A, Brown A, Swadling L, Hutchings C, Hanke T, Chinnakannan S, Barnes E. Viral vectored hepatitis C virus vaccines generate pan-genotypic T cell responses to conserved subdominant epitopes. Vaccine 2020; 38:5036-5048. [PMID: 32532545 DOI: 10.1016/j.vaccine.2020.05.042] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2019] [Revised: 03/11/2020] [Accepted: 05/15/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Viral genetic variability presents a major challenge to the development of a prophylactic hepatitis C virus (HCV) vaccine. A promising HCV vaccine using chimpanzee adenoviral vectors (ChAd) encoding a genotype (gt) 1b non-structural protein (ChAd-Gt1b-NS) generated high magnitude T cell responses. However, these T cells showed reduced cross-recognition of dominant epitope variants and the vaccine has recently been shown to be ineffective at preventing chronic HCV. To address the challenge of viral diversity, we developed ChAd vaccines encoding HCV genomic sequences that are conserved between all major HCV genotypes and adjuvanted by truncated shark invariant chain (sIitr). METHODS Age-matched female mice were immunised intramuscularly with ChAd (108 infectious units) encoding gt-1 and -3 (ChAd-Gt1/3) or gt-1 to -6 (ChAd-Gt1-6) conserved segments spanning the HCV proteome, or gt-1b (ChAd-Gt1b-NS control), with immunogenicity assessed 14-days post-vaccination. RESULTS Conserved segment vaccines, ChAd-Gt1/3 and ChAd-Gt1-6, generated high-magnitude, broad, and functional CD4+ and CD8+ T cell responses. Compared to the ChAd-Gt1b-NS vaccine, these vaccines generated significantly greater responses against conserved non-gt-1 antigens, including conserved subdominant epitopes that were not targeted by ChAd-Gt1b-NS. Epitopes targeted by the conserved segment HCV vaccine induced T cells, displayed 96.6% mean sequence homology between all HCV subtypes (100% sequence homology for the majority of genotype-1, -2, -4 sequences and 94% sequence homology for gt-3, -6, -7, and -8) in contrast to 85.1% mean sequence homology for epitopes targeted by ChAd-Gt1b-NS induced T cells. The addition of truncated shark invariant chain (sIitr) increased the magnitude, breadth, and cross-reactivity of the T cell response. CONCLUSIONS We have demonstrated that genetically adjuvanted ChAd vectored HCV T cell vaccines encoding genetic sequences conserved between genotypes are immunogenic, activating T cells that target subdominant conserved HCV epitopes. These pre-clinical studies support the use of conserved segment HCV T cell vaccines in human clinical trials.
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Affiliation(s)
- Timothy Donnison
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, OX1 3SY, United Kingdom
| | - Annette von Delft
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, OX1 3SY, United Kingdom
| | - Anthony Brown
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, OX1 3SY, United Kingdom
| | - Leo Swadling
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, OX1 3SY, United Kingdom
| | - Claire Hutchings
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, OX1 3SY, United Kingdom
| | - Tomáš Hanke
- Jenner Institute, Nuffield Department of Medicine, University of Oxford, OX3 7DQ, United Kingdom; Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan
| | - Senthil Chinnakannan
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, OX1 3SY, United Kingdom
| | - Eleanor Barnes
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, OX1 3SY, United Kingdom; Jenner Institute, Nuffield Department of Medicine, University of Oxford, OX3 7DQ, United Kingdom.
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Zied HY, Abo Alnasr NM, El-Bendary AS, Abd-Elsalam S, Hagag RY. Effect of treatment with direct antiviral agents (DAAs) on glycemic control in patients with type 2 diabetes mellitus & hepatitis C virus genotype 4. Diabetes Metab Syndr 2020; 14:679-682. [PMID: 32438332 DOI: 10.1016/j.dsx.2020.05.024] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 05/09/2020] [Accepted: 05/10/2020] [Indexed: 01/13/2023]
Abstract
BACKGROUND AND AIMS It is widely recognized that chronic hepatitis C is a metabolic disease that is strongly associated with type 2 diabetes mellitus (T2DM) and insulin resistance (IR). The evidence behind the effect of Direct Anti-Viral Agents (DAAs) therapy on T2DM is conflicting. The aim of the present study was to evaluate the effect of treatment with DAAs on glycemic control in patients with type-2 diabetes mellitus and chronic hepatitis C virus genotype 4. METHODS This study was a prospective study that conducted on 100 patients with chronic hepatitis C and Type-2 diabetes mellitus, selected from Kafr El-Sheikh Liver Research Center treated with Direct Anti-Viral Agents (DAAs) during the period from September 1, 2017 to last of August 2018. All patients in the study were subjected to the following: Full history taking stressing on the age, gender, previous treatment; clinical examination and laboratory investigations. HBA1C was assessed before and after DAAs treatment. RESULTS In the present study, there was a significant decrease of baseline fasting blood glucose levels after treatment when compared with before treatment. Also, there was a significant decrease of 2 h post prandial blood glucose after treatment when compared with before treatment. There was significant decrease of HBA1c levels after treatment when compared with before treatment. CONCLUSIONS DAAs treatment significantly improved the fasting blood glucose and help better glycemic control. This study augments the importance and the benefits of new Direct Anti-Viral Agents interferon free regimens in diabetic HCV infected patients.
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34
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Chen YY, Chen CL, Chen JW, Hsu NT, Wei ST, Hou SM, Lu SN, Chen PJ. Secular Trends and Geographic Maps of Hepatitis C Virus Infection among 4 Million Blood Donors in Taiwan from 1999 to 2017. Hepatol Commun 2020; 4:1193-1205. [PMID: 32766478 PMCID: PMC7395065 DOI: 10.1002/hep4.1531] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 04/08/2020] [Accepted: 04/23/2020] [Indexed: 12/27/2022] Open
Abstract
The prevalence of hepatitis C virus (HCV) infection in Taiwan was approximately 4% a decade ago, much higher than the worldwide average. This study aimed to assess the HCV burden among 4 million voluntary blood donors after 2 decades of prevention and treatment policies. We retrieved screening results for anti‐HCV and HCV RNA from the Database for Evaluating Voluntary Taiwanese Eligible Donors. First‐time blood donors who donated blood after 1999 and repeat donors who donated blood more than once between 2013 and 2017 were included to estimate HCV prevalence and incidence, respectively. The Cox proportional hazards model was used to estimate hazard ratios. Geographic variation in HCV prevalence and incidence in 364 townships was also analyzed. The prevalence study included 3,656,598 first‐time donors. The overall crude prevalence of anti‐HCV decreased from 15.5 to 4.5 per 1,000 donors between 1999 and 2017. Younger birth cohorts had a significantly lower prevalence of anti‐HCV. The majority of townships (64.3%) in Taiwan showed a significantly decreased prevalence. The incidence study included 1,393,014 repeat donors followed for 3,436,607 person‐years. Ninety‐eight donors seroconverted to HCV RNA positivity, resulting in an HCV incidence of 2.9 per 100,000 person‐years. Donors living in townships where HCV RNA prevalence was greater than 2 per 1,000 had at least 2.5‐fold greater risk of new HCV infection. Conclusion: HCV prevalence in Taiwanese first‐time blood donors decreased by 71% in the last 2 decades. However, townships with higher HCV prevalence also showed higher HCV incidence and require more active intervention.
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Affiliation(s)
- Yun-Yuan Chen
- Head Office Taiwan Blood Services Foundation Taipei Taiwan
| | - Chi-Ling Chen
- Graduate Institute of Clinical Medicine College of Medicine National Taiwan University Taipei Taiwan.,Institute of Epidemiology and Preventive Medicine College of Public Health National Taiwan University Taipei Taiwan
| | - Jen-Wei Chen
- Head Office Taiwan Blood Services Foundation Taipei Taiwan
| | - Nien-Tzu Hsu
- Division of Hepatogastroenterology Department of Internal Medicine Kaohsiung Chang Gung Memorial Hospital Kaohsiung Taiwan.,Biostatistics Center, Kaohsiung Chang Gung Memorial Hospital Kaohsiung Taiwan
| | - Sheng-Tang Wei
- Head Office Taiwan Blood Services Foundation Taipei Taiwan
| | - Sheng-Mou Hou
- Head Office Taiwan Blood Services Foundation Taipei Taiwan.,Shin Kong Wu Ho-Su Memorial Hospital Taipei Taiwan
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology Department of Internal Medicine Kaohsiung Chang Gung Memorial Hospital Kaohsiung Taiwan.,Graduate Institute of Clinical Medical Sciences College of Medicine Chang Gung University Taoyuan Taiwan.,Division of Hepatogastroenterology Department of Internal Medicine Chiayi Chang Gung Memorial Hospital Chiayi Taiwan
| | - Pei-Jer Chen
- Graduate Institute of Clinical Medicine College of Medicine National Taiwan University Taipei Taiwan.,Department of Internal Medicine National Taiwan University Hospital Taipei Taiwan.,Hepatitis Research Center National Taiwan University Hospital Taipei Taiwan
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Gordon CJ, Tchesnokov EP, Woolner E, Perry JK, Feng JY, Porter DP, Götte M. Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency. J Biol Chem 2020; 295:6785-6797. [PMID: 32284326 PMCID: PMC7242698 DOI: 10.1074/jbc.ra120.013679] [Citation(s) in RCA: 700] [Impact Index Per Article: 140.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 04/09/2020] [Indexed: 12/15/2022] Open
Abstract
Effective treatments for coronavirus disease 2019 (COVID-19) are urgently needed to control this current pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Replication of SARS-CoV-2 depends on the viral RNA-dependent RNA polymerase (RdRp), which is the likely target of the investigational nucleotide analogue remdesivir (RDV). RDV shows broad-spectrum antiviral activity against RNA viruses, and previous studies with RdRps from Ebola virus and Middle East respiratory syndrome coronavirus (MERS-CoV) have revealed that delayed chain termination is RDV's plausible mechanism of action. Here, we expressed and purified active SARS-CoV-2 RdRp composed of the nonstructural proteins nsp8 and nsp12. Enzyme kinetics indicated that this RdRp efficiently incorporates the active triphosphate form of RDV (RDV-TP) into RNA. Incorporation of RDV-TP at position i caused termination of RNA synthesis at position i+3. We obtained almost identical results with SARS-CoV, MERS-CoV, and SARS-CoV-2 RdRps. A unique property of RDV-TP is its high selectivity over incorporation of its natural nucleotide counterpart ATP. In this regard, the triphosphate forms of 2′-C-methylated compounds, including sofosbuvir, approved for the management of hepatitis C virus infection, and the broad-acting antivirals favipiravir and ribavirin, exhibited significant deficits. Furthermore, we provide evidence for the target specificity of RDV, as RDV-TP was less efficiently incorporated by the distantly related Lassa virus RdRp, and termination of RNA synthesis was not observed. These results collectively provide a unifying, refined mechanism of RDV-mediated RNA synthesis inhibition in coronaviruses and define this nucleotide analogue as a direct-acting antiviral.
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Affiliation(s)
- Calvin J Gordon
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2R3, Canada
| | - Egor P Tchesnokov
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2R3, Canada
| | - Emma Woolner
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2R3, Canada
| | - Jason K Perry
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta T6G 2R3, Canada
| | - Joy Y Feng
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta T6G 2R3, Canada
| | - Danielle P Porter
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta T6G 2R3, Canada
| | - Matthias Götte
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2R3, Canada .,Gilead Sciences, Inc., Foster City, California 94404
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Buonomo AR, Scotto R, Coppola C, Pinchera B, Viceconte G, Rapillo CM, Staiano L, Saturnino M, Scarano F, Portunato F, Pisaturo M, De Pascalis S, Martini S, Tosone G, Nappa S, Coppola N, Gentile I. Direct acting antivirals treatment for hepatitis C virus infection does not increase the incidence of de novo hepatocellular carcinoma occurrence: Results from an Italian real-life cohort (LINA cohort). Medicine (Baltimore) 2020; 99:e18948. [PMID: 32028404 PMCID: PMC7015572 DOI: 10.1097/md.0000000000018948] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The effectiveness of direct-acting antivirals (DAAs) against hepatitis C virus (HCV) infection is ascertained. However, some authors raised the issue of an increased incidence of de novo hepatocellular carcinoma (HCC) in patients treated with DAAs. Aim of the study was to evaluate the rate of HCC occurrence in a real-life cohort of patients who received anti-HCV treatment with DAAs.A prospective multicentre study was conducted. All adult patients with HCV infection who received treatment between March 2015 and December 2017 in 4 hospital of Campania region (South Italy) with at least 6 months of follow-up were enrolled.A total of 323 patients were included in the study. Most patients had HCV genotype 1b (61.8%). The overall SVR12 rate was 95.5%. Median time of observation was 10 months. The incidence rate of HCC was 0.2 per 100 person-months (crude incidence rate 3.4%, 95 confidence interval: 1.5%-5.3%). The median time for HCC occurrence was 11 months. HCC occurrence rate was significantly higher among patients who did not achieve SVR12 compared with patients who did (28.6% vs 2.8%, P < 0.05). No patient with F0-F3 fibrosis developed HCC. Among patients with cirrhosis, at the multivariate time-to-event analysis, no covariates were independently associated with the risk of HCC occurrence.Treatment with DAAs did not increase the risk of HCC occurrence. Patients who achieved SVR12 had a lower rate of HCC occurrence. Further studies are needed to estimate the incidence and the risk for HCC in the long-term follow-up among patients undergoing treatment with DAAs.
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Affiliation(s)
- Antonio Riccardo Buonomo
- Department of Clinical Medicine and Surgery – Section of Infectious Diseases, University of Naples Federico II
| | - Riccardo Scotto
- Department of Clinical Medicine and Surgery – Section of Infectious Diseases, University of Naples Federico II
| | - Carmine Coppola
- Department of Internal Medicine - Unit of Hepatology and Interventional Ultrasonography. OORR Area Stabiese, Plesso Nuovo Gragnano, Naples
| | - Biagio Pinchera
- Department of Clinical Medicine and Surgery – Section of Infectious Diseases, University of Naples Federico II
| | - Giulio Viceconte
- Department of Clinical Medicine and Surgery – Section of Infectious Diseases, University of Naples Federico II
| | - Costanza Maria Rapillo
- Department of Clinical Medicine and Surgery – Section of Infectious Diseases, University of Naples Federico II
| | - Laura Staiano
- Department of Internal Medicine - Unit of Hepatology and Interventional Ultrasonography. OORR Area Stabiese, Plesso Nuovo Gragnano, Naples
| | - Mariarosaria Saturnino
- Department of Internal Medicine - Unit of Hepatology and Interventional Ultrasonography. OORR Area Stabiese, Plesso Nuovo Gragnano, Naples
| | - Ferdinando Scarano
- Department of Internal Medicine - Unit of Hepatology and Interventional Ultrasonography. OORR Area Stabiese, Plesso Nuovo Gragnano, Naples
| | - Federica Portunato
- Department of Mental Health and Public Medicine – Infectious Diseases Unit, University of Campania Luigi Vanvitelli, Caserta, Italy
| | - Mariantonietta Pisaturo
- Department of Mental Health and Public Medicine – Infectious Diseases Unit, University of Campania Luigi Vanvitelli, Caserta, Italy
| | - Stefania De Pascalis
- Department of Mental Health and Public Medicine – Infectious Diseases Unit, University of Campania Luigi Vanvitelli, Caserta, Italy
| | - Salvatore Martini
- Department of Mental Health and Public Medicine – Infectious Diseases Unit, University of Campania Luigi Vanvitelli, Caserta, Italy
| | - Grazia Tosone
- Department of Clinical Medicine and Surgery – Section of Infectious Diseases, University of Naples Federico II
| | - Salvatore Nappa
- Department of Clinical Medicine and Surgery – Section of Infectious Diseases, University of Naples Federico II
| | - Nicola Coppola
- Department of Mental Health and Public Medicine – Infectious Diseases Unit, University of Campania Luigi Vanvitelli, Caserta, Italy
| | - Ivan Gentile
- Department of Clinical Medicine and Surgery – Section of Infectious Diseases, University of Naples Federico II
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Zappulo E, Scotto R, Buonomo AR, Maraolo AE, Pinchera B, Gentile I. Efficacy and safety of a fixed dose combination tablet of asunaprevir + beclabuvir + daclatasvir for the treatment of Hepatitis C. Expert Opin Pharmacother 2020; 21:261-273. [PMID: 31914336 DOI: 10.1080/14656566.2019.1697674] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Introduction: Hepatitis C virus (HCV) is estimated to infect approximately 70 million people worldwide. If left untreated, chronic infection can progress to cirrhosis, liver failure or hepatocellular carcinoma. The advent of new direct-acting antivirals (DAA) has revolutionized patients' chances of treatment and viral elimination. Currently, several DAA options are available on the market.Areas covered: This review focuses on the pharmacokinetics, efficacy, tolerability and safety profile of DCV-TRIO, a twice-daily fixed-dose combination of daclatasvir, asunaprevir and beclabuvir approved in Japan for the treatment of genotype 1 HCV infection.Expert opinion: The DCV-TRIO combination achieved good response rates in genotype 1 patients (SVR12 ≥ 95% in naïve subtype 1b), independently from IL28B genotype, cirrhotic status and prior interferon exposure. On the other hand, unsatisfying response rates were reported in DAA-experienced patients and the risk of RAS selection should not be underestimated. Moreover, DCV-TRIO lacks differentiation from its earlier-launched DAA rivals, presents an inconvenient twice-daily dosing schedule and is not recommended in patients with advanced liver and kidney disease. All these drawbacks considerably limit its effective commercial potential. However, it can be a therapeutic option against HCV in tailored approaches according to the needs of different markets across the world.Abbreviations AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; ASV: asunaprevir; AUC: area under the curve; BCRP: Breast Cancer Resistance Protein; BCV: boceprevir; BID: bis in die; CI: confidence intervals; CLcr: creatinine clearance; DAA: direct acting antivirals; DCV: daclatasvir; EC50: Half maximal effective concentration; GT: genotype; HCV: Hepatitis C virus; IFN: Interferon; NHL: non-Hodgkin lymphoma; OATP: Organic anion transporting polypeptides; OR: odds ratio; P-gp: P-glycoprotein; PK: pharmacokinetics; QD: quo die; RAS: resistance-associated substitutions; SVR: sustained virological response; USD: Unites States dollar.
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Affiliation(s)
- Emanuela Zappulo
- Department of Clinical Medicine and Surgery, Section of Infectious Diseases, University of Naples Federico II, Naples, Italy
| | - Riccardo Scotto
- Department of Clinical Medicine and Surgery, Section of Infectious Diseases, University of Naples Federico II, Naples, Italy
| | - Antonio Riccardo Buonomo
- Department of Clinical Medicine and Surgery, Section of Infectious Diseases, University of Naples Federico II, Naples, Italy
| | - Alberto Enrico Maraolo
- Department of Clinical Medicine and Surgery, Section of Infectious Diseases, University of Naples Federico II, Naples, Italy
| | - Biagio Pinchera
- Department of Clinical Medicine and Surgery, Section of Infectious Diseases, University of Naples Federico II, Naples, Italy
| | - Ivan Gentile
- Department of Clinical Medicine and Surgery, Section of Infectious Diseases, University of Naples Federico II, Naples, Italy
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Systematic Review with Meta-Analysis: Efficacy and Safety of Direct-Acting Antivirals for Chronic Hepatitis C Genotypes 5 and 6. BIOMED RESEARCH INTERNATIONAL 2019; 2019:2301291. [PMID: 31815126 PMCID: PMC6877942 DOI: 10.1155/2019/2301291] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 08/14/2019] [Accepted: 09/20/2019] [Indexed: 02/07/2023]
Abstract
Direct-acting antivirals (DAAs) are modern treatments for chronic hepatitis C infection, but majority of available evidence on its treatment effect covers genotypes 1 to 4. Therefore, the efficacy and safety of DAAs for genotypes 5 and 6 need to be analysed. Studies were identified from Medline, Scopus, and CENTRAL and a Chinese database CNKI, from inception until Dec 4, 2018. Clinical trials were included if they enrolled patients with genotypes 5 and/or 6 infection, any type of second-generation DAAs was studied, and sustained virological response was assessed at the 12th week after treatment (SVR12) as outcome measure. Meta-analysis using metaprop statistical program was applied for pooling proportions if data were sufficient (i.e., at least 2 studies). Thirteen studies were included in the analysis. Four studies assessed the efficacy of four DAA regimens in genotype 5 patients, which were mainly sofosbuvir (SOF) plus pegylated-interferon/ribavirin (PR) or other DAAs, with SVR12 ranging from 94.4% to 100%. Twelve studies assessed the efficacy of seven DAA regimens among genotype 6 patients, but only two DAA regimens (i.e., SOF + PR and SOF/ledipasvir) had sufficient data for pooling. The pooled SVR12 rates (95% CI) were 99.6% (92.2 to 100) for SOF + PR and 99.2% (96.5 to 100) for SOF/ledipasvir. No treatment-related serious adverse event was reported, while the nonserious adverse events were comparable to other genotypes. In conclusion, DAAs are effective and may be safe for the treatment of chronic hepatitis C genotypes 5 and 6. However, our evidence is based on noncomparative studies; hence, further larger-scale randomized controlled trials in these genotypes are still required.
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La saga du virus de l’hépatite C, 1989–2019 : de la découverte d’un nouvel agent pathogène vers l’éradication d’une maladie virale chronique à multiples facettes. Rev Med Interne 2019; 40:567-569. [DOI: 10.1016/j.revmed.2018.12.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 12/16/2018] [Indexed: 01/06/2023]
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Arora SS, Axley P, Ahmed Z, Satapathy SK, Wong R, Kuo YF, Singal AK. Decreasing frequency and improved outcomes of hepatitis C-related liver transplantation in the era of direct-acting antivirals - a retrospective cohort study. Transpl Int 2019; 32:854-864. [PMID: 30866110 DOI: 10.1111/tri.13424] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 11/16/2018] [Accepted: 03/08/2019] [Indexed: 12/12/2022]
Abstract
Benefit of direct-acting antivirals (DAA) for hepatitis C virus (HCV) on clinical outcomes is unclear. We examined temporal trends in liver transplant (LT) listings, receipt of LT, re-LT, and survival between pre-DAA (2009-2012) and DAA era (2013-2016) using UNOS database. Of 32 319 first adult LT, 15 049 (47%) were performed for HCV. Trends on listing, first LT, and of re-LT for HCV showed 23%, 20%, and 21% decrease in DAA compared to pre-DAA era (P < 0.0001). One-year liver graft and patient survival among HCV LT improved in DAA era (90% vs. 86% and 92% vs. 88%, respectively, P < 0.0001). Non-HCV LT showed no improvement in survival (89% vs. 89% and 92% vs. 92.4%, P = NS). On cox regression, compared to non-HCV LTs in DAA era, LT for HCV in pre-DAA era had worse patient survival (HR 1.56 [1.04-2.35]). The outcome was similar when compared to LTs for HCV in DAA era and for non-HCV in pre-DAA era. Burden of HCV-related LT waitlist and LT is declining in DAA era, with improved post-transplant outcomes, more so in later than earlier DAA era. Our findings negate recent Cochrane meta-analysis on DAA therapy and encourage studies to examine HCV clinical outcomes outside LT setting.
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Affiliation(s)
- Sumant S Arora
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Iowa Hospital & Clinics, Iowa City, IA, USA
| | - Page Axley
- Department of Internal Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Zunirah Ahmed
- Department of Internal Medicine, University of Alabama at Birmingham - Montgomery Regional Campus, Birmingham, AL, USA
| | - Sanjaya K Satapathy
- Division of Transplant Hepatology, University of Tennessee Health Sciences Center, Memphis, TN, USA
| | - Robert Wong
- Division of Gastroenterology and Hepatology, Alameda Health System, Highland Hospital, Oakland, CA, USA
| | - Young-Fang Kuo
- Department of Biostatistics, University of Texas Medical Branch, Galveston, TX, USA
| | - Ashwani K Singal
- Sanford School of Medicine and Avera Transplant Institute, University of South Dakota, Sioux Falls, SD, USA
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Xiao J, Wang F, Wong NK, He J, Zhang R, Sun R, Xu Y, Liu Y, Li W, Koike K, He W, You H, Miao Y, Liu X, Meng M, Gao B, Wang H, Li C. Global liver disease burdens and research trends: Analysis from a Chinese perspective. J Hepatol 2019; 71:212-221. [PMID: 30871980 DOI: 10.1016/j.jhep.2019.03.004] [Citation(s) in RCA: 373] [Impact Index Per Article: 62.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2018] [Revised: 02/14/2019] [Accepted: 03/03/2019] [Indexed: 02/05/2023]
Abstract
Liver diseases affect millions of people worldwide. In most developed countries, the incidence of viral hepatitis is waning as a result of modern advances in disease prevention, diagnosis, and therapies. Expanded programmes for systematic immunisation against hepatitis B virus have also significantly brought down the number of new cases in many countries, including China. In contrast, with the improvement in living standards, the prevalence of metabolic liver diseases including non-alcoholic fatty liver disease and alcohol-related liver disease is set to rise, ultimately leading to more cases of end-stage liver diseases (liver failure, cirrhosis, and liver cancer). Over the past 30 years, visionary governments of major nations have provided strong incentives for basic/clinical research, vaccination programmes, and drug discovery and development in the field of hepatology. To get rid of her unflattering title as the "leader in liver diseases", China has also made a serious effort to initiate nationwide preventive measures for liver diseases, global partnerships, and mentoring programmes for young hepatologists. Instrumental to such progress is the continuous support of the National Natural Science Foundation of China (NSFC), which has helped hepatology to thrive in virtually all research directions within the country. In this article, we seek to provide stimulating glimpses into the evolving liver disease epidemiology, institutional research profiles, funding landscape, and drug development trends in China, with an attempt to compare her status and achievements with those of the United States, European countries, and Japan.
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Affiliation(s)
- Jia Xiao
- Laboratory of Neuroendocrinology, Fujian Key Laboratory of Developmental and Neurobiology, School of Life Sciences, Fujian Normal University, Fuzhou, China; Department of Health Sciences, National Natural Science Foundation of China, Beijing, China
| | - Fei Wang
- Department of Health Sciences, National Natural Science Foundation of China, Beijing, China; Division of Gastroenterology and Hepatology, Digestive Disease Institute, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Nai-Kei Wong
- State Key Discipline of Infectious Diseases, Shenzhen Third People's Hospital, The Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen, China
| | - Jinhan He
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Rui Zhang
- Clinical Research Institute, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Ruijuan Sun
- Department of Health Sciences, National Natural Science Foundation of China, Beijing, China
| | - Yanying Xu
- Department of Health Sciences, National Natural Science Foundation of China, Beijing, China
| | - Yingxia Liu
- State Key Discipline of Infectious Diseases, Shenzhen Third People's Hospital, The Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen, China
| | - Wei Li
- Faculty of Pharmaceutical Sciences, Toho University, Chiba, Japan
| | - Kazuo Koike
- Faculty of Pharmaceutical Sciences, Toho University, Chiba, Japan
| | - Weiling He
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hong You
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yinglei Miao
- Department of Gastroenterology, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Xiaowei Liu
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, China
| | - Mingming Meng
- Department of Gastroenterology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Hua Wang
- Department of Oncology, The First Affiliated Hospital, Institute for Liver Diseases of Anhui Medical University, Hefei, China.
| | - Cui Li
- Department of Health Sciences, National Natural Science Foundation of China, Beijing, China.
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Ogawa E, Furusyo N, Nakamuta M, Nomura H, Satoh T, Takahashi K, Koyanagi T, Kajiwara E, Dohmen K, Kawano A, Ooho A, Azuma K, Kato M, Shimoda S, Hayashi J. Glecaprevir and pibrentasvir for Japanese patients with chronic hepatitis C genotype 1 or 2 infection: Results from a multicenter, real-world cohort study. Hepatol Res 2019; 49:617-626. [PMID: 30849206 DOI: 10.1111/hepr.13328] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2018] [Revised: 02/25/2019] [Accepted: 03/02/2019] [Indexed: 02/08/2023]
Abstract
AIM Glecaprevir (GLE) and pibrentasvir (PIB) are new direct-acting antiviral agents (DAAs) with pangenotypic inhibitors that respectively target the hepatitis C virus (HCV) NS3/4 protease and NS5A. The aim of this study was to evaluate the effectiveness and safety of combining GLE and PIB for patients with HCV genotype (GT) 1 or 2 infection in the clinical setting, including patients DAA-experienced or on hemodialysis. METHODS This multicenter, real-world, retrospective, cohort study consisted of 314 Japanese patients who were treated with GLE (300 mg) and PIB (120 mg) for a fixed 8- or 12-week duration. We evaluated the sustained virologic response rate 12 weeks after the end of treatment (SVR12) and adverse events. RESULTS Among the treated patients, 122 had GT1 and 192 GT2 infection. The overall SVR12 rates in the per-protocol populations were 99.2% (119/120) for GT1 and 98.9% (183/185) for GT2. High SVR12 rates were observed in almost all subgroups, including cirrhosis, receiving hemodialysis, or previous all-oral DAA groups treated with asunaprevir and daclatasvir (GT1b), ledipasvir/sofosbuvir (GT1), or sofosbuvir and ribavirin (GT2). Virological relapse occurred in only 1.0% (3/305) of the patients who completed treatment. The most common adverse events were pruritus and fatigue (>5% of patients). Serious adverse events were rare and discontinuation due to an adverse event was required for 1.6% of the patients. CONCLUSIONS In this real-world cohort study, treatment with GLE/PIB achieved high SVR12 rates with a low rate of serious adverse events among patients with HCV GT1 or 2 infection.
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Affiliation(s)
- Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Norihiro Furusyo
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Makoto Nakamuta
- Department of Gastroenterology, Kyushu Medical Center, National Hospital Organization, Fukuoka, Japan
| | - Hideyuki Nomura
- The Center for Liver Disease, Shin-Kokura Hospital, Kitakyushu, Japan
| | - Takeaki Satoh
- Center for Liver Disease, National Hospital Organization Kokura Medical Center, Kitakyushu, Japan
| | | | | | | | - Kazufumi Dohmen
- Department of Internal Medicine, Chihaya Hospital, Fukuoka, Japan
| | - Akira Kawano
- Department of Medicine, Kitakyushu Municipal Medical Center, Kitakyushu, Japan
| | - Aritsune Ooho
- Department of Hepatology, Steel Memorial Yawata Hospital, Kitakyushu, Japan
| | - Koichi Azuma
- Department of Medicine, Kyushu Central Hospital, Fukuoka, Japan
| | - Masaki Kato
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shinji Shimoda
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Jun Hayashi
- Kyushu General Internal Medicine Center, Haradoi Hospital, Fukuoka, Japan
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Kalantari H, Bagherpour B, Tavakoli T, Khodadoostan M, Hejazi SM, Saadatmand A. The interleukin 28B gene polymorphism, rs8099917, in patients with chronic hepatitis C and response to the treatment with pegylated interferon and ribavirin. JOURNAL OF RESEARCH IN MEDICAL SCIENCES 2019; 24:12. [PMID: 30988680 PMCID: PMC6421889 DOI: 10.4103/jrms.jrms_621_18] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 09/26/2018] [Accepted: 12/04/2018] [Indexed: 12/30/2022]
Abstract
Background The present study aimed to determine the frequency of the IL28B polymorphism rs8099917 in patients with genotype 1 hepatitis C virus (HCV) infection treated with pegylated-interferon-α2b (PEG-IFN-α2b) and ribavirin (RBV) and its treatment outcome. Materials and Methods The IL28B rs8099917 genotypes were determined among 100 HCV-infected patients and the viral load was also estimated. PEG-IFN-α2b and RBV combination were administrated to the patients for 48 weeks and the treatment outcome was defined. Results Sixty-seven (67%), 27 (27%), and 6 (6%) of 100 patients were determined as TT, GT, and GG genotype, respectively. The response rate to treatment was significantly higher in patients with TT genotype. Conclusion According to the results of the present study, patients with IL28B rs8099917 TT genotype achieve higher sustained virological response than the GT and GG genotypes. Thus, when there are no alternatives, treatment with PEG-IFN-α2b and RBV combination can be suggested in patients with IL28B TT genotype.
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Affiliation(s)
- Hamid Kalantari
- Department of Gastroenterology, Isfahan Liver Disease Research Center, Isfahan, Iran
| | - Bahram Bagherpour
- Acquired Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Tahmine Tavakoli
- Department of Gastroenterology, Isfahan Liver Disease Research Center, Isfahan, Iran
| | - Mahsa Khodadoostan
- Department of Gastroenterology, Isfahan Liver Disease Research Center, Isfahan, Iran
| | - Seyed Mehdi Hejazi
- Health Information Technology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Alireza Saadatmand
- Department of Gastroenterology, Isfahan Liver Disease Research Center, Isfahan, Iran
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Pourmarzi D, Hall L, Hepworth J, Smirnov A, Rahman T, FitzGerald G. Clinical effectiveness, cost effectiveness and acceptability of community-based treatment of hepatitis C virus infection: A mixed method systematic review. J Viral Hepat 2019; 26:432-453. [PMID: 30516874 DOI: 10.1111/jvh.13045] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 11/05/2018] [Accepted: 11/07/2018] [Indexed: 12/11/2022]
Abstract
Several community-based models for treating hepatitis C virus (HCV) infection have been implemented to improve treatment accessibility and health outcomes. However, there is a lack of knowledge regarding how well these models achieve the desired goals. We conducted a mixed-method systematic review of quantitative and qualitative evidence about clinical effectiveness, cost effectiveness and acceptability of community-based HCV treatment models. Seventeen databases were researched for published and unpublished studies. Methodological quality was assessed using The Joanna Briggs Institute Critical Appraisal tools. Quantitative findings were synthesized in narrative form and qualitative findings were synthesized using meta-synthesis. Forty-two quantitative and six qualitative studies were included. No relevant cost effectiveness studies were found. Five categories of community-based models were identified: telehealth, integration of HCV and addiction services, integration of HCV and HIV services, integration of HCV and primary care, and implementation by a home care and health care management company. The range of reported outcomes included; end of treatment response: 48.7% to 96%, serious side effects: 3.3% to 27.8%, sustained virological response: 22.3% to 95.5%, relapse: 2.2% to 16.7%, and treatment completion: 33.4% to 100%. Inconsistent measures of uptake and adherence were used; uptake ranged from 8.3% to 92%, and 68.4% to 100% of patients received ≥80% of prescribed doses. Patient reported experiences included trusted and supportive care providers, safe and trusted services, easily accessible care, and positive psychological and behavioural changes. The clinical effectiveness and acceptability reported from the included studies are similar to or better than reported outcomes from systematic reviews of studies in tertiary settings. Studies of the cost effectiveness of community-based models for treating HCV are needed.
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Affiliation(s)
- Davoud Pourmarzi
- School of Public Health and Social Work, Faculty of Health, Institute of Health and Biomedical Innovation (IHBI), Queensland University of Technology, Brisbane, Queensland, Australia
| | - Lisa Hall
- School of Public Health and Social Work, Faculty of Health, Institute of Health and Biomedical Innovation (IHBI), Queensland University of Technology, Brisbane, Queensland, Australia.,School of Public Health, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Julie Hepworth
- Mater Research Institute, The University of Queensland, Brisbane, Queensland, Australia
| | - Andrew Smirnov
- School of Public Health, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Tony Rahman
- School of Nursing, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia.,Department of Gastroenterology and Hepatology, The Prince Charles Hospital, Brisbane, Australia
| | - Gerrard FitzGerald
- School of Public Health and Social Work, Faculty of Health, Institute of Health and Biomedical Innovation (IHBI), Queensland University of Technology, Brisbane, Queensland, Australia
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Long-term follow-up after cure from chronic hepatitis C virus infection shows occult hepatitis and a risk of hepatocellular carcinoma in noncirrhotic patients. Eur J Gastroenterol Hepatol 2019; 31:506-513. [PMID: 30461522 PMCID: PMC6416012 DOI: 10.1097/meg.0000000000001316] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVES Curing of hepatitis C virus (HCV) infection primarily aims to prevent severe liver complications. Our objectives were to investigate the long-term presence and impact of occult HCV infection (OCI) and to study the outcomes in terms of liver disease after virological cure. PATIENTS AND METHODS A total of 97 patients with achieved sustained virological response (SVR) during 1990-2005 were followed either by a clinical follow-up (FU) visit with blood sampling and liver elastography (n=54) or through national registries for outcomes (n=43). To diagnose OCI among patients with SVR, a highly sensitive method was used to detect HCV-RNA traces in whole blood. The FU duration was a median of 10.5 years, with samples up to 21.5 years after the end of treatment (EOT). RESULTS The majority of patients [52 (96%)] were HCV-RNA negative at FU, and regression of fibrosis was statistically significant. OCI was found in two (4%) of them at 8 and 9 years after EOT. These patients had F1 and F2 fibrosis before treatment and F2 at FU, but no other abnormal findings. Three previously noncirrhotic men were diagnosed with hepatocellular carcinoma 8-11 years after EOT. CONCLUSION Occult infection could be detected many years after the achievement of SVR but was not associated with serious liver disease. The majority had persistent viral eradication and regression of fibrosis after SVR. However, an increased risk of hepatocellular carcinoma may persist in the long term after SVR even in noncirrhotic patients. Further studies with FU after direct-acting antiviral therapy and on the long-term impact after cure are needed.
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Wang Z, Chen Z, Li J, Huang J, Zheng C, Liu JP. Combined 3D-QSAR, molecular docking and molecular dynamics study on the benzimidazole inhibitors targeting HCV NS5B polymerase. J Biomol Struct Dyn 2019; 38:1071-1082. [PMID: 30915896 DOI: 10.1080/07391102.2019.1593244] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The hepatitis C virus (HCV)-infected population has continued to grow during recent years, and novel HCV antiviral agents are urgently needed. In this work, a combined theoretical study was performed on the HCV non-structural 5B (NS5B) polymerase and 53 benzimidazole inhibitors. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were carried out with ligand-based and receptor-based alignments. Ligand-based QSAR models (cross-validated q2 of 0.918 for CoMFA and 0.825 for CoMSIA) were found to be superior to receptor-based approaches (cross-validated q2 of 0.765 for CoMFA and 0.740 for CoMSIA). Based on the most predictive CoMFA and CoMSIA models, the structural features that were essential for the inhibitory activity of benzimidazoles were characterized. A molecular dynamics study revealed that the induced fit effect between NS5B and its substrate may be responsible for the inferiority of the receptor-based CoMFA and CoMSIA models. The binding-free energy calculated using the MM/PBSA method correlated well with the experimental results and revealed that the van der Waals and electrostatic interactions most contributed to the binding. In addition, energetically favorable NS5B residues were identified by the per-residue decomposition of binding-free energy. The results presented in this work provide meaningful information for the design of novel benzimidazole inhibitors targeting the NS5B polymerase.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Zhiguo Wang
- Institute of Ageing Research, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Zhenming Chen
- Laboratory of Biocatalysis, College of Life & Environmental Sciences, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Jianfeng Li
- Institute of Ageing Research, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Jing Huang
- Institute of Ageing Research, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Chenni Zheng
- Laboratory of Biocatalysis, College of Life & Environmental Sciences, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Jun-Ping Liu
- Institute of Ageing Research, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China.,Department of Immunology, Central Eastern Clinical School, Monash University, Melbourne, Vitoria, Australia.,Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia
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Tolentino B, Singh RR, Misra S, Dieterich DT, Sarpel D. An update on the management of hepatitis C virus and human immunodeficiency virus co-infection. Future Virol 2019. [DOI: 10.2217/fvl-2018-0116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
An estimated 2.3 million people globally are co-infected with HIV and HCV. Liver disease is now a leading cause of non-AIDS-related mortality among HIV-infected patients. The development of direct-acting antiviral agents has revolutionized the treatment of HIV/HCV co-infection with sustained virologic response response rates above 95% in most patient populations. This article provides an update on the management of acute and chronic HCV in patients co-infected with HIV including a section on drug–drug interactions.
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Affiliation(s)
- Bryan Tolentino
- Department of Medicine, Division of Infectious Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Ritu R Singh
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Suresh Misra
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Douglas T Dieterich
- Department of Medicine, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Dost Sarpel
- Department of Medicine, Division of Infectious Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Torun D, Soydas B, Tekkarismaz N, Ozelsancak R, Micozkadioglu H, Haberal M. Experience with antiviral agents for treatment of hepatitis C virus infection in hemodialysis patients on the kidney wait list. Hemodial Int 2019; 23:E78-E82. [PMID: 30762283 DOI: 10.1111/hdi.12719] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 10/18/2018] [Accepted: 10/18/2018] [Indexed: 01/26/2023]
Abstract
INTRODUCTION Hepatitis C virus (HCV) infection is associated with increased mortality and morbidity in kidney transplant patients. The ability to establish a sustained viral response before renal transplant is important for these patients. Direct-acting antiviral agents can increase the sustained viral response in most patients with HCV infection. In this case series, we aimed to determine the efficacy and safety of a combined therapy of ombitasvir, paritaprevir, ritonavir, and dasabuvir with or without ribavirin in patients with HCV genotype 1 infection without cirrhosis and on hemodialysis who were awaiting deceased-donor kidney transplant. METHODS Our study included eight male and two female HCV ribonucleic acid (RNA)-positive hemodialysis patients (mean age 50.7 ± 15 years, mean hemodialysis duration 14 ± 5.5 years, mean HCV duration 18 ± 3.7 years). FINDINGS Three patients with genotype 1a received oral therapy with 12.5 mg ombitasvir, 150 mg paritaprevir, 7 5 mg ritonavir, and 250 mg dasabuvir plus 200 mg ribavirin for 12 weeks. Seven patients with genotype 1b received 12.5 mg ombitasvir, 150 mg paritaprevir, 75 mg ritonavir, and 250 mg dasabuvir without ribavirin treatment for 12 weeks. The sustained virologic response rate was 100% at 12 weeks after completion of antiviral treatment in both treatment groups. No serious adverse effects were observed in either treatment group. Five patients had constitutional symptoms such as nausea, anorexia, and fatigue. During the treatment period, hemoglobin, white cell blood count, thrombocyte, and ferritin levels were similar to pretreatment levels. Treatment did not affect weekly erythropoietin and monthly intravenous iron treatment doses. DISCUSSION Direct-acting antiviral agents are safe and effective for generating a sustained viral response in HCV genotype 1-infected hemodialysis patients on kidney wait lists.
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Affiliation(s)
- Dilek Torun
- Department of Nephrology, Adana Dr Turgut Noyan Research and Medical Center, Baskent University Faculty of Medicine, Adana, Turkey
| | - Baris Soydas
- Department of Gastroenterology, Adana Dr Turgut Noyan Research and Medical Center, Baskent University Faculty of Medicine, Adana, Turkey
| | - Nihan Tekkarismaz
- Department of Nephrology, Adana Dr Turgut Noyan Research and Medical Center, Baskent University Faculty of Medicine, Adana, Turkey
| | - Ruya Ozelsancak
- Department of Nephrology, Adana Dr Turgut Noyan Research and Medical Center, Baskent University Faculty of Medicine, Adana, Turkey
| | - Hasan Micozkadioglu
- Department of Nephrology, Adana Dr Turgut Noyan Research and Medical Center, Baskent University Faculty of Medicine, Adana, Turkey
| | - Mehmet Haberal
- Department of Transplantation and General Surgery, Baskent University Faculty of Medicine, Adana, Turkey
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Marciniewicz E, Podgórski P, Pawłowski T, Małyszczak K, Fleischer-Stępniewska K, Knysz B, Waliszewska-Prosół M, Żelwetro A, Rymer W, Inglot M, Ejma M, Sąsiadek M, Bladowska J. Evaluation of brain volume alterations in HCV-infected patients after interferon-free therapy: A pilot study. J Neurol Sci 2019; 399:36-43. [PMID: 30769221 DOI: 10.1016/j.jns.2019.02.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 01/31/2019] [Accepted: 02/01/2019] [Indexed: 12/20/2022]
Abstract
The study was performed to evaluate cerebral volume changes in HCV-infected subjects before and after interferon-free therapy with direct-acting antiviral agents (DAA). We aimed also to estimate the impact of successful DAA therapy on the neuropsychological state of patients. Eleven HCV genotype 1 (GT1) patients treated with ombitasvir/paritaprevir (boosted with ritonavir) and dasabuvir, with or without ribavirin underwent brain magnetic resonance (MR) before and 24 weeks after completion of therapy. All patients achieved sustained viral response. Precise automatic parcellation was made using the fully-available software FreeSurfer 6.0. Statistically significant volume deceleration six months after treatment was found in the subcallosal cingulate gyrus, transverse frontopolar gyri and sulci, anterior segment of the circular sulcus of the insula and horizontal ramus of the anterior segment of the lateral sulcus. After DAA therapy we found statistically significant improvement in the performance of all three tasks of the Rey Complex Figure Test that permits the evaluation of different functions (attention, planning, working,memory). Additionally, significant amelioration in Percentage Conceptual Level Responses in The Wisconsin Card Sorting Test (a neurocognitive test for assessing intellectual functioning) was also discovered. Successful interferon-free therapy may lead to transient cerebral atrophy, probably by reducing neuroinflammation and oedema. This is the first pilot study of the alterations in brain volume after successful interferon-free therapy in chronic HCV patients. Longitudinal follow-up study is needed to observe further effects of therapy on cerebral structures volume changes.
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Affiliation(s)
- Ewelina Marciniewicz
- Department of General Radiology, Interventional Radiology and Neuroradiology, Radiology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland.
| | - Przemysław Podgórski
- Department of General Radiology, Interventional Radiology and Neuroradiology, Radiology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland
| | - Tomasz Pawłowski
- Division of Psychotherapy and Psychosomatic Medicine, Department of Psychiatry, Wroclaw Medical University, L. Pasteura 10, 50-367 Wroclaw, Poland.
| | - Krzysztof Małyszczak
- Division of Psychotherapy and Psychosomatic Medicine, Department of Psychiatry, Wroclaw Medical University, L. Pasteura 10, 50-367 Wroclaw, Poland
| | - Katarzyna Fleischer-Stępniewska
- Department of Infectious Diseases, Liver Diseases and Acquired Immune Deficiences, Wroclaw Medical University, Koszarowa 5, 51-149 Wroclaw, Poland
| | - Brygida Knysz
- Department of Infectious Diseases, Liver Diseases and Acquired Immune Deficiences, Wroclaw Medical University, Koszarowa 5, 51-149 Wroclaw, Poland
| | | | - Agnieszka Żelwetro
- The Institute of Psychology, University of Wroclaw, J.W. Dawida 1, 50-527 Wroclaw, Poland
| | - Weronika Rymer
- Department of Infectious Diseases, Liver Diseases and Acquired Immune Deficiences, Wroclaw Medical University, Koszarowa 5, 51-149 Wroclaw, Poland.
| | - Małgorzata Inglot
- Department of Infectious Diseases, Liver Diseases and Acquired Immune Deficiences, Wroclaw Medical University, Koszarowa 5, 51-149 Wroclaw, Poland.
| | - Maria Ejma
- Department of Neurology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland.
| | - Marek Sąsiadek
- Department of General Radiology, Interventional Radiology and Neuroradiology, Radiology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland.
| | - Joanna Bladowska
- Department of General Radiology, Interventional Radiology and Neuroradiology, Radiology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland
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Mahboubi Rabbani SMI, Vahabpour R, Hajimahdi Z, Zarghi A. Design, Synthesis, Molecular Modeling Studies and Biological Evaluation of N'-Arylidene-6-(benzyloxy)-4-oxo-1,4-dihydroquinoline-3-carbohydrazide Derivatives as Novel Anti-HCV Agents. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2019; 18:1790-1802. [PMID: 32184846 PMCID: PMC7059030 DOI: 10.22037/ijpr.2019.112186.13586] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
HCV-induced hepatitis is one of the most debilitating diseases. The limited number of anti-HCV drugs and drug-resistance necessitate developing of new scaffolds with different mode of actions. HCV non-structural protein 5B (NS5B) is an attractive target for development of novel inhibitors of HCV replication. In this paper, new N'-arylidene-6-(benzyloxy)-4-oxo-1,4-dihydroquinoline-3-carbohydrazide derivatives were designed based on the pharmacophores of HCV NS5B active site binding inhibitors. Designed compounds were synthesized and evaluated for their inhibitory activities in a cell-based HCV replicon system assay. Among tested compounds, compounds 18 and 20 were found to be the most active (EC50 = 35 and 70 µM, respectively) with good selectivity index (SI > 2) in the corresponding series. Molecular modeling studies showed that the designed compounds are capable of forming key coordination with the two magnesium ions as well as interactions with other key residues at the active site of HCV NS5B.
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Affiliation(s)
| | - Rouhollah Vahabpour
- Department of Medical Lab Technology, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Zahra Hajimahdi
- Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Afshin Zarghi
- Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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