1
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Sheehan LP, Wright MP, Rhudy C, Osborne T, Platt T, Duckworth DL. Implementation of a novel framework for hepatitis C diagnosis and treatment in an academic health system. Am J Health Syst Pharm 2025; 82:e551-e558. [PMID: 39612913 DOI: 10.1093/ajhp/zxae373] [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: 12/21/2023] [Indexed: 12/01/2024] Open
Abstract
PURPOSE Hepatitis C viral infection is a major public health concern and leading cause of chronic liver disease in the United States. Hepatitis C is primarily transmitted through blood exchange and is highly prevalent among people who inject drugs. Despite the availability of direct-acting antiviral (DAA) treatment, cost and barriers to access remain prohibitive for many patients. SUMMARY In 2018, University of Kentucky HealthCare (UKHC) began a screening program for patients admitted to its emergency department (ED). Despite identifying hepatitis C RNA-positive patients, connection to care proved challenging due to unavailability of follow-up clinic appointments, communication barriers, and lack of insurance coverage. In 2023, UKHC implemented a pharmacist-led hepatitis C screening, assessment, and treatment initiative in the ED following American Association for the Study of Liver Diseases (AASLD) simplified treatment guidelines. Pharmacists order needed laboratory assessments and complete imaging for liver fibrosis in eligible patients. Patients diagnosed with hepatitis C who meet simplified treatment criteria are prescribed DAA therapy by a hepatitis C advanced practice provider employed by the program. The UKHC specialty pharmacy then follows up with dispensing of DAA therapy and proactive refill management for subsequent fills. CONCLUSION This holistic, interdisciplinary treatment model has allowed UKHC to increase treatment attachment rates for hepatitis C diagnoses in the ED from approximately 10% to 54%. This program has also reduced the median time to treatment of hepatitis C-infected individuals encountered in the ED from approximately 420 days to 17 days.
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Affiliation(s)
- Lindsey P Sheehan
- Specialty Pharmacy and Infusion Services, UK HealthCare, Lexington, KY, USA
| | - Maribeth P Wright
- Specialty Pharmacy and Infusion Services, UK HealthCare, Lexington, KY, USA
| | - Christian Rhudy
- Specialty Pharmacy and Infusion Services, UK HealthCare, Lexington, KY, USA
| | - Thai Osborne
- Specialty Pharmacy and Infusion Services, UK HealthCare, Lexington, KY, USA
| | - Thom Platt
- Specialty Pharmacy and Infusion Services, UK HealthCare, Lexington, KY, USA
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Boesch M, Baty F, Kalra S, Brutsche MH, Rassouli F. Chronicity of disease mandates quality-of-life prioritization - a role for digital health and patient-reported outcome measures. Eur J Intern Med 2025; 135:1-4. [PMID: 40069046 DOI: 10.1016/j.ejim.2025.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 02/27/2025] [Accepted: 03/04/2025] [Indexed: 05/06/2025]
Affiliation(s)
- Maximilian Boesch
- Lung Center, HOCH Health Ostschweiz, Kantonsspital St.Gallen, Universitäres Lehr- und Forschungsspital, St.Gallen, Switzerland; Medical Oncology and Hematology, HOCH Health Ostschweiz, Kantonsspital St.Gallen, Universitäres Lehr- und Forschungsspital, St.Gallen, Switzerland.
| | - Florent Baty
- Lung Center, HOCH Health Ostschweiz, Kantonsspital St.Gallen, Universitäres Lehr- und Forschungsspital, St.Gallen, Switzerland
| | - Sanjay Kalra
- Department of Medicine, Division of Pulmonary, Critical Care & Sleep Medicine, Mayo Clinic, Rochester, MN, USA
| | - Martin H Brutsche
- Lung Center, HOCH Health Ostschweiz, Kantonsspital St.Gallen, Universitäres Lehr- und Forschungsspital, St.Gallen, Switzerland
| | - Frank Rassouli
- Lung Center, HOCH Health Ostschweiz, Kantonsspital St.Gallen, Universitäres Lehr- und Forschungsspital, St.Gallen, Switzerland
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3
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Hilton B, De Angelis D, Mitchell H, Harris R. Heterogeneity in Risk and Implications for Hepatitis C Reinfection in People Who Inject Drugs in England. J Viral Hepat 2025; 32:e14052. [PMID: 39815998 PMCID: PMC11736538 DOI: 10.1111/jvh.14052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 10/30/2024] [Accepted: 12/04/2024] [Indexed: 01/18/2025]
Abstract
Chronic hepatitis C virus (HCV) infection is associated with significant morbidity, mortality and health economic burden. Over 90% of HCV cases in England occur in people who inject drugs (PWID). Current treatments for HCV are effective but do not protect against reinfection. This research characterised HCV infection and reinfection risk in PWID in England using 2011-2021 data from the annual, cross-sectional, bio-behavioural survey of PWID, Unlinked Anonymous Monitoring. Risk factors for HCV infection were explored using multivariable logistic regression. Shared frailty models for the force of infection (FOI) were used to estimate the risk of HCV infection throughout injecting career with unmeasured risk variation modelled using gamma-shaped frailty distributions. HCV reinfection rates were derived using the frailty distributions of FOI models fitted to UAM data. Infection rates were highest in the first year of injecting (24 per 100 person-years) but fell to between 5 and 8 infections per 100 person-years subsequently. The estimated average annual risks of HCV primary infection and reinfection were 10.0% and 14.2%, indicating a 42% higher risk of reinfection compared to primary infection. Even those with no a priori risk factors were predicted to have high rates of reinfection if previously infected. These findings support the recognition of primary HCV infection as an independent risk factor for reinfection in PWID and emphasise the importance of reducing high-risk behaviours to prevent HCV reinfection following treatment of primary infection. Public health policies must recognise the importance of preventing reinfection in efforts to reduce HCV infection prevalence.
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Affiliation(s)
- Bryn Hilton
- MPhil Population Health Sciences, Department of Public Health and Primary CareUniversity of CambridgeCambridgeUK
| | - Daniela De Angelis
- MRC Biostatistics Unit, School of Clinical MedicineUniversity of CambridgeCambridgeUK
- Blood Safety, Hepatitis, STI and HIV DivisionUK Health Security AgencyLondonUK
| | - Holly Mitchell
- Blood Safety, Hepatitis, STI and HIV DivisionUK Health Security AgencyLondonUK
| | - Ross Harris
- Statistics, Modelling and Economics DepartmentUK Health Security AgencyLondonUK
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Di Marco L, Cannova S, Ferrigno E, Landro G, Nonni R, Mantia CL, Cartabellotta F, Calvaruso V, Di Marco V. A Comprehensive Review of Antiviral Therapy for Hepatitis C: The Long Journey from Interferon to Pan-Genotypic Direct-Acting Antivirals (DAAs). Viruses 2025; 17:163. [PMID: 40006918 PMCID: PMC11860415 DOI: 10.3390/v17020163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 01/19/2025] [Accepted: 01/20/2025] [Indexed: 02/27/2025] Open
Abstract
The treatment landscape for hepatitis C virus (HCV) infection has transformed over the past few decades, evolving from the limited efficacy of interferon (IFN) monotherapy to the highly successful pan-genotypic direct-acting antivirals (DAAs) used today. Initially, alpha-interferon monotherapy, introduced in the 1990s, was the standard treatment, yet it provided low sustained virological response (SVR) rates and caused significant adverse effects, limiting its utility. The development of pegylated interferon (peg-IFN) improved the pharmacokinetic profile of IFN, allowing for less frequent dosing and modestly improved response rates. When combined with ribavirin, peg-IFN achieved higher SVR rates, especially in non-genotype 1 HCV infections, but the combination also brought additional side effects, such as anemia and depression. The advent of the first-generation DAAs, such as telaprevir and boceprevir, marked a significant milestone. Combined with peg-IFN and ribavirin, these protease inhibitors boosted response rates in patients with genotype 1 HCV. However, high rates of adverse effects and drug resistance remained challenges. Second-generation DAAs, like sofosbuvir and ledipasvir, introduced IFN-free regimens with improved safety profiles and efficacy. The most recent advances are pan-genotypic DAAs, including glecaprevir-pibrentasvir and sofosbuvir-velpatasvir, which offer high SVR rates across all genotypes, shorter treatment durations, and fewer side effects. Current pan-genotypic regimens represent a cornerstone in HCV therapy, providing an accessible and effective solution globally.
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Affiliation(s)
- Lorenza Di Marco
- SIcilian Network for Therapy, Epidemiology and Screening In Hepatology (SINTESI), 90127 Palermo, Italy; (L.D.M.); (F.C.); (V.C.)
- Department of Oncology and Hematology, Azienda Ospedaliero-University Hospital of Mod, 41124 Modena, Italy
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41100 Modena, Italy
| | - Simona Cannova
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (S.C.); (E.F.); (G.L.); (R.N.); (C.L.M.)
| | - Emanuele Ferrigno
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (S.C.); (E.F.); (G.L.); (R.N.); (C.L.M.)
| | - Giuseppe Landro
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (S.C.); (E.F.); (G.L.); (R.N.); (C.L.M.)
| | - Rosario Nonni
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (S.C.); (E.F.); (G.L.); (R.N.); (C.L.M.)
| | - Claudia La Mantia
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (S.C.); (E.F.); (G.L.); (R.N.); (C.L.M.)
| | - Fabio Cartabellotta
- SIcilian Network for Therapy, Epidemiology and Screening In Hepatology (SINTESI), 90127 Palermo, Italy; (L.D.M.); (F.C.); (V.C.)
- Department of Medicine, Buccheri-La Ferla Hospital, 90123 Palermo, Italy
| | - Vincenza Calvaruso
- SIcilian Network for Therapy, Epidemiology and Screening In Hepatology (SINTESI), 90127 Palermo, Italy; (L.D.M.); (F.C.); (V.C.)
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (S.C.); (E.F.); (G.L.); (R.N.); (C.L.M.)
| | - Vito Di Marco
- SIcilian Network for Therapy, Epidemiology and Screening In Hepatology (SINTESI), 90127 Palermo, Italy; (L.D.M.); (F.C.); (V.C.)
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (S.C.); (E.F.); (G.L.); (R.N.); (C.L.M.)
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Chowdhury R, Rashid W, Singh T, Rehman A, Daterdiwala NF, Mkosi V, Limbu B, Bukhari SA, Ramadhan A, Dabas MM, Shehryar A, Khan R. Outcomes of Direct-Acting Antivirals Versus Interferon-Based Therapy in Chronic Hepatitis C Infection. Cureus 2024; 16:e75902. [PMID: 39830527 PMCID: PMC11738830 DOI: 10.7759/cureus.75902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/17/2024] [Indexed: 01/22/2025] Open
Abstract
This systematic review evaluates the outcomes of direct-acting antivirals (DAAs) compared to interferon-based therapies in patients with chronic hepatitis C infection. DAAs consistently demonstrate higher sustained virologic response (SVR) rates and better safety profiles across various patient populations, including those with cirrhosis and treatment-experienced individuals. The studies included highlight the superior efficacy of DAAs, with fewer adverse events such as anemia and fatigue, making them more tolerable and suitable for long-term treatment. These findings reinforce the clinical importance of DAAs as the standard of care for managing hepatitis C virus (HCV), particularly in special populations. Although interferon-based therapies remain relevant in resource-limited settings, this review emphasizes the need for broader access to DAAs to improve global health outcomes and reduce HCV-related morbidity and mortality.
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Affiliation(s)
- Ratna Chowdhury
- Internal Medicine, Saint James School of Medicine, Arnos Vale, VCT
| | - Wardah Rashid
- Internal Medicine, Khawaja Muhammad Safdar Medical College, Sialkot, PAK
| | - Taranpreet Singh
- Internal Medicine, Mahatma Gandhi Mission (MGM) Medical College and Hospital, Mumbai, IND
| | | | | | - Varaidzo Mkosi
- Internal Medicine, Ternopil National Medical University, Ternopil, UKR
| | - Bhumikala Limbu
- Emergency Medicine, Bishweshwar Prasad Koirala Institute of Health Sciences, Dharan, NPL
| | | | - Afif Ramadhan
- Internal Medicine, Universitas Gadjah Mada, Yogyakarta, IDN
| | | | | | - Ramadan Khan
- Internal Medicine, Dera Ghazi Khan Medical College, Dera Ghazi Khan, PAK
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6
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Balcar L, Schwarz M, Dorn L, Jachs M, Hartl L, Weseslindtner L, Pfisterer N, Hennlich B, Stückler A, Strassl R, Voill‐Glaninger A, Hübl W, Willheim M, Köhrer K, Jansen‐Skoupy S, Tomez S, Krugluger W, Madl C, Burghart L, Antonitsch L, Weidinger G, Riedl F, Laferl H, Hind J, Wenisch C, Sebesta C, Wachter‐Welzl J, Watzl P, Neuhauser M, Chromy D, Mandorfer M, Schmid D, Gschwantler M, Reiberger T, Maieron A, Bauer DJ, Schwarz C. A systematic PCR record-based re-call of HCV-RNA-positive people enables re-linkage to care and HCV elimination in Austria - The ELIMINATE project. Liver Int 2024; 44:3151-3163. [PMID: 39351692 PMCID: PMC11586887 DOI: 10.1111/liv.16076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 07/14/2024] [Accepted: 08/07/2024] [Indexed: 11/26/2024]
Abstract
BACKGROUND AND AIMS Identification of people living with hepatitis C virus (HCV) via readily available laboratory records could be a key strategy for macro-elimination, aligning with the WHO elimination goal. Therefore, the ELIMINATE(ELIMINation of HCV in AusTria East) project aimed to systematically re-link people with a 'last-positive' HCV-RNA PCR record to care. METHODS In 10 major liver centres in Eastern Austria, a systematic readout of 'last-positive' HCV-RNA PCR test records obtained between 2008 and 2020 were conducted and linked to available patient contact data. Between 2020 and 2023, individuals were contacted first by phone, then by letter, to inform them about the availability of effective direct-acting antiviral (DAA) treatment and invite them for pre-treatment evaluation. RESULTS The overall cohort of last-positive HCV+ individuals included 5695 subjects (62.5% males, mean age 57.3 ± 17.3 years); of note, 1931 (34%) of them had died and 759 (13%) individuals had no valid contact information. Of the remaining 3005 individuals, 1171 (40.0%) had already achieved sustained virological response (SVR) at the time of re-call. We successfully reached 617 (20.5%), of whom 417 (67.6%) attended their pre-treatment visit, and 397 (64.3%) commenced DAA-therapy. HCV cure has been confirmed in 326 individuals, corresponding to an SVR rate of 82.1%. CONCLUSION The ELIMINATE project identified 5695 people living with HCV who were 'lost to care' despite documented HCV viraemia. While invalid contact data were an evident barrier to HCV elimination, premature deaths among the cohort underscored the severity of untreated HCV. The implementation of a systematic HCV-RNA PCR recorded-based re-call workflow represents an effective strategy supporting the WHO goal of HCV elimination.
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Affiliation(s)
- Lorenz Balcar
- Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
| | - Michael Schwarz
- Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Department of Internal Medicine IVKlinik OttakringViennaAustria
| | - Livia Dorn
- Internal Medicine II, Gastroenterology and Hepatology and Rheumatology, Karl Landsteiner University of Health SciencesUniversity Hospital of St. PöltenSt. PöltenAustria
| | - Mathias Jachs
- Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
| | - Lukas Hartl
- Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
| | | | - Nikolaus Pfisterer
- Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Department of Internal Medicine IVKlinik LandstraßeViennaAustria
| | - Barbara Hennlich
- Department of Internal Medicine IVKlinik LandstraßeViennaAustria
| | - Annika Stückler
- Department of Internal Medicine IVKlinik LandstraßeViennaAustria
| | - Robert Strassl
- Clinical Institute for Laboratory MedicineMedical University of ViennaViennaAustria
| | | | | | - Martin Willheim
- Clinical Institute of Laboratory MedicineUniversity Clinic St. PöltenSt. PöltenAustria
| | - Karin Köhrer
- Institute of Medical‐Chemical and Molecular biological Laboratory Diagnostics with Blood DepotLandesklinikum Wiener NeustadtWiener NeustadtAustria
| | | | - Sabine Tomez
- Institute of Laboratory Medicine with Blood DepotKlinik DonaustadtViennaAustria
| | - Walter Krugluger
- Institute of Laboratory Medicine with Blood DepotKlinik DonaustadtViennaAustria
- Institute of Laboratory Medicine and Blood DepotKlinik FloridsdorfViennaAustria
| | - Christian Madl
- Department of Internal Medicine IVKlinik LandstraßeViennaAustria
- Sigmund Freud UniversityViennaAustria
| | - Lukas Burghart
- Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Department of Internal Medicine IVKlinik OttakringViennaAustria
| | - Lukas Antonitsch
- Department of Internal Medicine, Gastroenterology and HepatologyLandesklinikum Wiener NeustadtWiener NeustadtAustria
| | - Gerhard Weidinger
- Department of Internal Medicine, Gastroenterology and HepatologyLandesklinikum Wiener NeustadtWiener NeustadtAustria
| | - Florian Riedl
- Internal Medicine II, Gastroenterology and Hepatology and Rheumatology, Karl Landsteiner University of Health SciencesUniversity Hospital of St. PöltenSt. PöltenAustria
| | - Hermann Laferl
- Department of Internal Medicine IVKlinik FavoritenViennaAustria
| | - Julian Hind
- Department of Internal Medicine IVKlinik FavoritenViennaAustria
| | | | - Christian Sebesta
- Department of Internal Medicine and GastroenterologyKlinik FloridsdorfViennaAustria
- Department of Internal Medicine IIKlinik DonaustadtViennaAustria
| | - Julia Wachter‐Welzl
- Department of Internal Medicine IILandesklinikum MistelbachMistelbachAustria
| | - Paul Watzl
- Department of Internal Medicine IIBarmherzige Schwestern HospitalViennaAustria
| | - Magdalena Neuhauser
- Department of Internal Medicine IIBarmherzige Schwestern HospitalViennaAustria
| | - David Chromy
- Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
| | - Daniela Schmid
- Austrian Agency for Health and Food Safety (AGES)ViennaAustria
| | - Michael Gschwantler
- Department of Internal Medicine IVKlinik OttakringViennaAustria
- Sigmund Freud UniversityViennaAustria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
| | - Andreas Maieron
- Internal Medicine II, Gastroenterology and Hepatology and Rheumatology, Karl Landsteiner University of Health SciencesUniversity Hospital of St. PöltenSt. PöltenAustria
| | - David J.M. Bauer
- Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Department of Internal Medicine IVKlinik OttakringViennaAustria
| | - Caroline Schwarz
- Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Department of Internal Medicine IVKlinik OttakringViennaAustria
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Yao X, Gao S, Yan N. Structural biology of voltage-gated calcium channels. Channels (Austin) 2024; 18:2290807. [PMID: 38062897 PMCID: PMC10761187 DOI: 10.1080/19336950.2023.2290807] [Citation(s) in RCA: 21] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
Voltage-gated calcium (Cav) channels mediate Ca2+ influx in response to membrane depolarization, playing critical roles in diverse physiological processes. Dysfunction or aberrant regulation of Cav channels can lead to life-threatening consequences. Cav-targeting drugs have been clinically used to treat cardiovascular and neuronal disorders for several decades. This review aims to provide an account of recent developments in the structural dissection of Cav channels. High-resolution structures have significantly advanced our understanding of the working and disease mechanisms of Cav channels, shed light on the molecular basis for their modulation, and elucidated the modes of actions (MOAs) of representative drugs and toxins. The progress in structural studies of Cav channels lays the foundation for future drug discovery efforts targeting Cav channelopathies.
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Affiliation(s)
- Xia Yao
- TaiKang Center for Life and Medical Sciences, School of Pharmaceutical Sciences, Wuhan University, Wuhan, China
| | - Shuai Gao
- TaiKang Center for Life and Medical Sciences, School of Pharmaceutical Sciences, Wuhan University, Wuhan, China
| | - Nieng Yan
- Beijing Frontier Research Center for Biological Structures, State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
- Shenzhen Medical Academy of Research and Translation, Shenzhen, China
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8
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Ferrari C, Ashraf B, Saeed Z, Tadros M. Understanding Why Metabolic-Dysfunction-Associated Steatohepatitis Lags Behind Hepatitis C in Therapeutic Development and Treatment Advances. GASTROENTEROLOGY INSIGHTS 2024; 15:944-962. [DOI: 10.3390/gastroent15040066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2025] Open
Abstract
Therapeutic development for metabolic-dysfunction-associated steatohepatitis (MASH) trails behind the success seen in hepatitis C virus (HCV) management. HCV, characterized by a viral etiology, benefits from direct-acting antivirals (DAAs) targeting viral proteins, achieving cure rates exceeding 90%. In contrast, MASH involves complex metabolic, genetic, and environmental factors, presenting challenges for drug development. Non-invasive diagnostics like ultrasound, FibroScan, and serum biomarkers, while increasingly used, lack the diagnostic accuracy of liver biopsy, the current gold standard. This review evaluates therapies for MASH, including resmetirom (Rezdiffra) and combinations like pioglitazone and vitamin E, which show potential but offer modest improvements due to MASH’s heterogeneity. The limited efficacy of these treatments highlights the need for multi-targeted strategies addressing metabolic and fibrotic components. Drawing parallels to HCV’s success, this review emphasizes advancing diagnostics and therapies for MASH. Developing effective, patient-specific therapies is crucial to closing the gap between MASH and better-managed liver diseases, optimizing care for this growing health challenge.
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Affiliation(s)
- Caesar Ferrari
- Department of Gastroenterology and Hepatology, Albany Medical College, Albany, NY 12208, USA
| | - Bilal Ashraf
- HCA Houston Healthcare Kingwood, Kingwood, TX 77339, USA
| | - Zainab Saeed
- Houston Methodist Baytown Hospital, Baytown, TX 77521, USA
| | - Micheal Tadros
- Department of Gastroenterology and Hepatology, Albany Medical College, Albany, NY 12208, USA
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9
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Kashani M, Karimi M, Sharifi Rayeni A, Azizi Nadian MA, Mortezazadeh M, Parsaei A, Abolghasemi N, Shirsalimi N, Mofidi A, Seyyed Mahmoudi ST. Efficacy of Direct Acting Antivirals (DAA) therapy in patients with recurrent hepatitis C after liver and kidney transplantation: a cross-sectional study. Front Med (Lausanne) 2024; 11:1460372. [PMID: 39444819 PMCID: PMC11496299 DOI: 10.3389/fmed.2024.1460372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Accepted: 09/05/2024] [Indexed: 10/25/2024] Open
Abstract
Background and objectives Direct-acting antiviral (DAA) agents are now widely used to treat patients with hepatitis C infection (HCV) and effectively increase their sustained virologic response (SVR). However, the literature seems to lack or deficient evidence of DAA efficacy in more complicated patients, especially those with HCV reinfection after liver transplantation (LT) or liver-kidney (hepatorenal) transplantation (LKT). This study aimed to retrospectively evaluate the effectiveness of two different DAA regimens in LT and LKT patients with HCV reinfection. Methods This cross-sectional study was conducted at three hospitals in Tehran, Iran, from 2014 to 2020, enrolling 53 patients with recurrent HCV infection after LT (n = 35) or LKT (n = 18). Patients were treated for 12 weeks with one of two DAA regimens: 37 patients (70%) received Daclatasvir and Sofosbuvir (SOF + DCV), while 16 patients (30%) received Sofosbuvir and Ledipasvir (SOF + LDV). Ribavirin (RBV) was added as an adjunct antiviral in 28 patients (52.8%). To assess the SVR, all patients were followed for 12 weeks after treatment. Results Both DAA regimens were well-tolerated and effective, with 94.6% (35 of 37) achieving SVR-12 in the SOF + DCV group and 93.8% (15 of 16) in the SOF + LDV group. Additionally, SVR-12 rates were promising across treatment durations, with 93.9% (31 of 33) in the 12-week group and 95% (19 of 20) in the 24-week group achieving undetectable HCV RNA. No significant difference in SVR was observed between the two regimens (p = 0.439). Conclusion The DAA-based therapeutic regimen was well tolerated and showed significant effectiveness in achieving the virologic response in patients with HCV reinfection after LT or LKT.
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Affiliation(s)
- Mehdi Kashani
- Department of Gastroenterology, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehdi Karimi
- Bogomolets National Medical University (NMU), Kyiv, Ukraine
| | | | | | - Masoud Mortezazadeh
- Department of Internal Medicine, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Nooshin Abolghasemi
- Department of Pharmacology, Islamic Azad University - Pharmaceutical Sciences Branch, Tehran, Iran
| | - Niyousha Shirsalimi
- Faculty of Medicine, Hamadan University of Medical Science (UMSHA), Hamadan, Iran
| | - Abbas Mofidi
- Faculty of Medicine, Hamadan University of Medical Science (UMSHA), Hamadan, Iran
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10
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Lei PK, Liu Z, Ung COL, Hu H. Efficacy and safety of direct-acting antiviral regimen for patients with hepatitis C virus genotype 2: a systematic review and meta-analysis. BMC Gastroenterol 2024; 24:331. [PMID: 39350091 PMCID: PMC11440749 DOI: 10.1186/s12876-024-03414-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 09/10/2024] [Indexed: 10/04/2024] Open
Abstract
BACKGROUND Direct-acting antivirals (DAAs) show high cure rates in treating chronic hepatitis C virus (HCV). However, the effect of DAAs on patients infected with genotype 2 (GT2) is difficult to determine despite the availability of several DAA regimens. METHODS A systematic search of six databases (PubMed, Embase, Cochrane Library, Web of Science, CNKI, and Clinicaltrial.gov) was conducted through April 20, 2022. We considered the sustained virological response 12 weeks after treatment (SVR12) as the efficacy outcome, and adverse events (AEs) as the safety outcome. By calculating the mean SVR12 and the proportion of AEs among patients, we considered the intervention effect for each DAA regimen. The random effect model was then used in all meta-analyses. This systematic review and meta-analysis aimed to summarize the evidence on efficacy and safety of DAAs in patients infected with HCV GT2. The Bayesian Markov Chain Monte Carlo (MCMC) network metanalysis was used to indirectly compare regimen in GT2 patients. RESULTS Among 31 articles included (2,968 participants), consisting of 1,387 treatment-naive patients and 354 patients with cirrhosis. The overall pooled SVR12 rate was 94.62% (95% CI: 92.43-96.52%) among the participants who received all doses of treatment. Meta-analysis results of AEs revealed that fatigue was the most common AE (14.0%, 95% CI: 6.4-21.6%), followed by headache (13.1%, 95% CI: 9.2-17.1%), whereas death and serious adverse events were uncommon. CONCLUSIONS We compared DAA-based treatments indirectly using meta-analysis and found the combination of Sofosbuvir plus Velpatasvir and Glecaprevir plus Pibrentasvir, each administered over a 12-week period, were identified as the most effective and relatively safe in managing chronic hepatitis C virus genotype 2 (HCV GT2) infection. Both treatments achieved a SVR12 of 100% (95% CI 99-100%).
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Affiliation(s)
- Pek Kei Lei
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
| | - Zicheng Liu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
| | - Carolina Oi Lam Ung
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
- Centre for Pharmaceutical Regulatory Sciences, University of Macau, Macao SAR, China
- Department of Public Health and Medicinal Administration, Faculty of Health Sciences, University of Macau, Macao SAR, China
| | - Hao Hu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China.
- Centre for Pharmaceutical Regulatory Sciences, University of Macau, Macao SAR, China.
- Department of Public Health and Medicinal Administration, Faculty of Health Sciences, University of Macau, Macao SAR, China.
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11
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Sohal A, Singh C, Bhalla A, Kalsi H, Roytman M. Renal Manifestations of Chronic Hepatitis C: A Review. J Clin Med 2024; 13:5536. [PMID: 39337023 PMCID: PMC11433393 DOI: 10.3390/jcm13185536] [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: 08/31/2024] [Revised: 09/13/2024] [Accepted: 09/16/2024] [Indexed: 09/30/2024] Open
Abstract
Hepatitis C virus (HCV) has emerged as a major global health concern and, if left untreated, can lead to significant liver damage, including cirrhosis, decompensated liver disease, and hepatocellular carcinoma (HCC). Approximately 40% of patients with HCV infection experience extrahepatic manifestations, including renal involvement. HCV-related renal disease is of significant importance among patients with chronic kidney disease (CKD), leading to higher morbidity and mortality. The renal damage due to HCV infection primarily results from cryoglobulinemia and glomerulonephritis, with conditions such as membranoproliferative glomerulonephritis (MPGN) and membranous nephropathy (MN) being most prevalent. Despite advancements in treatment, including the use of directly acting antiviral agents (DAAs), renal complications remain a significant burden in untreated patients. HCV-positive patients on hemodialysis (HD) or those who have undergone kidney transplantation face increased mortality rates compared to their HCV-negative counterparts. Managing HCV infection before kidney transplantation is crucial to mitigate the risk of HCV-related renal complications. Conversely, kidney transplantation from HCV-infected donors is well established, as post-transplant treatment for HCV is safe and effective, potentially reducing mortality and morbidity for patients on transplant waiting lists. This review aims to provide a comprehensive analysis of the renal manifestations of HCV, emphasizing the importance of early diagnosis and treatment to improve patient outcomes.
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Affiliation(s)
- Aalam Sohal
- Division of Gastroenterology and Hepatology, Creighton University School of Medicine, Phoenix, AZ 2500, USA
| | - Carol Singh
- Department of Internal Medicine, Dayanand Medical College and Hospital, Ludhiana 141001, Punjab, India
| | - Akshita Bhalla
- Department of Internal Medicine, Punjab Institute of Medical Sciences, Jalandhar 144006, Punjab, India
| | - Harsimran Kalsi
- Department of Internal Medicine, University of Central Florida College of Medicine, Orlando, FL 32827, USA
| | - Marina Roytman
- Division of Gastroenterology and Hepatology, University of California San Francisco, Fresno, CA 93701, USA
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12
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Quirino A, Marascio N, Branda F, Ciccozzi A, Romano C, Locci C, Azzena I, Pascale N, Pavia G, Matera G, Casu M, Sanna D, Giovanetti M, Ceccarelli G, Alaimo di Loro P, Ciccozzi M, Scarpa F, Maruotti A. Viral Hepatitis: Host Immune Interaction, Pathogenesis and New Therapeutic Strategies. Pathogens 2024; 13:766. [PMID: 39338957 PMCID: PMC11435051 DOI: 10.3390/pathogens13090766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 08/30/2024] [Accepted: 09/02/2024] [Indexed: 09/30/2024] Open
Abstract
Viral hepatitis is a major cause of liver illness worldwide. Despite advances in the understanding of these infections, the pathogenesis of hepatitis remains a complex process driven by intricate interactions between hepatitis viruses and host cells at the molecular level. This paper will examine in detail the dynamics of these host-pathogen interactions, highlighting the key mechanisms that regulate virus entry into the hepatocyte, their replication, evasion of immune responses, and induction of hepatocellular damage. The unique strategies employed by different hepatitis viruses, such as hepatitis B, C, D, and E viruses, to exploit metabolic and cell signaling pathways to their advantage will be discussed. At the same time, the innate and adaptive immune responses put in place by the host to counter viral infection will be analyzed. Special attention will be paid to genetic, epigenetic, and environmental factors that modulate individual susceptibility to different forms of viral hepatitis. In addition, this work will highlight the latest findings on the mechanisms of viral persistence leading to the chronic hepatitis state and the potential implications for the development of new therapeutic strategies. Fully understanding the complex host-pathogen interactions in viral hepatitis is crucial to identifying new therapeutic targets, developing more effective approaches for treatment, and shedding light on the mechanisms underlying progression to more advanced stages of liver damage.
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Affiliation(s)
- Angela Quirino
- Unit of Clinical Microbiology, Department of Health Sciences, “Magna Græcia” University of Catanzaro “Renato Dulbecco” Teaching Hospital, 88100 Catanzaro, Italy; (A.Q.); (N.M.); (G.P.); (G.M.)
| | - Nadia Marascio
- Unit of Clinical Microbiology, Department of Health Sciences, “Magna Græcia” University of Catanzaro “Renato Dulbecco” Teaching Hospital, 88100 Catanzaro, Italy; (A.Q.); (N.M.); (G.P.); (G.M.)
| | - Francesco Branda
- Unit of Medical Statistics and Molecular Epidemiology, Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (C.R.); (M.C.)
| | - Alessandra Ciccozzi
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (A.C.); (C.L.); (D.S.); (F.S.)
| | - Chiara Romano
- Unit of Medical Statistics and Molecular Epidemiology, Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (C.R.); (M.C.)
| | - Chiara Locci
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (A.C.); (C.L.); (D.S.); (F.S.)
- Department of Veterinary Medicine, University of Sassari, 07100 Sassari, Italy; (I.A.); (N.P.); (M.C.)
| | - Ilenia Azzena
- Department of Veterinary Medicine, University of Sassari, 07100 Sassari, Italy; (I.A.); (N.P.); (M.C.)
| | - Noemi Pascale
- Department of Veterinary Medicine, University of Sassari, 07100 Sassari, Italy; (I.A.); (N.P.); (M.C.)
- Department of Chemical Physical Mathematical and Natural Sciences, University of Sassari, 07100 Sassari, Italy
| | - Grazia Pavia
- Unit of Clinical Microbiology, Department of Health Sciences, “Magna Græcia” University of Catanzaro “Renato Dulbecco” Teaching Hospital, 88100 Catanzaro, Italy; (A.Q.); (N.M.); (G.P.); (G.M.)
| | - Giovanni Matera
- Unit of Clinical Microbiology, Department of Health Sciences, “Magna Græcia” University of Catanzaro “Renato Dulbecco” Teaching Hospital, 88100 Catanzaro, Italy; (A.Q.); (N.M.); (G.P.); (G.M.)
| | - Marco Casu
- Department of Veterinary Medicine, University of Sassari, 07100 Sassari, Italy; (I.A.); (N.P.); (M.C.)
| | - Daria Sanna
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (A.C.); (C.L.); (D.S.); (F.S.)
| | - Marta Giovanetti
- Department of Sciences and Technologies for Sustainable Development and One Health, Università Campus Bio-Medico di Roma, 00128 Rome, Italy;
- Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte 30190-002, MG, Brazil
- Climate Amplified Diseases and Epidemics (CLIMADE), Brasilia 70070-130, GO, Brazil
| | - Giancarlo Ceccarelli
- Department of Public Health and Infectious Diseases, University Hospital Policlinico Umberto I, Sapienza University of Rome, 00161 Rome, Italy;
| | | | - Massimo Ciccozzi
- Unit of Medical Statistics and Molecular Epidemiology, Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (C.R.); (M.C.)
| | - Fabio Scarpa
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (A.C.); (C.L.); (D.S.); (F.S.)
| | - Antonello Maruotti
- Department GEPLI, Libera Università Maria Ss Assunta, 00193 Rome, Italy;
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13
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Wright NJ, Zhang F, Suo Y, Kong L, Yin Y, Fedor JG, Sharma K, Borgnia MJ, Im W, Lee SY. Antiviral drug recognition and elevator-type transport motions of CNT3. Nat Chem Biol 2024; 20:1144-1153. [PMID: 38418906 PMCID: PMC11625470 DOI: 10.1038/s41589-024-01559-8] [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] [Received: 09/01/2023] [Accepted: 01/22/2024] [Indexed: 03/02/2024]
Abstract
Nucleoside analogs have broad clinical utility as antiviral drugs. Key to their systemic distribution and cellular entry are human nucleoside transporters. Here, we establish that the human concentrative nucleoside transporter 3 (CNT3) interacts with antiviral drugs used in the treatment of coronavirus infections. We report high-resolution single-particle cryo-electron microscopy structures of bovine CNT3 complexed with antiviral nucleosides N4-hydroxycytidine, PSI-6206, GS-441524 and ribavirin, all in inward-facing states. Notably, we found that the orally bioavailable antiviral molnupiravir arrests CNT3 in four distinct conformations, allowing us to capture cryo-electron microscopy structures of drug-loaded outward-facing and drug-loaded intermediate states. Our studies uncover the conformational trajectory of CNT3 during membrane transport of a nucleoside analog antiviral drug, yield new insights into the role of interactions between the transport and the scaffold domains in elevator-like domain movements during drug translocation, and provide insights into the design of nucleoside analog antiviral prodrugs with improved oral bioavailability.
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Affiliation(s)
- Nicholas J Wright
- Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA
| | - Feng Zhang
- Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA
| | - Yang Suo
- Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA
| | - Lingyang Kong
- Departments of Biological Sciences, Chemistry, and Bioengineering, Lehigh University, Bethlehem, PA, USA
| | - Ying Yin
- Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA
| | - Justin G Fedor
- Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA
| | - Kedar Sharma
- Department of Health and Human Services, Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, NC, USA
| | - Mario J Borgnia
- Department of Health and Human Services, Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, NC, USA
| | - Wonpil Im
- Departments of Biological Sciences, Chemistry, and Bioengineering, Lehigh University, Bethlehem, PA, USA
| | - Seok-Yong Lee
- Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA.
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14
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Zaid AB, Almady SK, Awad SM, Elabd MG, Saied SA, Saied AA, Elmalawany AM. Sofosbuvir (+) daclatasvir (+) ribavirin in Egyptian patients with hepatitis C virus: Therapeutic outcomes and the prognostic role of natural killer cells. Curr Res Transl Med 2024; 72:103443. [PMID: 38447269 DOI: 10.1016/j.retram.2024.103443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 02/02/2024] [Accepted: 02/29/2024] [Indexed: 03/08/2024]
Abstract
BACKGROUND One of the prominent causes of chronic liver disease worldwide is the hepatitis C virus (HCV). HCV believed that innate immunity contributes to a sustained virological response (SVR) to the treatment of Sofosbuvir (SOF) (+) Daclatasvir (DCV) (+) Ribavirin (RBV). This study aimed to evaluate the impact of SOF (+) DCV (+) RBV therapy and persistent HCV infection on the subset of natural killer cells (NK) in HCV genotype four patients from Egypt. MATERIALS AND METHODS One hundred and ten patients with persistent HCV infections requiring SOF (+) DCV (+) RBV therapy were grouped, and a flow cytometry (FCM) study of the NK cell subset in peripheral blood was performed. The assessment was performed before and after three and/or six months of the cessation of viral suppression therapy when a patient had a long-term viral response (SVR). One hundred and ten volunteers from the National Liver Institute's (NLI) blood bank were selected as controls. RESULTS Patients with chronic HCV infection before therapy had considerably lower CD16+ and CD3- CD56+ cells than controls. Their levels increase during SOF (+) DCV (+) RBV therapy. In patients with SVR during treatment, CD16+ and CD3- CD56+ cells increased significantly compared to those who did not get SVR. Furthermore, CD56+ cells were significantly higher in patients with persistent infection before treatment than controls but diminished with the response to treatment. CONCLUSION NK cell activation following SOF (+) DCV (+) RBV therapy and polarization to cytotoxicity occurred early in HCV antiviral therapy and was elevated in the respondents. Our data illustrated that establishing an inhibitory cytotoxic NK profile is related to therapeutic outcomes.
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Affiliation(s)
- Ahmed B Zaid
- Department of Clinical Pathology, National Liver Institute, Menoufia University, Shibin Elkom 32511, Egypt
| | - Shimaa K Almady
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shibin-Elkom 32511, Egypt
| | - Samah M Awad
- Department of Clinical Microbiology, National Liver Institute, Menoufia University, Shibin Elkom 32511, Egypt
| | - Mona G Elabd
- Department of Clinical Pathology, National Liver Institute, Menoufia University, Shibin Elkom 32511, Egypt
| | - Sara A Saied
- Department of Clinical Pathology, National Liver Institute, Menoufia University, Shibin Elkom 32511, Egypt
| | | | - Alshimaa M Elmalawany
- Department of Clinical Pathology, National Liver Institute, Menoufia University, Shibin Elkom 32511, Egypt.
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15
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Konishi K, Kusakabe S, Kawaguchi N, Shishido T, Ito N, Harada M, Inoue S, Maeda K, Hall WW, Orba Y, Sawa H, Sasaki M, Sato A. β-d-N 4-hydroxycytidine, a metabolite of molnupiravir, exhibits in vitro antiviral activity against rabies virus. Antiviral Res 2024; 229:105977. [PMID: 39089332 DOI: 10.1016/j.antiviral.2024.105977] [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: 05/12/2024] [Revised: 07/08/2024] [Accepted: 07/30/2024] [Indexed: 08/03/2024]
Abstract
Rabies is a fatal neurological disorder caused by rabies virus (RABV) infection. Approximately 60,000 patients die from rabies annually, and there are no effective treatments for this disease. Nucleoside analogs are employed as antiviral drugs based on their broad antiviral spectrum, and certain nucleoside analogs have been reported to exhibit anti-RABV activity. The nucleoside analog β-d-N4-hydroxycytidine (NHC) has antiviral effects against a range of RNA viruses. Molnupiravir (MPV), a prodrug of NHC, is clinically used as an oral antiviral drug for coronavirus infections. Despite its broad-spectrum activity, the antiviral activity of NHC against RABV remains unclear. In this study, we reveal that NHC exhibits comparable in vitro anti-RABV activity as ribavirin and favipiravir (also known as T-705) with a 90% effective concentration of 6 μM in mouse neuroblastoma cells. NHC reduced viral loads in neuronal and nonneuronal cells in a dose-dependent manner. Both laboratory and field RABVs (fixed and street strains, respectively) were susceptible to NHC. However, no increase in survival or reduction in viral titers in the brain was observed in RABV-infected mice treated prophylactically with MPV. These findings highlight the potential and challenges of NHC in the treatment of RABV infection.
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Affiliation(s)
- Kei Konishi
- Laboratory for Drug Discovery & Disease Research, Shionogi & Co., Ltd., Osaka, Japan; Division of Anti-Virus Drug Research, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
| | - Shinji Kusakabe
- Laboratory for Drug Discovery & Disease Research, Shionogi & Co., Ltd., Osaka, Japan; Division of Anti-Virus Drug Research, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
| | - Nijiho Kawaguchi
- Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
| | - Takao Shishido
- Laboratory for Drug Discovery & Disease Research, Shionogi & Co., Ltd., Osaka, Japan
| | - Naoto Ito
- Laboratory of Zoonotic Diseases, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
| | - Michiko Harada
- Department of Veterinary Science, National Institute of Infectious Diseases (NIID), Tokyo, Japan
| | - Satoshi Inoue
- Department of Veterinary Science, National Institute of Infectious Diseases (NIID), Tokyo, Japan
| | - Ken Maeda
- Department of Veterinary Science, National Institute of Infectious Diseases (NIID), Tokyo, Japan
| | - William W Hall
- International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; National Virus Reference Laboratory, School of Medicine, University College of Dublin, Ireland; Global Virus Network, Baltimore, MD, USA; Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan
| | - Yasuko Orba
- Division of Anti-Virus Drug Research, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan; One Health Research Center, Hokkaido University, Sapporo, Japan
| | - Hirofumi Sawa
- Division of Anti-Virus Drug Research, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; Global Virus Network, Baltimore, MD, USA; Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan; One Health Research Center, Hokkaido University, Sapporo, Japan
| | - Michihito Sasaki
- Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan.
| | - Akihiko Sato
- Laboratory for Drug Discovery & Disease Research, Shionogi & Co., Ltd., Osaka, Japan; Division of Anti-Virus Drug Research, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan.
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16
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Gomaa A, Gomaa M, Allam N, Waked I. Hepatitis C Elimination in Egypt: Story of Success. Pathogens 2024; 13:681. [PMID: 39204281 PMCID: PMC11357586 DOI: 10.3390/pathogens13080681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 08/06/2024] [Accepted: 08/09/2024] [Indexed: 09/03/2024] Open
Abstract
Egypt has long been overwhelmed by the hepatitis C virus (HCV) infection, and it used to be the country with the world's highest prevalence rates. The disease had been a significant public health problem, affecting millions of Egyptians and posing severe economic and social challenges. By the early 2000s, it was estimated that around 10% of the Egyptian population was infected with HCV. However, in recent years, with the availability of direct-acting antiviral therapies, the country has made enormous steps in combating this public health threat. The combination of innovative health strategies and political will enabled Egypt to establish a successful model of care for HCV management and to be the first country to eliminate hepatitis C, setting a model for the rest of the world. In 2023, Egypt became the first country to fulfill the World Health Organization's set programmatic criteria of reduction of hepatitis C incidence and mortalities to levels close to elimination of disease or achieve the "gold tier" status on the path to disease elimination.
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Affiliation(s)
- Asmaa Gomaa
- Hepatology and Gastroenterology Department, National Liver Institute, Menofia University, Shebin El-Kom 32511, Egypt; (A.G.); (N.A.)
| | - Mohamed Gomaa
- Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, QC J1H 5N4, Canada;
| | - Naglaa Allam
- Hepatology and Gastroenterology Department, National Liver Institute, Menofia University, Shebin El-Kom 32511, Egypt; (A.G.); (N.A.)
| | - Imam Waked
- Hepatology and Gastroenterology Department, National Liver Institute, Menofia University, Shebin El-Kom 32511, Egypt; (A.G.); (N.A.)
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17
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Liu CH, Chang YP, Kao JH. Cutting-edge pharmacotherapy for hepatitis C virus infection: a comprehensive review. Expert Opin Pharmacother 2024; 25:1691-1706. [PMID: 39169665 DOI: 10.1080/14656566.2024.2396024] [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: 07/17/2024] [Revised: 08/17/2024] [Accepted: 08/20/2024] [Indexed: 08/23/2024]
Abstract
INTRODUCTION Pharmacotherapy against hepatitis C virus (HCV) infection has tremendously improved since the advent of interferon (IFN)-free direct-acting antivirals (DAAs). Additionally, fixed-dose pangenotypic DAAs, which are safe, potent, easy for use, and can cover a wide spectrum of patients, have been recommended by professional guidelines for DAA-naïve and DAA-experienced patients with HCV. AREAS COVERED We review the pharmacokinetics, pharmacodynamics, and potential drug-drug interactions (DDIs) of fixed-dose pangenotypic DAA regimens, including glecaprevir/pibrentasvir (GLE/PIB), sofosbuvir/velpatasvir (SOF/VEL), and sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX). Additionally, we summarize the efficacy and safety of these regimens in clinical trials as well as real-world studies for treating different populations. Lastly, we discuss unmet medical needs in managing HCV in the era of fixed-dose pangenotypic DAAs. EXPERT OPINION Protease inhibitors (PIs), including GLE and VOX, are prone to have more frequent DDIs, compared to the non-structural (NS) 5A and 5B inhibitors. These regimens are generally well tolerated and can be applied to different populations, except for the contraindicated use of PI-containing DAA regimens in decompensated cirrhosis. Using the first-line GLE/PIB and SOF/VEL can eradicate HCV in more than 95% of DAA-naïve patients across different populations. The viral cure usually exceeds 95% when using the rescue SOF/VEL/VOX regimen for prior DAA failures.
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Affiliation(s)
- Chen-Hua Liu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Douliou, Taiwan
| | - Yu-Ping Chang
- Department of Internal Medicine, National Taiwan University Biomedical Park Hospital, Hsin-Chu, Taiwan
| | - Jia-Horng Kao
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
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Park Y, Na SK, Yoon JH, Kim SE, Park JW, Kim GA, Lee HY, Lee YS, Kim JH. Prognosis Following Sustained Virologic Response in Korean Chronic Hepatitis C Patients Treated with Sofosbuvir-Based Treatment: Data from a Multicenter Prospective Observational Study up to 7 Years. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:1132. [PMID: 39064561 PMCID: PMC11279039 DOI: 10.3390/medicina60071132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 07/08/2024] [Accepted: 07/12/2024] [Indexed: 07/28/2024]
Abstract
Background and Objectives: Chronic hepatitis C (CHC) can be cured with direct-acting antiviral (DAA) therapy. In Korea, sofosbuvir (SOF) and ledipasvir (LDV)/SOF were launched in 2016. Patients who achieve a sustained virologic response (SVR) following DAA treatment are predicted to have a favorable prognosis. Nevertheless, little is known regarding the prognosis of Korean CHC patients who receive SOF-based treatment and achieve SVR. Therefore, the purpose of this study was to look into the long-term outcomes for these patients. Materials and Methods: This was a prospective, multicenter observational study. CHC patients were enrolled who, following SOF or LDV/SOF treatment, had achieved SVR. The last day for follow-up was December 2023. The primary endpoint was HCC occurrence, which was checked at least once per year. Results: A total of 516 patients were included in this analysis, with a median follow-up duration of 39.0 months. Among them, 231 were male patients (44.8%), with a median age of 62.0 years. Genotypes were 1 (90, 17.4%), 2 (423, 82.0%), and 3 (3, 0.6%). The combination of SOF plus ribavirin was the most common treatment (394, 76.4%). In total, 160 patients were cirrhotic (31.0%), and the mean Child-Pugh score was 5.1. Within a maximum of 7 years, 21 patients (4.1%) developed HCC. Patients with HCC were older (69 vs. 61 years, p = 0.013) and had a higher cirrhosis incidence (81.0 vs. 28.9%, p < 0.001), higher AFP (6.0 vs. 3.3, p = 0.003) and higher APRI (0.8 vs. 0.5, p = 0.005). Age over 65 (p = 0.016) and cirrhosis (p = 0.005) were found to be significant risk factors for HCC by Cox regression analysis. Conclusions: Patients who achieved SVR with SOF-based treatment had a relatively favorable prognosis. However, the risk of HCC was not eliminated, especially in older and cirrhotic patients. Therefore, routine follow-up, surveillance, and early treatment are required.
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Affiliation(s)
- Yewan Park
- Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul 02447, Republic of Korea; (Y.P.); (G.-A.K.)
| | - Seong-Kyun Na
- Department of Internal Medicine, Inje University Sanggye Paik Hospital, Seoul 01757, Republic of Korea; (S.-K.N.); (H.-Y.L.)
| | - Jae-Hyun Yoon
- Department of Internal Medicine, School of Medicine, Chonnam National University Hospital, Gwangju 61469, Republic of Korea;
| | - Sung-Eun Kim
- Department of Internal Medicine, Hallym University College of Medicine, Anyang 14068, Republic of Korea; (S.-E.K.); (J.-W.P.)
| | - Ji-Won Park
- Department of Internal Medicine, Hallym University College of Medicine, Anyang 14068, Republic of Korea; (S.-E.K.); (J.-W.P.)
| | - Gi-Ae Kim
- Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul 02447, Republic of Korea; (Y.P.); (G.-A.K.)
| | - Hyo-Young Lee
- Department of Internal Medicine, Inje University Sanggye Paik Hospital, Seoul 01757, Republic of Korea; (S.-K.N.); (H.-Y.L.)
| | - Young-Sun Lee
- Department of Internal Medicine, Korea University Medical Center, Seoul 08308, Republic of Korea;
| | - Jeong-Han Kim
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul 05030, Republic of Korea
- Research Institute of Medical Science, Konkuk University School of Medicine, Seoul 05029, Republic of Korea
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Hashem M, Medhat MA, Abdeltawab D, Makhlouf NA. Expanding the liver donor pool worldwide with hepatitis C infected livers, is it the time? World J Transplant 2024; 14:90382. [PMID: 38947961 PMCID: PMC11212581 DOI: 10.5500/wjt.v14.i2.90382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 02/29/2024] [Accepted: 04/12/2024] [Indexed: 06/13/2024] Open
Abstract
Liver transplantation (LT) provides a life-saving option for cirrhotic patients with complications and hepatocellular carcinoma. Despite the increasing number of liver transplants performed each year, the number of LT candidates on the waitlist remains unchanged due to an imbalance between donor organ supply and the demand which increases the waitlist time and mortality. Living donor liver transplant had a great role in increasing the donor pool and shortened waitlist time for LT candidates. Nevertheless, further strategies can be implemented to increase the pool of potential donors in deceased donor LT, such as reducing the rate of organ discards. Utilizing hepatitis C virus (HCV) seropositive liver grafts is one of the expanded donor organ criteria. A yearly increase of hundreds of transplants is anticipated as a result of maximizing the utilization of HCV-positive organs for HCV-negative recipients. Direct-acting antiviral therapy's efficacy has revolutionized the treatment of HCV infection and the use of HCV-seropositive donors in transplantation. The American Society of Transplantation advises against performing transplants from HCV-infected liver donors (D+) into HCV-negative recipient (R-) unless under Institutional Review Board-approved study rules and with full informed consent of the knowledge gaps associated with such transplants. Proper selection of patients to be transplanted with HCV-infected grafts and confirming their access to direct-acting antivirals if needed is important. National and international consensuses are needed to regulate this process to ensure the maximum benefit and the least adverse events.
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Affiliation(s)
- Mai Hashem
- Fellow of Tropical Medicine and Gastroenterology, Assiut University Hospital, Assiut 71515, Egypt
| | - Mohammed A Medhat
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
| | - Doaa Abdeltawab
- Department of Tropical Medicine and Gastroenterology, Al-Rajhi Liver Hospital, Assiut University, Assiut 71515, Egypt
| | - Nahed A Makhlouf
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
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20
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Boesch M, Baty F, Rassouli F, Brutsche MH. What is disease modification and is this concept even helpful? Eur J Intern Med 2024; 124:1-4. [PMID: 38555252 DOI: 10.1016/j.ejim.2024.03.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 02/12/2024] [Accepted: 03/25/2024] [Indexed: 04/02/2024]
Affiliation(s)
| | - Florent Baty
- Lung Center, Cantonal Hospital St.Gallen, St.Gallen, Switzerland
| | - Frank Rassouli
- Lung Center, Cantonal Hospital St.Gallen, St.Gallen, Switzerland
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21
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Wang R, Huang S, Wang P, Tang X, Xu H, Zhang W, Shi L, Zhong X, Lü M, Zhou X, Shi X. Research status and hotspots in the field of endoplasmic reticulum stress and liver disease: A bibliometric study. Medicine (Baltimore) 2024; 103:e38450. [PMID: 39259055 PMCID: PMC11142769 DOI: 10.1097/md.0000000000038450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 04/10/2024] [Accepted: 05/10/2024] [Indexed: 09/12/2024] Open
Abstract
Recently, the study of endoplasmic reticulum stress (ERS) and liver disease has attracted much attention, but bibliometric analysis on this field is scarce. Therefore, to address this gap, we conducted a bibliometric analysis to explore the research status, hotspots, and trends in this field. We searched the Web of Science Core Collection database for publications on ERS and liver disease from 2007 to 2022. Bibliometric online analysis platform, VOSviewer, and CiteSpace were used to perform bibliometric analysis. Two thousand seven hundred fifty-one publications were retrieved form the Web of Science Core Collection database. The USA was the most productive and influential country. Seoul National University, International Journal of Molecular Sciences, and Kaufman RJ were the most productive institution, journal, and author. "Endoplasmic reticulum stress," "nonalcoholic fatty liver disease," "inflammation," "oxidative stress" and "insulin resistance" were the high-frequency keywords, "necrosis factor alpha" was the keywords with the strongest citation bursts, and "nonalcoholic fatty liver," "fibrosis" and "lipid droplet" were the keywords that were still bursting in 2022. The number of publications on ERS and liver disease has increased over the past years. The USA was the most productive and influential country. China has become the country with the largest number of annual publications, but it still needs to work on the quality. ERS and nonalcoholic fatty liver disease, especially the insulin resistance and lipotoxicity in hepatocytes may be the research hotspots and trends in this field of ERS and liver disease.
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Affiliation(s)
- Ruiyu Wang
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China
| | - Shu Huang
- Department of Gastroenterology, Lianshui County People’ Hospital, Huaian, China
- Department of Gastroenterology, Lianshui People’ Hospital of Kangda College, Affiliated to Nanjing Medical University, Huaian, China
| | - Ping Wang
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China
| | - Xiaowei Tang
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China
| | - Huan Xu
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China
| | - Wei Zhang
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China
| | - Lei Shi
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China
| | - Xiaolin Zhong
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China
| | - Muhan Lü
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China
| | - Xian Zhou
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China
| | - Xiaomin Shi
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China
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22
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Sallam M, Khalil R. Contemporary Insights into Hepatitis C Virus: A Comprehensive Review. Microorganisms 2024; 12:1035. [PMID: 38930417 PMCID: PMC11205832 DOI: 10.3390/microorganisms12061035] [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: 04/30/2024] [Revised: 05/15/2024] [Accepted: 05/20/2024] [Indexed: 06/28/2024] Open
Abstract
Hepatitis C virus (HCV) remains a significant global health challenge. Approximately 50 million people were living with chronic hepatitis C based on the World Health Organization as of 2024, contributing extensively to global morbidity and mortality. The advent and approval of several direct-acting antiviral (DAA) regimens significantly improved HCV treatment, offering potentially high rates of cure for chronic hepatitis C. However, the promising aim of eventual HCV eradication remains challenging. Key challenges include the variability in DAA access across different regions, slightly variable response rates to DAAs across diverse patient populations and HCV genotypes/subtypes, and the emergence of resistance-associated substitutions (RASs), potentially conferring resistance to DAAs. Therefore, periodic reassessment of current HCV knowledge is needed. An up-to-date review on HCV is also necessitated based on the observed shifts in HCV epidemiological trends, continuous development and approval of therapeutic strategies, and changes in public health policies. Thus, the current comprehensive review aimed to integrate the latest knowledge on the epidemiology, pathophysiology, diagnostic approaches, treatment options and preventive strategies for HCV, with a particular focus on the current challenges associated with RASs and ongoing efforts in vaccine development. This review sought to provide healthcare professionals, researchers, and policymakers with the necessary insights to address the HCV burden more effectively. We aimed to highlight the progress made in managing and preventing HCV infection and to highlight the persistent barriers challenging the prevention of HCV infection. The overarching goal was to align with global health objectives towards reducing the burden of chronic hepatitis, aiming for its eventual elimination as a public health threat by 2030.
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Affiliation(s)
- Malik Sallam
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman 11942, Jordan
- Department of Clinical Laboratories and Forensic Medicine, Jordan University Hospital, Amman 11942, Jordan
| | - Roaa Khalil
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman 11942, Jordan
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23
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Niu ZX, Hu J, Sun JF, Wang YT. Fluorine in the pharmaceutical industry: Synthetic approaches and application of clinically approved fluorine-enriched anti-infectious medications. Eur J Med Chem 2024; 271:116446. [PMID: 38678824 DOI: 10.1016/j.ejmech.2024.116446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 04/14/2024] [Accepted: 04/22/2024] [Indexed: 05/01/2024]
Abstract
The strategic integration of fluorine atoms into anti-infectious agents has become a cornerstone in the field of medicinal chemistry, owing to the unique influence of fluorine on the chemical and biological properties of pharmaceuticals. This review examines the synthetic methodologies that enable the incorporation of fluorine into anti-infectious drugs, and the resultant clinical applications of these fluorine-enriched compounds. With a focus on clinically approved medications, the discussion extends to the molecular mechanisms. It further outlines the specific effects of fluorination, which contribute to the heightened efficacy of anti-infective therapies. By presenting a comprehensive analysis of current drugs and their developmental pathways, this review underscores the continuing evolution and significance of fluorine in advancing anti-infectious treatment options. The insights offered extend valuable guidance for future drug design and the development of next-generation anti-infectious agents.
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Affiliation(s)
- Zhen-Xi Niu
- Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou Children's Hospital, Zhengzhou, 450018, China
| | - Jing Hu
- Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou Children's Hospital, Zhengzhou, 450018, China.
| | - Jin-Feng Sun
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University, College of Pharmacy, Yanji, Jilin,133002, China.
| | - Ya-Tao Wang
- First People's Hospital of Shangqiu, Henan Province, Shangqiu, 476100, China; Rega Institute for Medical Research, Medicinal Chemistry, KU Leuven, Herestraat 49-Box 1041, 3000, Leuven, Belgium.
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24
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Dobrowolska K, Brzdęk M, Rzymski P, Flisiak R, Pawłowska M, Janczura J, Brzdęk K, Zarębska-Michaluk D. Revolutionizing hepatitis C treatment: next-gen direct-acting antivirals. Expert Opin Pharmacother 2024; 25:833-852. [PMID: 38768013 DOI: 10.1080/14656566.2024.2358139] [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: 04/11/2024] [Accepted: 05/17/2024] [Indexed: 05/22/2024]
Abstract
INTRODUCTION With the introduction of highly effective and safe therapies with next-generation direct-acting antivirals (DAAs), that act without interferon, hepatitis C virus (HCV) infection remains the only treatable chronic infectious disease. AREAS COVERED The review aims to provide an overview of the therapy revolution with a description of specific DAAs, their mechanisms of action, a summary of the safety and efficacy of specific regimens, and a discussion of populations requiring special therapeutic approaches. EXPERT OPINION DAAs are highly effective, safe, and easy to use. However, challenges such as access to health services and loss of patients from the cascade of care, especially in groups disproportionately affected by HCV infection, such as substance abusers, make it difficult to achieve the WHO's goal of HCV elimination. The proposed strategy to combat these difficulties involves a one-step approach to diagnosing and treating the infection, the availability of long-lasting forms of medication, and the development of an effective vaccine. The aforementioned opportunities are all the more important as the world is facing an opioid epidemic that is translating into an increase in HCV prevalence. This phenomenon is of greatest concern in women of childbearing age and in those already pregnant due to treatment limitations.
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Affiliation(s)
| | - Michał Brzdęk
- Collegium Medicum, Jan Kochanowski University, Kielce, Poland
| | - Piotr Rzymski
- Department of Environmental Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok, Poland
| | - Małgorzata Pawłowska
- Department of Infectious Diseases and Hepatology, Faculty of Medicine, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
| | - Jakub Janczura
- Collegium Medicum, Jan Kochanowski University, Kielce, Poland
| | - Kinga Brzdęk
- Collegium Medicum, Jan Kochanowski University, Kielce, Poland
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25
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Marzaban RN, AlMekhzangy HI, ElAkel W, ElBaz TM, ElShazly YM, ElSaeed K, Anees M, Said M, ElSerafy MA, Esmat GG, Doss WH. Diabetic patients with chronic hepatitis C virus response compared to non diabetics when treated with directly acting antiviral therapy. Arab J Gastroenterol 2024; 25:118-124. [PMID: 38378359 DOI: 10.1016/j.ajg.2023.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 11/30/2023] [Accepted: 12/30/2023] [Indexed: 02/22/2024]
Abstract
BACKGROUND AND STUDY AIMS Hepatitis C virus (HCV) impairs glucose homoestasis, thus influences its clinical picture and prognosis. This study aimed at evaluating Diabetes mellitus (DM) on Egyptian patients with chronic hepatitis C (CHC), and its impact on their virologic response when treated with directly acting antiviral (DAA) medications. PATIENTS AND METHODS Adult patients with CHC were divided into 2 groups; Diabetic patients, and Non diabetic patients serving as control group. All patients were subjected to thorough clinical evaluation, basic biochemical laboratory tests including fasting blood glucose/glycosylated haemoglobin (HbA1C), and virologic assay. They were treated with various combined DAAs, and were monitored during, at and after end of treatment. RESULTS Diabetic patients constituted 9.85 % of CHC, and had generally worse laboratory tests (significantly higher transaminases, platelet count, Fib4 and hepatic steatosis) than non diabetic patients, and a less sustained virologic response (SVR) (significantly in Sofosbuvir (SOF) + pegylated interferon (PegIFN) + ribavirin (RBV), SOF + RBV, SOF + daclatasvir (DAC)). Although DM did not play a significant influence on SVR, yet Fib4 and SOF + RBV + PEG-IFN were significant factors affecting SVR among diabetics, while female gender and viraemia were significant factors affecting SVR among non diabetics. Hepatic fibrosis and SOF/RBV significantly influenced SVR in both groups. CONCLUSIONS Diabetic patients with CHC have worse liver biochemical profile, yet DM per se did not influence the virologic response to DAAs, however, some factors played roles in affecting SVR among them.
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Affiliation(s)
- Raghda N Marzaban
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Egypt.
| | | | - Wafaa ElAkel
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Egypt.
| | - Tamer M ElBaz
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Egypt
| | - Yehia M ElShazly
- Internal Medicine, Faculty of Medicine, Ain Shams University, Egypt
| | - Kadry ElSaeed
- Tropical Medicine, Faculty of Medicine, Ain Shams University, Egypt
| | - Mahmoud Anees
- Tropical Medicine, Faculty of Medicine, Tanta University, Egypt
| | - Mohamed Said
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Egypt
| | - Magdy A ElSerafy
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Egypt
| | - Gamal G Esmat
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Egypt.
| | - Wahid H Doss
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Egypt
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26
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Formica M, Ferko B, Marsh T, Davidson TA, Yamazaki K, Dixon DJ. Second Generation Catalytic Enantioselective Nucleophilic Desymmetrization at Phosphorus (V): Improved Generality, Efficiency and Modularity. Angew Chem Int Ed Engl 2024; 63:e202400673. [PMID: 38381534 DOI: 10.1002/anie.202400673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 02/20/2024] [Accepted: 02/21/2024] [Indexed: 02/23/2024]
Abstract
A broadly improved second generation catalytic two-phase strategy for the enantioselective synthesis of stereogenic at phosphorus (V) compounds is described. This protocol, consisting of a bifunctional iminophosphorane (BIMP) catalyzed nucleophilic desymmetrization of prochiral, bench stable P(V) precursors and subsequent enantiospecific substitution allows for divergent access to a wide range of C-, N-, O- and S- substituted P(V) containing compounds from a handful of enantioenriched intermediates. A new ureidopeptide BIMP catalyst/thiaziolidinone leaving group combination allowed for a far wider substrate scope and increased reaction efficiency and practicality over previously established protocols. The resulting enantioenriched intermediates could then be transformed into an even greater range of distinct classes of P(V) compounds by displacement of the remaining leaving group as well as allowing for even further diversification downstream. Density functional theory (DFT) calculations were performed to pinpoint the origin of enantioselectivity for the BIMP-catalyzed desymmetrization, to rationalize how a superior catalyst/leaving group combination leads to increased generality in our second-generation catalytic system, as well as shed light onto observed stereochemical retention and inversion pathways when performing late-stage enantiospecific SN2@P reactions with Grignard reagents.
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Affiliation(s)
- Michele Formica
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, OX1 3TA, Oxford, UK
| | - Branislav Ferko
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, OX1 3TA, Oxford, UK
| | - Thomas Marsh
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, OX1 3TA, Oxford, UK
| | - Timothy A Davidson
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, OX1 3TA, Oxford, UK
| | - Ken Yamazaki
- Division of Applied Chemistry, Okayama University, Tsushimanaka, Okayama, 700-8530, Japan
| | - Darren J Dixon
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, OX1 3TA, Oxford, UK
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27
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Nasr MS, Talaat W, Morshedy S, Kaddah MMY, Omran G, Keshk RM. A new fluorescence probe for sofosbuvir analysis in dosage form and spiked human plasma. LUMINESCENCE 2024; 39:e4742. [PMID: 38637644 DOI: 10.1002/bio.4742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 03/09/2024] [Accepted: 03/15/2024] [Indexed: 04/20/2024]
Abstract
A simple, rapid, and low-cost technique was developed to allow reliable analysis of the anti-hepatitis C drug sofosbuvir in bulk, tablet form, and spiked human plasma. This method depends on the ability of sofosbuvir to quench the fluorescence of the newly synthesized 2-amino-3-cyano-4,6-dimethylpyridine (reagent 3). Elemental analysis and spectral data were used to validate the structure of the synthesized reagent. The newly synthesized reagent exhibited a satisfactory level of fluorescence emission at 365 nm after excitation at 247 nm. All experimental variables that might affect the quenching process were analyzed and optimized. Linearity, range, accuracy, precision, limit of detection (LOD), and limit of quantitation (LOQ) were all validated in accordance with the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. The concentration range was shown to be linear between 0.1 and 1.5 μg/mL. The technique was effectively utilized for sofosbuvir analysis in both its tablet dosage form and spiked human plasma, with mean percentage recoveries of 100.13 ± 0.35 and 94.26 ± 1.69, respectively.
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Affiliation(s)
- Mohamed S Nasr
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt
| | - Wael Talaat
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt
| | - Samir Morshedy
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt
| | - Mohamed M Y Kaddah
- Pharmaceutical and Fermentation Industries Development Center, City of Scientific Research and Technological Applications, New Borg El-Arab, Alexandria, Egypt
| | - Gamal Omran
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt
| | - Reda M Keshk
- Department of Chemistry, Faculty of Science, Damanhour University, Damanhour, Egypt
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28
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Bissonnette NB, Bisballe N, Tran AV, Rossi-Ashton JA, MacMillan DWC. Development of a General Organophosphorus Radical Trap: Deoxyphosphonylation of Alcohols. J Am Chem Soc 2024; 146:7942-7949. [PMID: 38470101 PMCID: PMC11474583 DOI: 10.1021/jacs.4c00557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/13/2024]
Abstract
Here we report the design of a general, redox-switchable organophosphorus alkyl radical trap that enables the synthesis of a broad range of C(sp3)-P(V) modalities. This "plug-and-play" approach relies upon in situ activation of alcohols and O═P(R2)H motifs, two broadly available and inexpensive sources of molecular complexity. The mild, photocatalytic deoxygenative strategy described herein allows for the direct conversion of sugars, nucleosides, and complex pharmaceutical architectures to their organophosphorus analogs. This includes the facile incorporation of medicinally relevant phosphonate ester prodrugs.
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Affiliation(s)
- Noah B Bissonnette
- Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, United States
| | - Niels Bisballe
- Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, United States
| | - Andrew V Tran
- Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, United States
| | - James A Rossi-Ashton
- Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, United States
| | - David W C MacMillan
- Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, United States
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Ullah S, Naveed M, Ali A, Bibi S, Idrees W, Rafique S, Idrees M, Waqas M, Uddin J, Jan A, Khan A, Al-Harrasi A. Assessment of ubiquitin specific Peptidase-18 gene in peripheral blood of chronic hepatitis C patients treated with direct-acting antiviral drugs. Heliyon 2024; 10:e24581. [PMID: 38298711 PMCID: PMC10828700 DOI: 10.1016/j.heliyon.2024.e24581] [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: 10/23/2023] [Revised: 12/30/2023] [Accepted: 01/10/2024] [Indexed: 02/02/2024] Open
Abstract
Hepatitis C virus (HCV) infection remains one of the leading causes of liver complications globally. Ubiquitin Specific Peptidase-18 (USP18) is a ubiquitin-specific protease that cleaves interferon-stimulated gene 15 (ISG15) from ISGylated protein complexes and is involved in regulating interferon responsiveness. To study the effect of direct-acting antivirals (DAAs) on the USP18 gene using qPCR, 132 participants were recruited and classified into different groups based on treatment duration. USP18 expression was raised compared to rapid virologic response (RVR) and early virologic response (EVR) groups with P = 0.0026 and P = 0.0016, respectively. USP18 was found to be 7.36 folds higher in naïve patients than those with RVR and sustained viral response (SVR). In RVR and SVR groups where patients had cleared HCV RNA after treatment with direct-acting antiviral agents (DAA) therapy, the expression of USP18 was found to be low, with a fold change of 1.3 and 1.4 folds, respectively. Expression of USP18 was significantly higher in the non-RVR group than in the RVR group. In the No EVR group, gene expression was significantly higher than in the EVR group. It is concluded that targeting HCV proteins using DAAs can cause USP18 expression to be normalized more effectively. Moreover, USP18 is a vital marker indicating treatment resistance and distinguishing responders from non-responders during DAA therapy.
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Affiliation(s)
- Sami Ullah
- Molecular Virology laboratory Centre for Applied Molecular Biology (CAMB), 87-West Canal Bank Road Thokar Niaz Baig, University of the Punjab, Lahore, Pakistan
| | - Mariam Naveed
- Molecular Virology laboratory Centre for Applied Molecular Biology (CAMB), 87-West Canal Bank Road Thokar Niaz Baig, University of the Punjab, Lahore, Pakistan
| | - Amjad Ali
- Molecular Virology laboratory Centre for Applied Molecular Biology (CAMB), 87-West Canal Bank Road Thokar Niaz Baig, University of the Punjab, Lahore, Pakistan
- Department of Biotechnology and Genetic Engineering, Hazara University Mansehra, Khyber Pakhtunkhwa, Pakistan
| | - Sadia Bibi
- Department of Botany, University of Malakand Chakdara, Dir lower, Khyber Pakhtunkhwa, Pakistan
| | - Wafa Idrees
- Khyber Medical College, Peshawar, Khyber Pakhtunkhwa, Pakistan
| | - Shazia Rafique
- Division of Molecular Virology, Centre of Excellence in Molecular Biology (CEMB), 87-West Canal Bank Road Thokar Niaz Baig, University of the Punjab, Lahore, Pakistan
| | - Muhammad Idrees
- Division of Molecular Virology, Centre of Excellence in Molecular Biology (CEMB), 87-West Canal Bank Road Thokar Niaz Baig, University of the Punjab, Lahore, Pakistan
- Vice Chancellor, University of Peshawar, Peshawar, Khyber Pakhtunkhwa, Pakistan
| | - Muhammad Waqas
- Department of Biotechnology and Genetic Engineering, Hazara University Mansehra, Khyber Pakhtunkhwa, Pakistan
- Natural and Medical Sciences Research Center, University of Nizwa, Birkat-ul-Mouz 616, Nizwa, Sultanate of Oman
| | - Jalal Uddin
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Khalid University, Abha, 62529, Kingdom of Saudi Arabia
| | - Afnan Jan
- Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah 21955, Saudi Arabia
| | - Ajmal Khan
- Natural and Medical Sciences Research Center, University of Nizwa, Birkat-ul-Mouz 616, Nizwa, Sultanate of Oman
| | - Ahmed Al-Harrasi
- Natural and Medical Sciences Research Center, University of Nizwa, Birkat-ul-Mouz 616, Nizwa, Sultanate of Oman
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Pang Z, Cravatt BF, Ye L. Deciphering Drug Targets and Actions with Single-Cell and Spatial Resolution. Annu Rev Pharmacol Toxicol 2024; 64:507-526. [PMID: 37722721 DOI: 10.1146/annurev-pharmtox-033123-123610] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/20/2023]
Abstract
Recent advances in chemical, molecular, and genetic approaches have provided us with an unprecedented capacity to identify drug-target interactions across the whole proteome and genome. Meanwhile, rapid developments of single-cell and spatial omics technologies are revolutionizing our understanding of the molecular architecture of biological systems. However, a significant gap remains in how we align our understanding of drug actions, traditionally based on molecular affinities, with the in vivo cellular and spatial tissue heterogeneity revealed by these newer techniques. Here, we review state-of-the-art methods for profiling drug-target interactions and emerging multiomics tools to delineate the tissue heterogeneity at single-cell resolution. Highlighting the recent technical advances enabling high-resolution, multiplexable in situ small-molecule drug imaging (clearing-assisted tissue click chemistry, or CATCH), we foresee the integration of single-cell and spatial omics platforms, data, and concepts into the future framework of defining and understanding in vivo drug-target interactions and mechanisms of actions.
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Affiliation(s)
- Zhengyuan Pang
- Department of Neuroscience, The Scripps Research Institute, La Jolla, California, USA;
| | - Benjamin F Cravatt
- Department of Chemistry, The Scripps Research Institute, La Jolla, California, USA;
| | - Li Ye
- Department of Neuroscience, The Scripps Research Institute, La Jolla, California, USA;
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA
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31
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Alrehaily A, Elfiky AA, Ibrahim IM, Ibrahim MN, Sonousi A. Novel sofosbuvir derivatives against SARS-CoV-2 RNA-dependent RNA polymerase: an in silico perspective. Sci Rep 2023; 13:23080. [PMID: 38155165 PMCID: PMC10754943 DOI: 10.1038/s41598-023-49712-y] [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: 10/26/2023] [Accepted: 12/11/2023] [Indexed: 12/30/2023] Open
Abstract
The human coronavirus, SARS-CoV-2, had a negative impact on both the economy and human health, and the emerging resistant variants are an ongoing threat. One essential protein to target to prevent virus replication is the viral RNA-dependent RNA polymerase (RdRp). Sofosbuvir, a uridine nucleotide analog that potently inhibits viral polymerase, has been found to help treat SARS-CoV-2 patients. This work combines molecular docking and dynamics simulation (MDS) to test 14 sofosbuvir-based modifications against SARS-CoV-2 RdRp. The results reveal comparable (slightly better) average binding affinity of five modifications (compounds 3, 4, 11, 12, and 14) to the parent molecule, sofosbuvir. Compounds 3 and 4 show the best average binding affinities against SARS-CoV-2 RdRp (- 16.28 ± 5.69 and - 16.25 ± 5.78 kcal/mol average binding energy compared to - 16.20 ± 6.35 kcal/mol for sofosbuvir) calculated by Molecular Mechanics Generalized Born Surface Area (MM-GBSA) after MDS. The present study proposes compounds 3 and 4 as potential SARS-CoV-2 RdRp blockers, although this has yet to be proven experimentally.
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Affiliation(s)
- Abdulwahed Alrehaily
- Biology Department, Faculty of Science, Islamic University of Madinah, 42351, Madinah, Saudi Arabia
| | - Abdo A Elfiky
- Biophysics Department, Faculty of Science, Cairo University, Giza, Egypt.
| | - Ibrahim M Ibrahim
- Biophysics Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Mohamed N Ibrahim
- Clinical Laboratories Department, College of Applied Medical Sciences, Jouf University, Qurrayat, Saudi Arabia
| | - Amr Sonousi
- Pharmaceutical Organic Department, Faculty of Pharmacy, Cairo University, Giza, Egypt
- University of Hertfordshire Hosted By Global Academic Foundation, New Administrative Capital, Cairo, Egypt
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32
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Georgieva M, Xenodochidis C, Krasteva N. Old age as a risk factor for liver diseases: Modern therapeutic approaches. Exp Gerontol 2023; 184:112334. [PMID: 37977514 DOI: 10.1016/j.exger.2023.112334] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 11/12/2023] [Accepted: 11/14/2023] [Indexed: 11/19/2023]
Abstract
Recent scientific interest has been directed towards age-related diseases, driven by the significant increase in global life expectancy and the growing population of individuals aged 65 and above. The ageing process encompasses various biological, physiological, environmental, psychological, behavioural, and social changes, leading to an augmented susceptibility to chronic illnesses. Cardiovascular, neurological, musculoskeletal, liver and oncological diseases are prevalent in the elderly. Moreover, ageing individuals demonstrate reduced regenerative capacity and decreased tolerance towards therapeutic interventions, including organ transplantation. Liver diseases, such as non-alcoholic fatty liver disease, alcoholic liver disease, hepatitis, fibrosis, and cirrhosis, have emerged as significant public health concerns. Paradoxically, these conditions remain underestimated despite their substantial global impact. Age-related factors are closely associated with the severity and unfavorable prognosis of various liver diseases, warranting further investigation to enhance clinical management and develop novel therapeutic strategies. This comprehensive review focuses specifically on age-related liver diseases, their treatment strategies, and contemporary practices. It provides a detailed account of the global burden, types, molecular mechanisms, and epigenetic alterations underlying these liver pathologies.
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Affiliation(s)
- Milena Georgieva
- Institute of Molecular Biology "Acad. Roumen Tsanev", Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria.
| | - Charilaos Xenodochidis
- Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria
| | - Natalia Krasteva
- Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria.
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Yao YL, Luo Y, Wang Q, Geng R, Chen Y, Liu MQ, Li B, Chen J, Wu CG, Jia JK, Luo JY, He YT, Jiang TT, Zhu Y, Hu B, Zhou P, Shi ZL. Identification of TMEM53 as a novel SADS-CoV restriction factor that targets viral RNA-dependent RNA polymerase. Emerg Microbes Infect 2023; 12:2249120. [PMID: 37584551 PMCID: PMC10467534 DOI: 10.1080/22221751.2023.2249120] [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: 05/12/2023] [Revised: 08/07/2023] [Accepted: 08/11/2023] [Indexed: 08/17/2023]
Abstract
ABSTRACTZoonotic transmission of coronaviruses (CoVs) poses a serious public health threat. Swine acute diarrhea syndrome coronavirus (SADS-CoV), originating from a bat HKU2-related CoV, causes devastating swine diseases and poses a high risk of spillover to humans. Currently, licensed therapeutics that can prevent potential human outbreaks are unavailable. Identifying the cellular proteins that restrict viral infection is imperative for developing effective interventions and therapeutics. We utilized a large-scale human cDNA screening and identified transmembrane protein 53 (TMEM53) as a novel cell-intrinsic SADS-CoV restriction factor. The inhibitory effect of TMEM53 on SADS-CoV infection was found to be independent of canonical type I interferon responses. Instead, TMEM53 interacts with non-structural protein 12 (NSP12) and disrupts viral RNA-dependent RNA polymerase (RdRp) complex assembly by interrupting NSP8-NSP12 interaction, thus suppressing viral RdRp activity and RNA synthesis. Deleting the transmembrane domain of TMEM53 resulted in the abrogation of TMEM53-NSP12 interaction and TMEM53 antiviral activity. Importantly, TMEM53 exhibited broad antiviral activity against multiple HKU2-related CoVs. Our findings reveal a novel role of TMEM53 in SADS-CoV restriction and pave the way to host-directed therapeutics against HKU2-related CoV infection.
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Affiliation(s)
- Yu-Lin Yao
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of China
| | - Yun Luo
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing, People’s Republic of China
| | - Qi Wang
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing, People’s Republic of China
| | - Rong Geng
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing, People’s Republic of China
| | - Ying Chen
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing, People’s Republic of China
| | - Mei-Qin Liu
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing, People’s Republic of China
| | - Bei Li
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of China
| | - Jing Chen
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of China
| | - Chun-Guang Wu
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing, People’s Republic of China
| | - Jing-Kun Jia
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing, People’s Republic of China
| | - Jing-Yi Luo
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing, People’s Republic of China
| | - Yan-Tong He
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing, People’s Republic of China
| | - Ting-Ting Jiang
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of China
| | - Yan Zhu
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of China
| | - Ben Hu
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of China
| | - Peng Zhou
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of China
- Guangzhou Laboratory, Guangzhou International Bio Island, Guangzhou, People’s Republic of China
| | - Zheng-Li Shi
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of China
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Peña-Longobardo LM, Oliva-Moreno J, Fernández-Rodriguez C. The effect of hepatitis C-associated premature deaths on labour productivity losses in Spain: a ten-year analysis. THE EUROPEAN JOURNAL OF HEALTH ECONOMICS : HEPAC : HEALTH ECONOMICS IN PREVENTION AND CARE 2023; 24:1271-1283. [PMID: 36352296 PMCID: PMC9646468 DOI: 10.1007/s10198-022-01540-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 10/11/2022] [Indexed: 06/16/2023]
Abstract
Hepatitis C virus (HCV) infection causes a substantial economic burden, not only in terms of healthcare costs, but also in labour productivity losses. The main objective of this study is to provide objective and comparable information about the trend in labour productivity losses caused by premature HCV-associated deaths in Spain in recent years (2009-2018). We used nationwide data from several official sources to create a simulation model based on the human capital approach and to estimate the flows in labour productivity losses due to deaths identified in the period considered. Based on a pessimistic scenario, the annual number of deaths due to HCV infections decreased by 19.7% between 2009 and 2018. The years of potential labour productive life lost (YPLPLL) decreased by 38.1%. That reduction led to a decrease in annual labour productivity losses from €236 million in 2009 to €156 million in 2018 (-33.8%). The aggregate HCV-related labour productivity losses between 2009 and 2018 ranged from €1742 million (optimistic scenario) to €1949 million (pessimistic scenario), with an intermediate estimation of €1846 million (moderately optimistic scenario). These results show a substantial reduction in annual deaths, working-age deaths, YPLPLL, and labour productivity losses associated with HCV infection over this period.
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Affiliation(s)
- L M Peña-Longobardo
- Department of Economic Analysis and Finance and Seminar on Economics and Health, Universidad de Castilla-La Mancha, Toledo, Spain
| | - J Oliva-Moreno
- Department of Economic Analysis and Finance and Seminar on Economics and Health, Universidad de Castilla-La Mancha, Toledo, Spain.
| | - C Fernández-Rodriguez
- Service of Gastroenterology, Fundación Alcorcón University Hospital, University Rey Juan Carlos, Madrid, Spain
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35
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Jay JS, Patterson JA, Zhang Y, Ijioma SC, Carroll NV, Holdford DA, Sterling RK, Gupta G, Yakubu I. Cost minimization analysis of short-duration antiviral prophylaxis for hepatitis C positive donor kidney transplants. J Am Pharm Assoc (2003) 2023; 63:1700-1705.e4. [PMID: 37414279 DOI: 10.1016/j.japh.2023.06.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 05/09/2023] [Accepted: 06/29/2023] [Indexed: 07/08/2023]
Abstract
BACKGROUND Trials describing 4-12 week courses of direct-acting antiviral drugs (DAAs) to treat hepatitis C virus (HCV) transmission from infected donors to uninfected kidney transplant recipients (D+/R-transplants), may be limited in application by costs and delayed access to expensive DAAs. A short prophylactic strategy may be safer and cost-effective. Here, we report a cost minimization analysis using the health system perspective to determine the least expensive DAA regimen, using available published strategies. OBJECTIVES To conduct cost-minimization analyses (CMAs) from the health system perspective of four DAA regimens to prevent and/or treat HCV transmission from D+/R-kidney transplants. METHODS CMAs comparing 4 strategies: 1) 7-day prophylaxis with generic sofosbuvir/velpatasvir (SOF/VEL), with 12-week branded glecaprevir/pibrentasvir (G/P) for those with transmission; 2) 8-day branded G/P prophylaxis, with 12-week branded SOF/VEL/voxilaprevir for those with transmission; 3) 4-week perioperative generic SOF/VEL prophylaxis, with 12-week branded G/P for those with transmission; and 4) 8-week branded G/P "transmit-and-treat." We included data from published literature to estimate the probability of viral transmission in patients who received DAA prophylaxis, and assumed a 100% transmission rate for those who received the "transmit-and-treat" approach. RESULTS In base-case analyses, strategies 1 (expected cost [EC]: $2326) and 2 (expected cost: $2646) were less expensive than strategies 3 (EC: $4859) and 4 (EC: $18,525). Threshold analyses for 7-day SOF/VEL versus 8-day G/P suggested that there were reasonable input levels at which the 8-day strategy may be least costly. The threshold values for the SOF/VEL prophylaxis strategies (7-day vs. 4- week) indicated that the 4-week strategy is unlikely to be less costly under any reasonable value of the input variables. CONCLUSIONS Short duration DAA prophylaxis using 7 days of SOF/VEL or 8 days of G/P has the potential to yield significant cost savings for D+/R- kidney transplants.
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Hochberg NS, Rao SPS, Angyalosi G, Zhao X, Carballo L, Demacq C, Braud-Perez S, Wieser D, Casas JP, Millholland J, Ngo D. An end is in sight: a perspective on PCR as an endpoint for Chagas disease treatment trials. FRONTIERS IN PARASITOLOGY 2023; 2:1272386. [PMID: 39816827 PMCID: PMC11731979 DOI: 10.3389/fpara.2023.1272386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 09/06/2023] [Indexed: 01/18/2025]
Abstract
Novel therapies for chronic indeterminate Chagas disease (CICD) are needed, but trials are limited by the absence of tests to detect infection and early treatment efficacy. This perspective highlights the shortfalls and strengths of polymerase chain reaction (PCR) as a study endpoint for anti-parasitic drug development. Serologic reversion, the gold standard test of cure, may take decades to occur in adults and therefore is challenging as an endpoint for drug development. Use of PCR as a marker of infection and treatment response has notable limitations due to low parasitemia in CICD, fluctuations in circulating (versus tissue) parasite burden, strain differences, and assay performance. It is, however, rapidly responsive to therapy, and technological advances have improved detection of different strains and may allow for parasite quantification. Until we have more sensitive tests for parasitological clearance, PCR as a measure of treatment failure may be the best available efficacy endpoint to accelerate early development of much-needed novel therapies. Adequately designed clinical studies are needed to correlate PCR clearance with clinical outcomes and to identify novel biomarkers predictive of clinical outcomes in patients with CICD. Public-private partnerships and health authority engagement are paramount to identify feasible trial endpoints and deliver promising new drug candidates for Chagas disease.
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Affiliation(s)
- Natasha S. Hochberg
- Novartis Biomedical Research, Cambridge, MA, United States
- Novartis Biomedical Research, Emeryville, CA, United States
| | - Srinivasa P. S. Rao
- Novartis Biomedical Research, Cambridge, MA, United States
- Novartis Biomedical Research, Emeryville, CA, United States
| | | | - Xiaojun Zhao
- Novartis Biomedical Research, Cambridge, MA, United States
- Novartis Biomedical Research, Emeryville, CA, United States
| | | | - Caroline Demacq
- Novartis Biomedical Research, Emeryville, CA, United States
- Novartis Pharma AG, Basel, Switzerland
| | | | - Daniela Wieser
- Novartis Biomedical Research, Cambridge, MA, United States
- Novartis Biomedical Research, Emeryville, CA, United States
| | - JP Casas
- Novartis Biomedical Research, Cambridge, MA, United States
- Novartis Biomedical Research, Emeryville, CA, United States
| | | | - Debby Ngo
- Novartis Biomedical Research, Cambridge, MA, United States
- Novartis Biomedical Research, Emeryville, CA, United States
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Odenwald MA, Roth HF, Reticker A, Segovia M, Pillai A. Evolving challenges with long-term care of liver transplant recipients. Clin Transplant 2023; 37:e15085. [PMID: 37545440 DOI: 10.1111/ctr.15085] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 07/17/2023] [Accepted: 07/23/2023] [Indexed: 08/08/2023]
Abstract
The number of liver transplants (LT) performed worldwide continues to rise, and LT recipients are living longer post-transplant. This has led to an increasing number of LT recipients requiring lifelong care. Optimal care post-LT requires careful attention to both the allograft and systemic issues that are more common after organ transplantation. Common causes of allograft dysfunction include rejection, biliary complications, and primary disease recurrence. While immunosuppression prevents rejection and reduces incidences of some primary disease recurrence, it has detrimental systemic effects. Most commonly, these include increased incidences of metabolic syndrome, various malignancies, and infections. Therefore, it is of utmost importance to optimize immunosuppression regimens to prevent allograft dysfunction while also decreasing the risk of systemic complications. Institutional protocols to screen for systemic disease and heightened clinical suspicion also play an important role in providing optimal long-term post-LT care. In this review, we discuss these common complications of LT as well as unique considerations when caring for LT recipients in the years after transplant.
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Affiliation(s)
- Matthew A Odenwald
- Department of Medicine, Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medicine, Chicago, USA
| | - Hannah F Roth
- Department of Medicine, Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medicine, Chicago, USA
| | - Anesia Reticker
- Department of Pharmacy, University of Chicago Medicine, Chicago, USA
| | - Maria Segovia
- Department of Medicine, Section of Gastroenterology, Duke University School of Medicine, Durham, USA
| | - Anjana Pillai
- Department of Medicine, Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medicine, Chicago, USA
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38
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Yu H, Xu F. Non-noble metal-catalyzed cross-dehydrogenation coupling (CDC) involving ether α-C(sp 3)-H to construct C-C bonds. Beilstein J Org Chem 2023; 19:1259-1288. [PMID: 37701303 PMCID: PMC10494247 DOI: 10.3762/bjoc.19.94] [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: 04/05/2023] [Accepted: 08/23/2023] [Indexed: 09/14/2023] Open
Abstract
Ether derivatives are widespread as essential building blocks in various drugs, natural products, agrochemicals, and materials. Modern economy requires developing green strategies with improved efficiency and reduction of waste. Due to its atom and step-economy, the cross-dehydrogenative coupling (CDC) reaction has become a major strategy for ether functionalization. This review covers C-H/C-H cross-coupling reactions of ether derivatives with various C-H bond substrates via non-noble metal catalysts (Fe, Cu, Co, Mn, Ni, Zn, Y, Sc, In, Ag). We discuss advances achieved in these CDC reactions and hope to attract interest in developing novel methodologies in this field of organic chemistry.
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Affiliation(s)
- Hui Yu
- Department of Pharmacy, Shi zhen College of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou 550200, P. R. China
| | - Feng Xu
- School of Mathematics and Information Science, Guiyang University, Guiyang, Guizhou 550005, P. R. China
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39
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Derayea SM, Abu-Hassan AA, Hamad AA, Eltoukhi WE, Hamad AE, Mohammed BS. Mathematical processing of absorption as green smart spectrophotometric methods for concurrent assay of hepatitis C antiviral drugs, Sofosbuvir and Simeprevir: application to combined pharmaceutical dosage forms and evaluation of the method greenness. BMC Chem 2023; 17:75. [PMID: 37452429 PMCID: PMC10347804 DOI: 10.1186/s13065-023-00984-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 06/30/2023] [Indexed: 07/18/2023] Open
Abstract
The present work was developed to create three rapid, simple, eco-friendly, cheap spectrophotometric methods for concurrent assay of Sofosbuvir (SOF) and Simeprevir (SMV) in their pure, laboratory prepared mixture and pharmaceutical dosage form with high degree of accuracy and precision. Three methods were developed including iso-absorptive point, ratio subtraction and dual wavelength. The linear range of the proposed methods was 3.0-50.0 and 2.0-50.0 µg mL-1 for SMV and SOF, respectively. The proposed methods were validated according to ICH guidelines in terms of linearity, accuracy, precision, limit of detection and limit of quantitation. The proposed approach is highly simple and the procedure is environmentally green making it suitable for the drug analysis in routine works.
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Affiliation(s)
- Sayed M Derayea
- Department of Analytical Chemistry, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt
| | - Ahmed A Abu-Hassan
- Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524, Egypt
| | - Ahmed A Hamad
- Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524, Egypt
| | - Walid E Eltoukhi
- Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524, Egypt
| | - Amal E Hamad
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Menoufia University, Shebin El-Kom, Menoufia, Egypt
| | - Bassam Shaaban Mohammed
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Menoufia University, Shebin El-Kom, Menoufia, Egypt.
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Mohamed Abdelnajid D, Elmowafy AY, Rostaing L, Elrakaiby MT. Prediction of response to sofosbuvir-based therapy using serum interleukin-12 and single nucleotide polymorphism of the interleukin 28B gene as predictive factors in HCV positive genotype-4 patients. Medicine (Baltimore) 2023; 102:e34125. [PMID: 37443472 PMCID: PMC10344568 DOI: 10.1097/md.0000000000034125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 06/07/2023] [Indexed: 07/15/2023] Open
Abstract
Some hepatitis-C virus patients have resistance to direct-acting-antivirals (DAAs). Genetic polymorphisms have been associated with drug resistance. This study aimed to evaluate the role of interleukin (IL)-28B gene polymorphism and IL-12 levels as predictors for a response to sofosbuvir/ribavirin (SOF/RBV) with (triple-therapy) or without (dual-therapy) Peg-alpha-interferon. 92 hepatitis C virus (HCV)/RNA (+)-patients treated with dual (n = 72) or triple (n = 20) therapy. IL28B genetic polymorphism and IL-12 level assessments. 30.4% of the patients were IL28B C/C genotype, 56.5% C/T-genotype, and 13% T/T-genotype. Mean baseline IL-12 levels were 27.5 ± 3.0 pg/mL. Rapid viral response was achieved in 86/92 patients. All patients achieved end-of-treatment virologic response. The 12- and 24-week sustained virologic responses (SVR) were achieved in 76 patients (82.6%), that is, a relapse was found in 16 patients (17.4%). 8 and 12-weeks after antiviral therapy, IL-12 levels decreased significantly, and became comparable to those of the control-group. That drop in IL-12 levels was similar across the dual- and triple-therapy patients. Finally, logistic regression analysis showed that the increase in baseline aspartate aminotransferase (AST) and T/T genotyping had an independent effect on increasing the probability a SVR failing in both dual- and triple-therapy groups (P = .0007 and P = .02, respectively). Single-nucleotide polymorphism (SNP) in IL-28B and IL-12 levels play roles as predictors in DAAs resistance.
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Affiliation(s)
- Doaa Mohamed Abdelnajid
- Department of Microbiology and Immunology, Military Medical Academy, Cairo, Egypt
- Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Kasr Al-Aini, Cairo, Egypt
| | | | - Lionel Rostaing
- Department of Nephrology, Hemodialysis, Apheresis, and Kidney Transplantation, CHU Grenoble-Alpes, France
- Grenoble Alpes University, Grenoble, France
| | - Marwa T. Elrakaiby
- Department of Microbiology and Immunology, Military Medical Academy, Cairo, Egypt
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Xu J, Xue Y, Bolinger AA, Li J, Zhou M, Chen H, Li H, Zhou J. Therapeutic potential of salicylamide derivatives for combating viral infections. Med Res Rev 2023; 43:897-931. [PMID: 36905090 PMCID: PMC10247541 DOI: 10.1002/med.21940] [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: 11/23/2021] [Revised: 11/09/2022] [Accepted: 02/26/2023] [Indexed: 03/12/2023]
Abstract
Since time immemorial human beings have constantly been fighting against viral infections. The ongoing and devastating coronavirus disease 2019 pandemic represents one of the most severe and most significant public health emergencies in human history, highlighting an urgent need to develop broad-spectrum antiviral agents. Salicylamide (2-hydroxybenzamide) derivatives, represented by niclosamide and nitazoxanide, inhibit the replication of a broad range of RNA and DNA viruses such as flavivirus, influenza A virus, and coronavirus. Moreover, nitazoxanide was effective in clinical trials against different viral infections including diarrhea caused by rotavirus and norovirus, uncomplicated influenza A and B, hepatitis B, and hepatitis C. In this review, we summarize the broad antiviral activities of salicylamide derivatives, the clinical progress, and the potential targets or mechanisms against different viral infections and highlight their therapeutic potential in combating the circulating and emerging viral infections in the future.
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Affiliation(s)
- Jimin Xu
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555, United States
| | - Yu Xue
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555, United States
| | - Andrew A. Bolinger
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555, United States
| | - Jun Li
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555, United States
| | - Mingxiang Zhou
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555, United States
| | - Haiying Chen
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555, United States
| | - Hongmin Li
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85721, United States
| | - Jia Zhou
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555, United States
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Sharma P, Sawtell R, Wang Q, Sise ME. Management of Hepatitis C Virus and Hepatitis B Virus Infection in the Setting of Kidney Disease. ADVANCES IN KIDNEY DISEASE AND HEALTH 2023; 30:343-355. [PMID: 37657881 PMCID: PMC10479952 DOI: 10.1053/j.akdh.2023.04.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 04/04/2023] [Accepted: 04/19/2023] [Indexed: 09/03/2023]
Abstract
Treatment of chronic hepatitis C virus (HCV) and hepatitis B virus (HBV) infection poses unique challenges in patients with kidney disease. Direct-acting antivirals have been a major breakthrough in eradicating HCV infection, and several pangenotypic regimens are available for patients with chronic kidney disease or end-stage kidney disease requiring dialysis with high cure rates and no need for dose adjustment. Direct-acting antiviral therapy alone can treat HCV-associated cryoglobulinemic glomerulonephritis; concurrent antiviral and immunosuppressive therapy is needed for cases of severe, organ-threatening manifestations of cryoglobulinemia. Immunosuppression may be needed for HBV-associated kidney disease (polyarteritis nodosa or membranous nephropathy) when there is evidence of severe immune-mediated injury while weighing the risk of potential viral activation. Most HBV antiviral agents need to be dose-adjusted in patients with chronic kidney disease or end-stage kidney disease requiring dialysis, and drug-drug interactions need to be carefully evaluated in patients with kidney transplants. Considerations for accepting HCV- and HBV-infected donors for kidney transplantation are discussed.
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Affiliation(s)
- Purva Sharma
- Department of Medicine, Division of Nephrology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell; Glomerular Disease Center at Northwell Health, Hempstead, NY
| | - Rani Sawtell
- Department of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, MA
| | - Qiyu Wang
- Department of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, MA
| | - Meghan E Sise
- Department of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, MA.
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Reau N, Cheng WH, Shao Q, Marx SE, Brooks H, Martinez A. Real-World Effectiveness of 8-Week Glecaprevir/Pibrentasvir in Treatment-Naïve, Compensated Cirrhotic HCV Patients. Infect Dis Ther 2023:10.1007/s40121-023-00823-z. [PMID: 37329414 PMCID: PMC10390440 DOI: 10.1007/s40121-023-00823-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 05/16/2023] [Indexed: 06/19/2023] Open
Abstract
INTRODUCTION The EXPEDITION-8 clinical trial has demonstrated that treatment-naïve patients with compensated cirrhosis (TN/CC) of HCV genotypes 1-6 can achieve a 98% intent-to-treat sustained virologic response rate 12 weeks post-treatment with an 8-week glecaprevir/pibrentasvir (G/P) regimen. Further real-world evidence is needed to support the effectiveness of 8-week G/P in a clinical practice setting and to consolidate these treatment recommendations. The aim of this study is to contribute real-world evidence for the effectiveness of an 8-week G/P treatment in TN/CC patients with HCV genotypes 1-6. METHODS Retrospective real-world data from 494 TN/CC patients with HCV genotypes 1-6 were collected between August 2017 to December 2020 from the Symphony Health Solutions administrative claims database. Demographic and clinical characteristics were collected at baseline. Patients were required to have a follow-up HCV ribonucleic acid level at least 8 weeks or more after the end of treatment. The percentage of patients achieving a sustained virologic response (SVR) is reported. RESULTS The majority of patients were male (58%) and Caucasian (40%), with a mean age of 58 years; 74%, 12%, 12%, and 1% of patients were HCV genotype 1, 2, 3, and 4-6 infected, respectively. SVR was achieved in 95.5% of all patients. Across patient subgroups, SVR was achieved in 95.6% of patients with HCV genotype 3 and in 93% of HCV patients with a recent diagnosis of illicit drug use or abuse (within 6 months prior to G/P initiation). CONCLUSION Early real-world evidence indicates high effectiveness of the 8-week G/P regimen in TN/CC patients of HCV genotypes 1-6 from a large US claims database.
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Affiliation(s)
- Nancy Reau
- Rush University Medical Center, 1725 W. Harrison St., Suite 158, Chicago, IL, 60612, USA.
| | | | | | | | | | - Anthony Martinez
- Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA
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Agosti-Gonzalez R, Falcato L, Grischott T, Senn O, Bruggmann P. Hepatitis C antibody test frequencies and positive rates in Switzerland from 2007 to 2017: a retrospective longitudinal study. Swiss Med Wkly 2023; 153:40085. [PMID: 37410941 DOI: 10.57187/smw.2023.40085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/08/2023] Open
Abstract
ACKGROUND AND AIMS The prevalence of chronic hepatitis C in Switzerland is currently estimated at approximately 32,000 affected individuals (0.37% of the permanent resident population). An estimated 40% of affected individuals in Switzerland is undiagnosed. The Swiss Federal Office of Public Health requires laboratories to report all positive hepatitis C virus (HCV) test results. Approximately 900 newly diagnosed cases are reported annually. The number of HCV tests performed, however, is not collected by the Federal Office of Public Health and positive rates are therefore unknown. The aim of this study was to describe the longitudinal course of the numbers of hepatitis C antibody tests and of positive rates in Switzerland for the years 2007 to 2017. METHODS Twenty laboratories were asked to provide the number of HCV antibody tests performed and the number of positive antibody tests per year. Using data from the Federal Office of Public Health reporting system for the years 2012 to 2017, we calculated a factor to correct our values for multiple tests of the same person. RESULTS The annual number of HCV antibody tests performed tripled linearly from 2007 to 2017 (from 42,105 to 121,266) while the number of positive HCV antibody test results increased by only 75% over the same period (from 1360 to 2379). The HCV antibody test positive rate steadily decreased from 3.2% in 2007 to 2.0% in 2017. After correction for multiple tests per person, the person-level HCV antibody tested positive rate decreased from 2.2% to 1.7% from 2012 to 2017. CONCLUSION In the Swiss laboratories considered, more HCV antibody tests were performed each year in the period (2007-2017) before and during the approval of the new hepatitis C drugs. At the same time, the HCV antibody positive rates decreased, both on a per-test as well as a per-person level. This study is the first to describe the evolution of tests performed and of positive rates for HCV antibody in Switzerland at the national level over several years. In order to more accurately guide future measures to achieve the goal of eliminating hepatitis C by 2030, we recommend annual collection and publication of positive rates by health authorities, along with mandatory reporting of numbers of tests and people treated.
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Affiliation(s)
| | - Luis Falcato
- Arud Centre for Addiction Medicine, Zurich, Switzerland
| | - Thomas Grischott
- Institute of Primary Care, University Hospital Zurich, University of Zurich, Switzerland
| | - Oliver Senn
- Institute of Primary Care, University Hospital Zurich, University of Zurich, Switzerland
| | - Philip Bruggmann
- Arud Centre for Addiction Medicine, Zurich, Switzerland
- Institute of Primary Care, University Hospital Zurich, University of Zurich, Switzerland
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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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Schwarz M, Schwarz C, Schütz A, Schwanke C, Krabb E, Schubert R, Liebich ST, Bauer D, Burghart L, Brinkmann L, Gutic E, Reiberger T, Haltmayer H, Gschwantler M. Combining treatment for chronic hepatitis C with opioid agonist therapy is an effective microelimination strategy for people who inject drugs with high risk of non-adherence to antiviral therapy. J Virus Erad 2023; 9:100319. [PMID: 36970063 PMCID: PMC10036924 DOI: 10.1016/j.jve.2023.100319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 01/17/2023] [Accepted: 02/27/2023] [Indexed: 03/05/2023] Open
Abstract
Background & aims Despite effective direct-acting antivirals (DAAs), hepatitis C virus (HCV) prevalence is high among people who inject drugs (PWIDs) and non-adherence to therapy remains a major obstacle towards HCV elimination in this subpopulation. To overcome this issue, we have combined ongoing opioid agonist therapy (OAT) with DAAs in a directly-observed therapy (DOT) setting. Method From September 2014 until January 2021 PWIDs at high risk of non-adherence to DAA therapy, who were also on OAT, were included into this microelimination project. Individuals received their OAT and DAAs under supervision of healthcare workers as DOT in a pharmacy or low-threshold facility. Results In total, 504 HCV RNA-positive PWIDs on OAT (387 men, 76.8%; median age: 38 years [IQR 33-45], HIV: 4.6%; hepatitis B: 1.4%) were included into this study. Two thirds reported ongoing intravenous drug use (IDU) and half of them had no permanent housing. Only 41 (8.1%) were lost to follow-up and two (0.4%) died of reasons unrelated to DAA toxicity. Overall, 90.7% of PWIDs achieved sustained virological response 12 weeks after treatment (SVR12) (95% CI: 88.1-93.2%). By excluding those lost to follow-up and hose who had died of causes unrelated to DAAs, the SVR12 rate was 99.1% (95% CI: 98.3-100.0%; modified intention-to-treat analysis). Four PWIDs (0.9%) experienced treatment failure. Over a median follow-up of 24 weeks (IQR 12-39), 27 reinfections (5.9%) were observed in individuals with the highest IDU rates (81.2%). Importantly, even though some were lost to follow-up, all completed their DAA treatment. By using DOT, adherence to DAAs was excellent with only a total of 86 missed doses (0.3% of 25,224 doses). Conclusions In this difficult-to-treat population of PWIDs with high rates of IDU , coupling DAA treatment to OAT in a DOT setting resulted in high SVR12 rates equivalent to conventional treatment settings in non-PWID populations.
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Brzdęk M, Zarębska-Michaluk D, Invernizzi F, Cilla M, Dobrowolska K, Flisiak R. Decade of optimizing therapy with direct-acting antiviral drugs and the changing profile of patients with chronic hepatitis C. World J Gastroenterol 2023; 29:949-966. [PMID: 36844142 PMCID: PMC9950869 DOI: 10.3748/wjg.v29.i6.949] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/22/2022] [Accepted: 01/09/2023] [Indexed: 02/10/2023] Open
Abstract
Chronic infection with the hepatitis C virus (HCV) remains a major health problem affecting approximately 58 million people worldwide. In the era of interferon (IFN)-based regimens, patients particularly infected with genotypes 1 and 4 achieved a low response rate. The implementation of direct-acting antivirals changed the landscape of HCV treatment. The increase in effectiveness provided us with the hope of eliminating HCV as a significant public threat by 2030. In the following years, there was an observed improvement in the treatment of HCV with genotype-specific regimens and highly effective pangenotypic options that are the most recent stage of the revolution. The optimization of therapy was accompanied by changes in the patient profile from the beginning of the IFN-free era over time. Patients treated with antiviral therapies were younger in successive periods, less burdened with comorbidities and comedications, more frequently treatment-naïve and had less advanced liver disease. Before the IFN-free era, specific subpopulations such as patients with HCV/HIV coinfection, those with a history of previous treatment, patients with renal impairment or with cirrhosis had lower chances for a virologic response. Currently, these populations should no longer be considered difficult to treat. Despite the high effectiveness of HCV therapy, there is a small percentage of patients with treatment failure. However, they can be effectively retreated with pangenotypic rescue regimens.
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Affiliation(s)
- Michał Brzdęk
- Collegium Medicum, Jan Kochanowski University, Kielce 25-516, Poland
| | | | - Federica Invernizzi
- Center for Liver Disease, Division of Internal Medicine and Hepatology, IRCCS Ospedale San Raffaele, Milan 20-132, Italy
| | - Marta Cilla
- Center for Liver Disease, Division of Internal Medicine and Hepatology, IRCCS Ospedale San Raffaele, Milan 20-132, Italy
| | | | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok 15-540, Poland
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Elseady WS, Keshk WA, Negm WA, Elkhalawany W, Elhanafy H, Ibrahim MAA, Radwan DA. Saffron extract attenuates Sofosbuvir-induced retinal neurodegeneration in albino rat. Anat Rec (Hoboken) 2023; 306:422-436. [PMID: 35451203 DOI: 10.1002/ar.24942] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 03/27/2022] [Accepted: 04/11/2022] [Indexed: 01/25/2023]
Abstract
Sofosbuvir is a novel drug candidate for the treatment of hepatitis C viral infection; however, vision loss is one of its growing adverse effects. Saffron is a natural biomolecule with a high antioxidant potential that has been efficiently used in some diseases caused by oxidative stress. This study evaluated Sofosbuvir's neurodegenerative effect on the retina of albino rat and examined the potential protective role of saffron aqueous extract. Twenty-one adult male albino rats were randomly divided into three groups: Control, Sofosbuvir-treated (41.1 mg/kg /day for 6 weeks), and Sofosbuvir + Saffron co-treated groups. Retinal specimens were biochemically analyzed for malondialdehyde (MDA), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) levels. In addition, light and transmission electron microscopic examination, as well as immunohistochemical staining for Caspase-3, COX-2, and GFAP were performed. Sofosbuvir treatment caused a significant increase in retinal MDA, IL-6, and TNF-α levels coupling with a significant decrease in retinal total antioxidant capacity level. Histopathological findings revealed disturbed retinal architecture, detached pigment epithelium, vacuolated photoreceptors, in addition to a significant decrease in the thicknesses of both outer and inner nuclear layers, and the number of ganglionic cells. Ultrastructural examination revealed extensive degenerative changes in all retinal layers. Caspase-3, COX-2, and GFAP immunohistochemical expressions were significantly increased. Meanwhile, concomitant treatment with Saffron significantly improved retinal redox status, inflammation, histological, and ultrastructural parameters. Saffron may protect the retina from the hazardous effects of Sofosbuvir. Saffron could be used as an adjuvant therapy to protect patients receiving Sofosbuvir from retinal damage.
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Affiliation(s)
- Walaa S Elseady
- Anatomy and Embryology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Walaa A Keshk
- Department of Medical Biochemistry, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Walaa A Negm
- Pharmacognosy Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Walaa Elkhalawany
- Tropical Medicine & Infectious Diseases Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Hend Elhanafy
- Anatomy and Embryology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Marwa A A Ibrahim
- Department of Histology and Cell Biology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Doaa A Radwan
- Anatomy and Embryology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
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Abdelhamed W, El-Kassas M. Hepatocellular carcinoma and hepatitis C virus treatments: The bold and the beautiful. J Viral Hepat 2023; 30:148-159. [PMID: 36461645 DOI: 10.1111/jvh.13778] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 10/07/2022] [Accepted: 11/26/2022] [Indexed: 12/04/2022]
Abstract
The occurrence of hepatocellular carcinoma (HCC) is one of the most serious complications of hepatitis C virus (HCV) infection. Recently, effective antiviral medications have made sustained viral response (SVR) or cure a realistic therapeutic goal for most chronic HCV patients. Given HCV's tumorigenic propensity, it is not surprising that achieving SVR is helpful in preventing HCC. This review briefly summarizes and discusses the existing evidence on the relationship between hepatic carcinogenesis and viral eradication by antivirals, which is mainly divided into interferon-based and direct-acting antivirals (DAAs) based therapy. DAAs have changed the treatment landscape of chronic HCV, reaching high rates of SVR even in patients with advanced cirrhosis, with few contraindications and little side effects. Although some early reports suggested that DAA treatment increased the chance of HCC occurrence, more subsequent observational studies have refuted this theory. The probability of HCC recurrence after HCV eradication appears to be decreasing over time following SVR. Despite virological suppression/cure, individuals with liver cirrhosis are still at risk of HCC and should be monitored. There is a considerable need for markers/scores to predict the long-term risk of HCC in patients with HCV-related liver disease who attain SVR with direct-acting antivirals.
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Affiliation(s)
- Walaa Abdelhamed
- Endemic Medicine Department, Faculty of Medicine, Sohag University, Sohag, Egypt
| | - Mohamed El-Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt
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Brzdęk M, Dobrowolska K, Flisiak R, Zarębska-Michaluk D. Genotype 4 hepatitis C virus-a review of a diverse genotype. Adv Med Sci 2023; 68:54-59. [PMID: 36640687 DOI: 10.1016/j.advms.2022.12.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 12/02/2022] [Accepted: 12/21/2022] [Indexed: 01/15/2023]
Abstract
PURPOSE Hepatitis C virus (HCV) infection remains a major health problem and one of the leading causes of chronic liver disease worldwide. The purpose of this paper was to summarize knowledge about the epidemiology of HCV genotype (GT) 4 infection, similarities and differences with other genotypes, specific problems associated with this genotype, and treatment regimens used to treat GT4-infected patients. METHODS We performed an accurate search for literature using the PubMed database to select high-quality reviews and original articles concerning this topic. RESULTS GT4 with a global prevalence of 8% takes third place, closing the global HCV podium in terms of frequency. However, there are regions where GT4 infections are dominant, such as sub-Saharan and North Africa, and the Middle East. The disease course and complications are generally similar to those of chronic hepatitis C caused by other genotypes, although the faster progression of fibrosis was demonstrated in patients with coexisting schistosomiasis. In the era of interferon-based therapy, GT4-infected patients were described as difficult to treat due to suboptimal response. A breakthrough in the treatment of HCV-infected patients, including those with GT4 infection, was the introduction of direct-acting antiviral drugs. CONCLUSIONS The availability of safe and effective therapy has created a real opportunity for HCV eradication in line with the goal set by the World Health Organization. An example of a country where this is happening is Egypt, where GT4 accounts for more than 90% of HCV infections. There, broad access to therapy has been effectively supported by population-based screening.
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Affiliation(s)
- Michał Brzdęk
- Collegium Medicum, Jan Kochanowski University, Kielce, Poland.
| | | | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Bialystok, Poland
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