|
1
|
Gömer A, Klöhn M, Jagst M, Nocke MK, Pischke S, Horvatits T, Schulze zur Wiesch J, Müller T, Hardtke S, Cornberg M, Wedemeyer H, Behrendt P, Steinmann E, Todt D. Emergence of resistance-associated variants during sofosbuvir treatment in chronically infected hepatitis E patients. Hepatology 2023; 78:1882-1895. [PMID: 37334496 PMCID: PMC10653298 DOI: 10.1097/hep.0000000000000514] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 04/21/2023] [Indexed: 06/20/2023]
Abstract
BACKGROUND AND AIMS Chronic HEV infections remain a serious problem in immunocompromised patients, as specifically approved antiviral drugs are unavailable. In 2020, a 24-week multicenter phase II pilot trial was carried out, evaluating the nucleotide analog sofosbuvir by treating nine chronically HEV-infected patients with sofosbuvir (Trial Number NCT03282474). During the study, antiviral therapy reduced virus RNA levels initially but did not lead to a sustained virologic response. Here, we characterize the changes in HEV intrahost populations during sofosbuvir treatment to identify the emergence of treatment-associated variants. APPROACH AND RESULTS We performed high-throughput sequencing on RNA-dependent RNA polymerase sequences to characterize viral population dynamics in study participants. Subsequently, we used an HEV-based reporter replicon system to investigate sofosbuvir sensitivity in high-frequency variants. Most patients had heterogenous HEV populations, suggesting high adaptability to treatment-related selection pressures. We identified numerous amino acid alterations emerging during treatment and found that the EC 50 of patient-derived replicon constructs was up to ~12-fold higher than the wild-type control, suggesting that variants associated with lower drug sensitivity were selected during sofosbuvir treatment. In particular, a single amino acid substitution (A1343V) in the finger domain of ORF1 could reduce susceptibility to sofosbuvir significantly in 8 of 9 patients. CONCLUSIONS In conclusion, viral population dynamics played a critical role during antiviral treatment. High population diversity during sofosbuvir treatment led to the selection of variants (especially A1343V) with lower sensitivity to the drug, uncovering a novel mechanism of resistance-associated variants during sofosbuvir treatment.
Collapse
Affiliation(s)
- André Gömer
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Mara Klöhn
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Michelle Jagst
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
- Institute of Virology, University of Veterinary Medicine Hannover, Hannover, Germany
| | - Maximilian K. Nocke
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Sven Pischke
- Medical Clinic and Polyclinic, University Medical Centre Hamburg Eppendorf, Hamburg, Germany
- German Center for Infection Research (DZIF), Partner Site Hamburg Lübeck-Borstel-Riems, Germany
| | - Thomas Horvatits
- Medical Clinic and Polyclinic, University Medical Centre Hamburg Eppendorf, Hamburg, Germany
- German Center for Infection Research (DZIF), Partner Site Hamburg Lübeck-Borstel-Riems, Germany
- Gastromedics Health Center, Eisenstadt, Austria
| | - Julian Schulze zur Wiesch
- Medical Clinic and Polyclinic, University Medical Centre Hamburg Eppendorf, Hamburg, Germany
- German Center for Infection Research (DZIF), Partner Site Hamburg Lübeck-Borstel-Riems, Germany
| | - Tobias Müller
- Department of Gastroenterology and Hepatology, Charité Campus Virchow-Klinikum (CVK), Berlin, Germany
| | - Svenja Hardtke
- German Center for Infection Research (DZIF); HepNet Study-House/German Liver Foundation (DLS), Hannover, Germany
- Institute for Infections Research and Vaccine, University Medical Centre Hamburg Eppendorf, Hamburg, Germany
| | - Markus Cornberg
- German Center for Infection Research (DZIF); HepNet Study-House/German Liver Foundation (DLS), Hannover, Germany
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Germany
- German Center for Infection Research (DZIF); Partner Site Hannover Braunschweig, Germany
- Center for Individualized Infection Medicine (CiiM), Hannover, Germany
| | - Heiner Wedemeyer
- German Center for Infection Research (DZIF); HepNet Study-House/German Liver Foundation (DLS), Hannover, Germany
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Germany
- German Center for Infection Research (DZIF); Partner Site Hannover Braunschweig, Germany
| | - Patrick Behrendt
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Germany
- German Center for Infection Research (DZIF); Partner Site Hannover Braunschweig, Germany
- Institute of Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, Hannover, Germany
| | - Eike Steinmann
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
- German Centre for Infection Research (DZIF), Bochum, Germany
| | - Daniel Todt
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
- European Virus Bioinformatics Center (EVBC), Jena, Germany
| |
Collapse
|
|
2
|
Comunale BA, Larson RJ, Jackson-Ward E, Singh A, Koback FL, Engineer LD. The Functional Implications of Broad Spectrum Bioactive Compounds Targeting RNA-Dependent RNA Polymerase (RdRp) in the Context of the COVID-19 Pandemic. Viruses 2023; 15:2316. [PMID: 38140557 PMCID: PMC10747147 DOI: 10.3390/v15122316] [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: 10/31/2023] [Revised: 11/20/2023] [Accepted: 11/21/2023] [Indexed: 12/24/2023] Open
Abstract
BACKGROUND As long as COVID-19 endures, viral surface proteins will keep changing and new viral strains will emerge, rendering prior vaccines and treatments decreasingly effective. To provide durable targets for preventive and therapeutic agents, there is increasing interest in slowly mutating viral proteins, including non-surface proteins like RdRp. METHODS A scoping review of studies was conducted describing RdRp in the context of COVID-19 through MEDLINE/PubMed and EMBASE. An iterative approach was used with input from content experts and three independent reviewers, focused on studies related to either RdRp activity inhibition or RdRp mechanisms against SARS-CoV-2. RESULTS Of the 205 records screened, 43 studies were included in the review. Twenty-five evaluated RdRp activity inhibition, and eighteen described RdRp mechanisms of existing drugs or compounds against SARS-CoV-2. In silico experiments suggested that RdRp inhibitors developed for other RNA viruses may be effective in disrupting SARS-CoV-2 replication, indicating a possible reduction of disease progression from current and future variants. In vitro, in vivo, and human clinical trial studies were largely consistent with these findings. CONCLUSIONS Future risk mitigation and treatment strategies against forthcoming SARS-CoV-2 variants should consider targeting RdRp proteins instead of surface proteins.
Collapse
Affiliation(s)
- Brittany A. Comunale
- Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Robin J. Larson
- Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
- Department of Palliative Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA
| | - Erin Jackson-Ward
- Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
- Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Aditi Singh
- Department of Biological Sciences, University of California San Diego, La Jolla, CA 92161, USA
| | | | - Lilly D. Engineer
- Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| |
Collapse
|
|
3
|
Liu Y, Sun S, Li J, Wang W, Zhu HJ. Cell-Dependent Activation of ProTide Prodrugs and Its Implications in Antiviral Studies. ACS Pharmacol Transl Sci 2023; 6:1340-1346. [PMID: 37854623 PMCID: PMC10580387 DOI: 10.1021/acsptsci.3c00050] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Indexed: 10/20/2023]
Abstract
The ProTide prodrug design is a powerful tool to improve cell permeability and enhance the intracellular activation of nucleotide antiviral analogues. Previous in vitro studies showed that the activation of ProTide prodrugs varied in different cell lines. In the present study, we investigated the activation profiles of two antiviral prodrugs tenofovir alafenamide (TAF) and sofosbuvir (SOF) in five cell lines commonly used in antiviral research, namely, Vero E6, Huh-7, Calu-3, A549, and Caco-2. We found that TAF and SOF were activated in a cell-dependent manner with Vero E6 being the least efficient and Huh-7 being the most efficient cell line for activating the prodrugs. We also demonstrated that TAF was activated at a significantly higher rate than SOF. We further analyzed the protein expressions of the activating enzymes carboxylesterase 1, cathepsin A, histidine triad nucleotide-binding protein 1, and the relevant drug transporters P-glycoprotein and organic anion-transporting polypeptides 1B1 and 1B3 in the cell lines using the proteomics data extracted from the literature and proteome database. The results revealed significant differences in the expression patterns of the enzymes and transporters among the cell lines, which might partially contribute to the observed cell-dependent activation of TAF and SOF. These findings highlight the variability of the abundance of activating enzymes and transporters between cell lines and emphasize the importance of selecting appropriate cell lines for assessing the antiviral efficacy of nucleoside/nucleotide prodrugs.
Collapse
Affiliation(s)
| | | | - Jiapeng Li
- Department of Clinical Pharmacy, University of Michigan College of Pharmacy, 428 Church Street, Ann Arbor, Michigan 48109, United States
| | - Weiwen Wang
- Department of Clinical Pharmacy, University of Michigan College of Pharmacy, 428 Church Street, Ann Arbor, Michigan 48109, United States
| | - Hao-Jie Zhu
- Department of Clinical Pharmacy, University of Michigan College of Pharmacy, 428 Church Street, Ann Arbor, Michigan 48109, United States
| |
Collapse
|
|
4
|
Kamzeeva PN, Aralov AV, Alferova VA, Korshun VA. Recent Advances in Molecular Mechanisms of Nucleoside Antivirals. Curr Issues Mol Biol 2023; 45:6851-6879. [PMID: 37623252 PMCID: PMC10453654 DOI: 10.3390/cimb45080433] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 08/12/2023] [Accepted: 08/14/2023] [Indexed: 08/26/2023] Open
Abstract
The search for new drugs has been greatly accelerated by the emergence of new viruses and drug-resistant strains of known pathogens. Nucleoside analogues (NAs) are a prospective class of antivirals due to known safety profiles, which are important for rapid repurposing in the fight against emerging pathogens. Recent improvements in research methods have revealed new unexpected details in the mechanisms of action of NAs that can pave the way for new approaches for the further development of effective drugs. This review accounts advanced techniques in viral polymerase targeting, new viral and host enzyme targeting approaches, and prodrug-based strategies for the development of antiviral NAs.
Collapse
Affiliation(s)
| | | | | | - Vladimir A. Korshun
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia; (P.N.K.); (A.V.A.); (V.A.A.)
| |
Collapse
|
|
5
|
Tsai CY, Chen GJ, Tsai CS, Liou BH, Yang CJ, Tsai HC, Lin CY, Huang SH, Lin KY, Wang NC, Chen TC, Lee CH, Hung CC. Evolution of estimated glomerular filtration rate in HIV/HCV-coinfected patients who received direct-acting antivirals: A multicenter retrospective study. JOURNAL OF MICROBIOLOGY, IMMUNOLOGY, AND INFECTION = WEI MIAN YU GAN RAN ZA ZHI 2023; 56:718-728. [PMID: 37045634 DOI: 10.1016/j.jmii.2023.03.009] [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: 09/09/2022] [Revised: 03/04/2023] [Accepted: 03/23/2023] [Indexed: 04/03/2023]
Abstract
BACKGROUND The short-term impact of sofosbuvir (SOF)-based direct-acting antivirals (DAAs) combined with antiretroviral therapy (ART) on renal function in patients with HIV/HCV-coinfection remains controversial. METHODS This multicenter, retrospective study aimed to sequentially record the estimated glomerular filtration rate (eGFR) at baseline, end of therapy (EOT), 12 weeks off-treatment (SVR12), and at time points after SVR12 (post-SVR12) and to identify the factors associated with an eGFR decline to <60 ml/min/1.73 m2 in HIV/HCV-coinfected patients receiving DAAs. The evolution of mean eGFRs between different ART and DAAs combinations among patients of different HIV transmission routes were compared using a generalized linear mixed effects model. The periods between baseline and EOT, between EOT and post-SVR12, and between baseline and post-SVR12 were defined as the on-treatment, post-treatment, and all-course periods, respectively. Acute kidney disease (AKD) was defined as a decline of eGFR to <60 ml/min/1.73 m2. RESULT A total of 445 patients with baseline eGFRs >60 ml/min/1.73 m2 were included. We found that eGFRs declined during the on-treatment period in the tenofovir-containing ART and SOF-based DAA groups. There were no differences in the slope coefficient during the on-treatment and post-treatment periods among all risk groups except for people who inject drug. Increasing age and plasma HIV RNA >20 copies/ml before DAA treatment were factors independently associated with AKD during the on-treatment period while increasing age was independently associated with AKD during the all-course period. CONCLUSION Only increasing age was an independent factor associated with AKD among HIV/HCV-coinfected patients during and after DAA treatments.
Collapse
Affiliation(s)
- Ching-Yen Tsai
- Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Guan-Jhou Chen
- Department of Internal Medicine, Min-Sheng General Hospital, Taoyuan, Taiwan; Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chin-Shiang Tsai
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Internal Medicine, National Cheng Kung University Hospital, Dou-Liou Branch, College of Medicine, National Cheng Kung University, Yunlin, Taiwan
| | - Bo-Huang Liou
- Department of Internal Medicine, Hsinchu Mackay Memorial Hospital, Hsinchu, Taiwan
| | - Chia-Jui Yang
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan
| | - Hung-Chin Tsai
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Chi-Ying Lin
- Department of Internal Medicine, National Taiwan University Hospital, Yunlin Branch, Yunlin, Taiwan
| | - Sung-Hsi Huang
- Department of Internal Medicine, National Taiwan University Hospital, Hsinchu Branch, Hsinchu, Taiwan; Department of Tropical Medicine and Parasitology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Kuan-Yin Lin
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Center of Infection Control, National Taiwan University Hospital, Taipei, Taiwan
| | - Ning-Chi Wang
- Department of Internal Medicine, Tri-Service General Hospital, Taipei, Taiwan
| | - Tun-Chieh Chen
- Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan; Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Chen-Hsiang Lee
- Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; College of Medicine, Chang Gung University, Kaohsiung, Taiwan; Department of Internal Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan.
| | - Chien-Ching Hung
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Yunlin Branch, Yunlin, Taiwan; Department of Tropical Medicine and Parasitology, National Taiwan University College of Medicine, Taipei, Taiwan
| |
Collapse
|
|
6
|
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: 15] [Impact Index Per Article: 7.5] [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.
Collapse
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
| |
Collapse
|
|
7
|
Xu S, Del Pozo J, Romiti F, Fu Y, Mai BK, Morrison RJ, Lee K, Hu S, Koh MJ, Lee J, Li X, Liu P, Hoveyda AH. Diastereo- and enantioselective synthesis of compounds with a trifluoromethyl- and fluoro-substituted carbon centre. Nat Chem 2022; 14:1459-1469. [PMID: 36376387 PMCID: PMC9772297 DOI: 10.1038/s41557-022-01054-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 08/26/2022] [Indexed: 11/16/2022]
Abstract
Molecules that contain one or more fluorine atoms are crucial to drug discovery. There are protocols available for the selective synthesis of different organofluorine compounds, including those with a fluoro-substituted or a trifluoromethyl-substituted stereogenic carbon centre. However, approaches for synthesizing compounds with a trifluoromethyl- and fluoro-substituent stereogenic carbon centre are far less common. This potentially impactful set of molecules thus remains severely underdeveloped. Here we introduce a catalytic regio-, diastereo- and enantioselective strategy for the preparation of homoallylic alcohols bearing a stereogenic carbon centre bound to a trifluoromethyl group and a fluorine atom. The process, which involves a polyfluoroallyl boronate and is catalysed by an in situ-formed organozinc complex, can be used for diastereodivergent preparation of tetrafluoro-monosaccharides, including ribose core analogues of the antiviral drug sofosbuvir (Sovaldi). Unexpected reactivity/selectivity profiles, probably originating from the trifluoromethyl- and fluoro-substituted carbon site, are discovered, foreshadowing other unique chemistries that remain unknown.
Collapse
Affiliation(s)
- Shibo Xu
- Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, MA, USA
| | - Juan Del Pozo
- Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, MA, USA
| | - Filippo Romiti
- Supramolecular Science and Engineering Institute, University of Strasbourg, CNRS, Strasbourg, France
| | - Yue Fu
- Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA
| | - Binh Khanh Mai
- Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA
| | - Ryan J Morrison
- Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, MA, USA
| | - KyungA Lee
- Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, MA, USA
| | - Shaowei Hu
- Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, MA, USA
| | - Ming Joo Koh
- Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, MA, USA
| | - Jaehee Lee
- Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, MA, USA
| | - Xinghan Li
- Supramolecular Science and Engineering Institute, University of Strasbourg, CNRS, Strasbourg, France
| | - Peng Liu
- Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA.
| | - Amir H Hoveyda
- Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, MA, USA.
- Supramolecular Science and Engineering Institute, University of Strasbourg, CNRS, Strasbourg, France.
| |
Collapse
|
|
8
|
Cavalli ES, Mies T, Rzepa HS, White AJP, Parsons PJ, Barrett AG. Pyrimidine Nucleosides Syntheses by Late-Stage Base Heterocyclization Reactions. Org Lett 2022; 24:8931-8935. [DOI: 10.1021/acs.orglett.2c03152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Elfie S. Cavalli
- Department of Chemistry, Molecular Sciences Research Hub, White City Campus, Imperial College London, 82 Wood Lane, London W12 0BZ, England
| | - Thomas Mies
- Department of Chemistry, Molecular Sciences Research Hub, White City Campus, Imperial College London, 82 Wood Lane, London W12 0BZ, England
| | - Henry S. Rzepa
- Department of Chemistry, Molecular Sciences Research Hub, White City Campus, Imperial College London, 82 Wood Lane, London W12 0BZ, England
| | - Andrew J. P. White
- Department of Chemistry, Molecular Sciences Research Hub, White City Campus, Imperial College London, 82 Wood Lane, London W12 0BZ, England
| | - Philip J. Parsons
- Department of Chemistry, Molecular Sciences Research Hub, White City Campus, Imperial College London, 82 Wood Lane, London W12 0BZ, England
| | - Anthony G.M. Barrett
- Department of Chemistry, Molecular Sciences Research Hub, White City Campus, Imperial College London, 82 Wood Lane, London W12 0BZ, England
| |
Collapse
|
|
9
|
Liu CH, Kao JH. Pan-genotypic direct-acting antivirals for patients with hepatitis C virus infection and chronic kidney disease stage 4 or 5. Hepatol Int 2022; 16:1001-1019. [PMID: 35876967 PMCID: PMC9309604 DOI: 10.1007/s12072-022-10390-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 07/03/2022] [Indexed: 12/17/2022]
Abstract
Hepatitis C virus (HCV) infection is a major health problem with significant clinical and economic burdens in patients with chronic kidney disease (CKD) stage 4 or 5. Current guidelines recommend pan-genotypic direct-acting antivirals (DAAs) to be the first-line treatment of choice for HCV. This review summarizes the updated knowledge regarding the epidemiology, natural history, public health perspectives of HCV in patients with CKD stage 4 or 5, including those on maintenance dialysis, and the performance of pan-genotypic DAAs in these patients. The prevalence and incidence of HCV are much higher in patients with CKD stage 4 or 5 than in the general population. The prognosis is compromised if HCV patients are left untreated regardless of kidney transplantation (KT). Following treatment-induced HCV eradication, patient can improve the health-related outcomes by maintaining a long-term aviremic state. The sustained virologic response (SVR12) rates and safety profiles of pan-genotypic DAAs against HCV are excellent irrespective of KT. No dose adjustment of pan-genotypic DAAs is required across CKD stages. Assessing drug-drug interactions (DDIs) before HCV treatment is vital to secure on-treatment safety. The use of prophylactic or preemptive pan-genotypic DAAs in HCV-negative recipients who receive HCV-positive kidneys has shown promise in shortening KT waiting time, achieving excellent on-treatment efficacy and safety, and maintaining post-KT patient and graft survival. HCV elimination is highly feasible through multifaceted interventions, including mass screening, treatment scale-up, universal precautions, and post-SVR12 reinfection surveillance.
Collapse
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, Yunlin, 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 and Hospital, 7 Chung-Shan South Road, Taipei, 10002 Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| |
Collapse
|
|
10
|
Abstract
Phosphoryl prodrugs are key compounds in drug development. Biologically active phosphoryl compounds often have negative charges on the phosphoryl group, and as a result, frequently have poor pharmacokinetic (PK) profiles. The use of lipophilic moieties bonded to the phosphorus (or attached oxygen atoms) masks the negative charge of the phosphoryl group, cleavage releasing the active molecule. The use of prodrugs to improve the PK of active parent molecules is an essential step in drug development. This review highlights promising trends in terminal elimination half-life, Cmax, clearance, oral bioavailability, and cLogP in phosphoryl prodrugs. We focus on specific prodrug families: esters, amidates, and ProTides. We conclude that moderating lipophilicity is a key part of prodrug success. This type of evaluation is important for drug development, regardless of clinical application. It is our hope that this analysis, and future ones like it, will play a significant role in prodrug evolution.
Collapse
Affiliation(s)
- Samuel A Kirby
- Department of Chemistry, George Washington University, Washington DC 20052
| | - Cynthia S Dowd
- Department of Chemistry, George Washington University, Washington DC 20052
| |
Collapse
|
|
11
|
Liu CH, Chen CY, Su WW, Tseng KC, Lo CC, Liu CJ, Chen JJ, Peng CY, Shih YL, Yang SS, Huang CS, Huang KJ, Chang CY, Tsai MC, Kao WY, Fang YJ, Chen PY, Su PY, Tseng CW, Huang JJ, Lee PL, Lai HC, Hsieh TY, Chang CH, Huang YJ, Lee FJ, Chang CC, Kao JH. Sofosbuvir/velpatasvir with or without low-dose ribavirin for patients with chronic hepatitis C virus infection and severe renal impairment. Gut 2022; 71:176-184. [PMID: 33408122 DOI: 10.1136/gutjnl-2020-323569] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 12/21/2020] [Accepted: 12/23/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Data regarding the real-world effectiveness and safety of sofosbuvir/velpatasvir (SOF/VEL) with or without low-dose ribavirin (RBV) in patients with chronic hepatitis C virus (HCV) infection and severe renal impairment (RI) are limited. We evaluated the performance of SOF/VEL with or without low-dose RBV in HCV-infected patients with chronic kidney disease stage 4 or 5. DESIGN 191 patients with compensated (n=181) and decompensated (n=10) liver diseases receiving SOF/VEL (400/100 mg/day) alone and SOF/VEL with low-dose RBV (200 mg/day) for 12 weeks were retrospectively recruited at 15 academic centres in Taiwan. The effectiveness was determined by sustained virological response at off-treatment week 12 (SVR12) in evaluable (EP) and per-protocol populations (PP). The safety profiles were assessed. RESULTS The SVR12 rates by EP and PP analyses were 94.8% (95% CI 90.6% to 97.1%) and 100% (95% CI 97.9% to 100%). In patients with compensated liver disease, the SVR12 rates were 95.0% and 100% by EP and PP analyses. In patients with decompensated liver disease, the SVR12 rates were 90.0% and 100% by EP and PP analyses. Ten patients who failed to achieve SVR12 were attributed to non-virological failures. Among the 20 serious adverse events (AEs), none were judged related to SOF/VEL or RBV. The AEs occurring in ≥10% included fatigue (14.7%), headache (14.1%), nausea (12.6%), insomnia (12.0%) and pruritus (10.5%). None had ≥grade 3 total bilirubin or alanine aminotransferase elevations. CONCLUSION SOF/VEL with or without low-dose RBV is effective and well-tolerated in HCV-infected patients with severe RI.
Collapse
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, Yunlin, Taiwan
| | - Chi-Yi Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi, Taiwan
| | - Wei-Wen Su
- Division of Gastroenterology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Kuo-Chih Tseng
- Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan.,School of Medicine, Tzuchi University, Hualien, Taiwan
| | - Ching-Chu Lo
- Department of Internal Medicine, St. Martin De Porres Hospital, Daya, Chiayi, Taiwan
| | - Chun-Jen Liu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Jyh-Jou Chen
- Division of Gastroenterology and Hepatology, Chi-Mei Medical Center, Liouying, Taiwan
| | - Cheng-Yuan Peng
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.,School of Medicine, China Medical University, Taichung, Taiwan
| | - Yu-Lueng Shih
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Sheng-Shun Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.,School of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Chia-Sheng Huang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Yang Ming Hospital, Chiayi, Taiwan
| | - Ke-Jhang Huang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Beigang Hospital, Yunlin, Taiwan
| | - Chi-Yang Chang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Fu Jen Catholic University Hospital, Taipei, Taiwan
| | - Ming-Chang Tsai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Wei-Yu Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yo-Jen Fang
- Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Yunlin, Taiwan
| | - Po-Yueh Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi, Taiwan
| | - Pei-Yuan Su
- Division of Gastroenterology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Chih-Wei Tseng
- Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan.,School of Medicine, Tzuchi University, Hualien, Taiwan
| | - Jow-Jyh Huang
- Department of Internal Medicine, St. Martin De Porres Hospital, Daya, Chiayi, Taiwan
| | - Pei-Lun Lee
- Division of Gastroenterology and Hepatology, Chi-Mei Medical Center, Liouying, Taiwan
| | - Hsueh-Chou Lai
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.,School of Medicine, China Medical University, Taichung, Taiwan
| | - Tsai-Yuan Hsieh
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chung-Hsin Chang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Yi-Jie Huang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Fu-Jen Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Fu Jen Catholic University Hospital, Taipei, Taiwan
| | - Chun-Chao Chang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, 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
| |
Collapse
|
|
12
|
Atta NF, Galal A, El-Gohary AR. Electrochemical sensing of dobutamine, paracetamol, amlodipine, and daclatasvir in serum based on thiourea SAMs over nano-gold particles-CNTs composite. NEW J CHEM 2022. [DOI: 10.1039/d2nj01822e] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
We report in this work a one-step approach for the formation of self-assembled monolayers (SAMs) from thiourea (TU) over gold nanoparticles dispersed in carbon nanotubes (CNTs-Aunano). The fabrication of the...
Collapse
|
|
13
|
Dowarah J, Marak BN, Yadav UCS, Singh VP. Potential drug development and therapeutic approaches for clinical intervention in COVID-19. Bioorg Chem 2021; 114:105016. [PMID: 34144277 PMCID: PMC8143914 DOI: 10.1016/j.bioorg.2021.105016] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 05/20/2021] [Indexed: 01/25/2023]
Abstract
While the vaccination is now available to many countries and will slowly dissipate to others, effective therapeutics for COVID-19 is still illusive. The SARS-CoV-2 pandemic has posed an unprecedented challenge to researchers, scientists, and clinicians and affected the wellbeing of millions of people worldwide. Since the beginning of the pandemic, a multitude of existing anti-viral, antibiotic, antimalarial, and anticancer drugs have been tested, and some have shown potency in the treatment and management of COVID-19, albeit others failed to leave any positive impact and a few also became controversial as they showed mixed clinical outcomes. In the present article, we have brought together some of the candidate therapeutic drugs being repurposed or used in the clinical trials and discussed their clinical efficacy and safety for COVID-19.
Collapse
Affiliation(s)
- Jayanta Dowarah
- Department of Chemistry, School of Physical Sciences, Mizoram University, Aizawl 796004, Mizoram, India
| | - Brilliant N Marak
- Department of Chemistry, School of Physical Sciences, Mizoram University, Aizawl 796004, Mizoram, India
| | | | - Ved Prakash Singh
- Department of Chemistry, School of Physical Sciences, Mizoram University, Aizawl 796004, Mizoram, India; Department of Industrial Chemistry, School of Physical Sciences, Mizoram University, Aizawl 796004, Mizoram, India.
| |
Collapse
|
|
14
|
Couturier S, Peyrottes S, Périgaud C. 2’‐Derivatisation of 3’‐
C‐
Methyl Pyrimidine Nucleosides. European J Org Chem 2021. [DOI: 10.1002/ejoc.202100236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Sarah Couturier
- UMR 5247 CNRS Université Montpellier, ENSCM Institut des Biomolécules Max Mousseron (IBMM) Campus Triolet case courrier 1705, Place E. Bataillon 34095 Montpellier France
| | - Suzanne Peyrottes
- UMR 5247 CNRS Université Montpellier, ENSCM Institut des Biomolécules Max Mousseron (IBMM) Campus Triolet case courrier 1705, Place E. Bataillon 34095 Montpellier France
| | - Christian Périgaud
- UMR 5247 CNRS Université Montpellier, ENSCM Institut des Biomolécules Max Mousseron (IBMM) Campus Triolet case courrier 1705, Place E. Bataillon 34095 Montpellier France
| |
Collapse
|
|
15
|
Shabani M, Sadegh Ehdaei B, Fathi F, Dowran R. A mini-review on sofosbuvir and daclatasvir treatment in coronavirus disease 2019. New Microbes New Infect 2021; 42:100895. [PMID: 33976895 PMCID: PMC8103737 DOI: 10.1016/j.nmni.2021.100895] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/01/2021] [Accepted: 05/04/2021] [Indexed: 12/28/2022] Open
Abstract
Sofosbuvir and daclatasvir have been used successfully since 2013 for hepatitis C treatment. It has been shown by different studies that sofosbuvir can inhibit RNA polymerase of other positive-strand RNA viruses including Flaviviridae and Togaviridae. Homology between hepatitis C virus RNA polymerase and severe acute respiratory syndrome coronavirus 2 has also been established. The efficacy of sofosbuvir and daclatasvir as potential choices in treating patients with coronavirus disease 2019 and their recovery can be hypothesized.
Collapse
Affiliation(s)
- M. Shabani
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - B. Sadegh Ehdaei
- Microbiology and Immunology Department, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - F. Fathi
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - R. Dowran
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
16
|
Sacramento CQ, Fintelman-Rodrigues N, Temerozo JR, Da Silva ADPD, Dias SDSG, da Silva CDS, Ferreira AC, Mattos M, Pão CRR, de Freitas CS, Soares VC, Hoelz LVB, Fernandes TVA, Branco FSC, Bastos MM, Boechat N, Saraiva FB, Ferreira MA, Jockusch S, Wang X, Tao C, Chien M, Xie W, Patel D, Garzia A, Tuschl T, Russo JJ, Rajoli RKR, Pedrosa CSG, Vitória G, Souza LRQ, Goto-Silva L, Guimarães MZ, Rehen SK, Owen A, Bozza FA, Bou-Habib DC, Ju J, Bozza PT, Souza TML. In vitro antiviral activity of the anti-HCV drugs daclatasvir and sofosbuvir against SARS-CoV-2, the aetiological agent of COVID-19. J Antimicrob Chemother 2021; 76:1874-1885. [PMID: 33880524 PMCID: PMC8083231 DOI: 10.1093/jac/dkab072] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Accepted: 02/10/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Current approaches of drug repurposing against COVID-19 have not proven overwhelmingly successful and the SARS-CoV-2 pandemic continues to cause major global mortality. SARS-CoV-2 nsp12, its RNA polymerase, shares homology in the nucleotide uptake channel with the HCV orthologue enzyme NS5B. Besides, HCV enzyme NS5A has pleiotropic activities, such as RNA binding, that are shared with various SARS-CoV-2 proteins. Thus, anti-HCV NS5B and NS5A inhibitors, like sofosbuvir and daclatasvir, respectively, could be endowed with anti-SARS-CoV-2 activity. METHODS SARS-CoV-2-infected Vero cells, HuH-7 cells, Calu-3 cells, neural stem cells and monocytes were used to investigate the effects of daclatasvir and sofosbuvir. In silico and cell-free based assays were performed with SARS-CoV-2 RNA and nsp12 to better comprehend the mechanism of inhibition of the investigated compounds. A physiologically based pharmacokinetic model was generated to estimate daclatasvir's dose and schedule to maximize the probability of success for COVID-19. RESULTS Daclatasvir inhibited SARS-CoV-2 replication in Vero, HuH-7 and Calu-3 cells, with potencies of 0.8, 0.6 and 1.1 μM, respectively. Although less potent than daclatasvir, sofosbuvir alone and combined with daclatasvir inhibited replication in Calu-3 cells. Sofosbuvir and daclatasvir prevented virus-induced neuronal apoptosis and release of cytokine storm-related inflammatory mediators, respectively. Sofosbuvir inhibited RNA synthesis by chain termination and daclatasvir targeted the folding of secondary RNA structures in the SARS-CoV-2 genome. Concentrations required for partial daclatasvir in vitro activity are achieved in plasma at Cmax after administration of the approved dose to humans. CONCLUSIONS Daclatasvir, alone or in combination with sofosbuvir, at higher doses than used against HCV, may be further fostered as an anti-COVID-19 therapy.
Collapse
Affiliation(s)
- Carolina Q Sacramento
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil
- National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, Brazil
| | - Natalia Fintelman-Rodrigues
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil
- National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, Brazil
| | - Jairo R Temerozo
- Laboratório de Pesquisas sobre o Timo, IOC, Fiocruz, Rio de Janeiro, RJ, Brazil
- National Institute for Science and Technology on Neuroimmunomodulation (INCT/NIM), IOC, Fiocruz, Rio de Janeiro, RJ, Brazil
| | - Aline de Paula Dias Da Silva
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil
- National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, Brazil
| | - Suelen da Silva Gomes Dias
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil
| | - Carine Dos Santos da Silva
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil
- National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, Brazil
| | - André C Ferreira
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil
- National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, Brazil
- Universidade Iguaçu, Nova Iguaçu, RJ, Brazil
| | - Mayara Mattos
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil
- National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, Brazil
| | - Camila R R Pão
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil
| | - Caroline S de Freitas
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil
- National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, Brazil
| | - Vinicius Cardoso Soares
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil
| | | | - Tácio Vinício Amorim Fernandes
- Instituto de Tecnologia de Fármacos (Farmanguinhos), Fiocruz, Rio de Janeiro, RJ, Brazil
- Laboratório de Macromoléculas, Diretoria de Metrologia Aplicada às Ciências da Vida, Instituto Nacional de Metrologia, Qualidade e Tecnologia-INMETRO, Duque de Caxias, RJ 25250-020, Brazil
| | | | - Mônica Macedo Bastos
- Instituto de Tecnologia de Fármacos (Farmanguinhos), Fiocruz, Rio de Janeiro, RJ, Brazil
| | - Núbia Boechat
- Instituto de Tecnologia de Fármacos (Farmanguinhos), Fiocruz, Rio de Janeiro, RJ, Brazil
| | - Felipe B Saraiva
- Instituto de Tecnologia em Imunobiológicos (Bio-Manguinhos), Fiocruz, Rio de Janeiro, RJ, Brazil
| | - Marcelo Alves Ferreira
- National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, Brazil
- Instituto de Tecnologia em Imunobiológicos (Bio-Manguinhos), Fiocruz, Rio de Janeiro, RJ, Brazil
| | - Steffen Jockusch
- Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY 10027, USA
- Department of Chemistry, Columbia University, New York, NY 10027, USA
| | - Xuanting Wang
- Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY 10027, USA
- Department of Chemical Engineering, Columbia University, New York, NY 10027, USA
| | - Chuanjuan Tao
- Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY 10027, USA
- Department of Chemical Engineering, Columbia University, New York, NY 10027, USA
| | - Minchen Chien
- Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY 10027, USA
- Department of Chemical Engineering, Columbia University, New York, NY 10027, USA
| | - Wei Xie
- Laboratory of Structural Biology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
| | - Dinshaw Patel
- Laboratory of Structural Biology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
| | - Aitor Garzia
- Laboratory of RNA Molecular Biology, Rockefeller University, New York, NY 10065, USA
| | - Thomas Tuschl
- Laboratory of RNA Molecular Biology, Rockefeller University, New York, NY 10065, USA
| | - James J Russo
- Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY 10027, USA
- Department of Chemical Engineering, Columbia University, New York, NY 10027, USA
| | - Rajith K R Rajoli
- Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L7 3NY, UK
| | | | | | | | | | - Marilia Zaluar Guimarães
- Instituto D'Or de Pesquisa e Ensino, Rio de Janeiro, RJ, Brazil
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Stevens K Rehen
- Instituto D'Or de Pesquisa e Ensino, Rio de Janeiro, RJ, Brazil
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Andrew Owen
- Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L7 3NY, UK
| | - Fernando A Bozza
- Instituto D'Or de Pesquisa e Ensino, Rio de Janeiro, RJ, Brazil
- Instituto Nacional de Infectologia Evandro Chagas, Fiocruz, Rio de Janeiro, RJ, Brazil
| | - Dumith Chequer Bou-Habib
- Laboratório de Pesquisas sobre o Timo, IOC, Fiocruz, Rio de Janeiro, RJ, Brazil
- National Institute for Science and Technology on Neuroimmunomodulation (INCT/NIM), IOC, Fiocruz, Rio de Janeiro, RJ, Brazil
| | - Jingyue Ju
- Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY 10027, USA
- Department of Chemical Engineering, Columbia University, New York, NY 10027, USA
- Department of Molecular Pharmacology and Therapeutics, Columbia University, New York, NY, 10032, USA
| | - Patrícia T Bozza
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil
| | - Thiago Moreno L Souza
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil
- National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, Brazil
| |
Collapse
|
|
17
|
Liu CH, Sun HY, Hsieh SM, Liu WC, Sheng WH, Liu CJ, Su TH, Tseng TC, Chen PJ, Hung CC, Kao JH. Evolution of estimated glomerular filtration rate in human immunodeficiency virus and hepatitis C virus-coinfected patients receiving sofosbuvir-based direct-acting antivirals and antiretroviral therapy. J Viral Hepat 2021; 28:887-896. [PMID: 33759290 DOI: 10.1111/jvh.13502] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 02/06/2021] [Accepted: 02/26/2021] [Indexed: 12/13/2022]
Abstract
The nephrotoxicity of sofosbuvir (SOF) on human immunodeficiency virus and hepatitis C virus (HIV/HCV)-coinfected patients receiving antiretroviral therapy (ART) remains controversial. We prospectively compared the estimated glomerular filtration rate (eGFR) changes in 167 patients receiving SOF-based direct-acting antivirals (DAAs) who also received tenofovir disoproxil fumarate (TFV)-based (n = 116) and TFV-free ART (n = 51). The eGFR was assessed by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, and the eGFR changes between ART regimens were compared by the generalized estimated equation. During DAA treatment, participants on TFV-based ART had a higher eGFR decline than those on TFV-free ART (slope coefficient difference: -0.82 ml/min/1.73 m2 /month [95% CI: -1.21 to -0.43]; p < 0.001), whereas the eGFR changes did not differ between groups (slope coefficient difference: 0.13 ml/min/1.73 m2 /month [95% CI: -0.32 to 0.58]; p = 0.42) after discontinuing DAAs. Participants on TFV TDF-based ART had a higher eGFR decline than those on TFV alafenamide fumarate (TAF)-based ART (slope coefficient difference: -0.31 ml/min/1.73 m2 /month [95% CI: -0.50 to -0.12]; p = 0.01). After discontinuing DAAs, the eGFR changes did not differ between groups (slope coefficient difference: 0.06 ml/min/1.73 m2 /month [95% CI: -0.98 to 1.10]; p = 0.91). In conclusion, HIV/HCV-coinfected patients on TFV-based ART had a slight eGFR decline compared to those on TFV-free ART during SOF-based DAA therapy. A similar trend between TDF-based and TAF-based ART was also observed. Because the differences of eGFR changes are limited, the physicians should not discourage the use of SOF-based DAAs in HIV-positive patients on TFV-based ART.
Collapse
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
| | - Hsin-Yun Sun
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Szu-Min Hsieh
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Wen-Chun Liu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Wang-Hui Sheng
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- 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
| | - Tung-Hung Su
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Tai-Chung Tseng
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- 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
| | - Chien-Ching Hung
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Department of Tropical Medicine and Parasitology, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.,China Medical University, Taichung, 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
| |
Collapse
|
|
18
|
Mondal R, Agbaria M, Nairoukh Z. Fluorinated Rings: Conformation and Application. Chemistry 2021; 27:7193-7213. [PMID: 33512034 DOI: 10.1002/chem.202005425] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Indexed: 12/16/2022]
Abstract
The introduction of fluorine atoms into molecules and materials across many fields of academic and industrial research is now commonplace, owing to their unique properties. A particularly interesting feature is the impact of fluorine substitution on the relative orientation of a C-F bond when incorporated into organic molecules. In this Review, we will be discussing the conformational behavior of fluorinated aliphatic carbo- and heterocyclic systems. The conformational preference of each system is associated with various interactions introduced by fluorine substitution such as charge-dipole, dipole-dipole, and hyperconjugative interactions. The contribution of each interaction on the stabilization of the fluorinated alicyclic system, which manifests itself in low conformations, will be discussed in detail. The novelty of this feature will be demonstrated by presenting the most recent applications.
Collapse
Affiliation(s)
- Rajarshi Mondal
- Institute of Chemistry, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Jerusalem, 9190401, Israel
| | - Mohamed Agbaria
- Institute of Chemistry, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Jerusalem, 9190401, Israel
| | - Zackaria Nairoukh
- Institute of Chemistry, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Jerusalem, 9190401, Israel
| |
Collapse
|
|
19
|
Villard AL, Aubertin AM, Peyrottes S, Périgaud C. An original pronucleotide strategy for the simultaneous delivery of two bioactive drugs. Eur J Med Chem 2021; 216:113315. [PMID: 33711763 DOI: 10.1016/j.ejmech.2021.113315] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 02/17/2021] [Accepted: 02/17/2021] [Indexed: 01/09/2023]
Abstract
The synthesis and in vitro anti-HIV activity of a novel series of phosphoramidate pronucleotides including a S-pivaloyl-2-thioethyl (tBuSATE) group as biolabile phosphate protecting group are reported. Such constructs, obtained through different phosphorus chemistries, are characterized by the association of two different anti-HIV nucleoside analogues linked to the phosphorus atom respectively by the sugar residue and the exocyclic amino function of the nucleobase. In vitro, comparative anti-HIV evaluation demonstrates that such original prodrugs are able to allow the efficient intracellular combination release of a 5'-mononucleotide as well as another nucleoside analogue. In human T4-lymphoblastoid cells, the pronucleotide 1 shows remarkable antiviral activity with an EC50 in the nanomolar range (0.6 ηM) and without additional cytotoxicity. In addition, these two pronucleotide models exhibit higher selectivity index than the equimolar mixture of their constitutive nucleoside analogues opening the way to further studies with regard to the current use of drug combinations.
Collapse
Affiliation(s)
- Anne-Laure Villard
- UMR 5247 CNRS, Université Montpellier, ENSCM, Campus Triolet, place Eugène Bataillon, 34095, Montpellier, France
| | - Anne-Marie Aubertin
- Laboratoire de Virologie de la Faculté de Médecine, Unité 74 INSERM, Université L. Pasteur, 3, rue Koeberlé, 67000, Strasbourg, France
| | - Suzanne Peyrottes
- UMR 5247 CNRS, Université Montpellier, ENSCM, Campus Triolet, place Eugène Bataillon, 34095, Montpellier, France
| | - Christian Périgaud
- UMR 5247 CNRS, Université Montpellier, ENSCM, Campus Triolet, place Eugène Bataillon, 34095, Montpellier, France.
| |
Collapse
|
|
20
|
Khan Z, Karataş Y, Ceylan A, Rahman H. COVID-19 and therapeutic drugs repurposing in hand: The need for collaborative efforts. LE PHARMACIEN HOSPITALIER ET CLINICIEN 2021. [PMCID: PMC7293532 DOI: 10.1016/j.phclin.2020.06.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
|
|
21
|
Liang W, Cai X, Dai M. Cu-catalyzed hydroxycyclopropanol ring-opening cyclization to tetrahydrofurans and tetrahydropyrans: short total syntheses of hyperiones. Chem Sci 2020; 12:1311-1316. [PMID: 34163894 PMCID: PMC8179039 DOI: 10.1039/d0sc05556e] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 11/20/2020] [Indexed: 01/04/2023] Open
Abstract
Tetrahydrofurans (THFs) and tetrahydropyrans (THPs) are important core scaffolds frequently found in many molecules of medicinal importance. Herein, we report a novel copper-catalyzed hydroxycyclopropanol ring-opening cyclization methodology to synthesize di- or tri-substituted THFs and THPs. In this reaction, a strained C-C bond was cleaved and a new Csp3-O bond was formed to produce the aforementioned O-heterocycles. The new THF synthesis features a broad substrate scope, scalability, and good functional-group tolerability. It enabled us to complete the shortest enantioselective syntheses of hyperiones A and B (3 and 4 steps, respectively), which is significantly shorter than the previously reported two total syntheses (≥10 steps).
Collapse
Affiliation(s)
- Weida Liang
- Department of Chemistry and Center for Cancer Research, Purdue University West Lafayette IN 47907 USA
| | - Xinpei Cai
- Department of Chemistry and Center for Cancer Research, Purdue University West Lafayette IN 47907 USA
| | - Mingji Dai
- Department of Chemistry and Center for Cancer Research, Purdue University West Lafayette IN 47907 USA
| |
Collapse
|
|
22
|
Analysis of drug-resistance-associated mutations and genetic barriers in hepatitis C virus NS5B sequences in China. Arch Virol 2020; 165:2013-2020. [PMID: 32601956 DOI: 10.1007/s00705-020-04713-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 05/22/2020] [Indexed: 12/16/2022]
Abstract
The hepatitis C virus (HCV) NS5B protein is an RNA-dependent RNA polymerase that is required for viral genome replication and constitutes the most important target region for drugs being developed as direct-acting antivirals (DAAs) against HCV genotype 1. However, the extreme genetic variability leading to drug resistance mutations and genetic barriers has dramatically compromised the effectiveness of DAA therapy. The purpose of this study was to analyze the genetic variability of NS5B polymerase in HCV patients from different provinces of China to identify the impact of these resistance sites on genetic barriers. We analyzed 3489 NS5B sequences of HCV strains circulating in different regions of China, obtained from the GenBank database, 153 of which were from three cities in Sichuan Province (Yibin, Zigong and Zhangzhou). Sequence alignment was conducted using MEGA 6.0, the genetic information was translated into amino acids, and the percentage of polymorphic amino acid sites was calculated. The Vijver method was used to evaluate the occurrence of genetic barriers in HCV NS5B sequences. Blood samples were collected from 153 HCV patients from Sichuan for NS5B sequence analysis using real-time PCR and the Sanger method. Of the 17 antiviral drug resistance sites summarized from the published literature, nine were found in Chinese NS5B sequences, and C316Y was identified as the dominant mutation. Analysis of genetic barriers revealed that the probability of mutation to a drug-resistance-associated amino acid, in response to selective pressure from antiviral drugs was 100% at site 96 and 99.7% at site 282. Our study is the first to analyze the drug resistance sites and to evaluate genetic barriers in NS5B sequences that could affect the responsiveness of Chinese HCV patients to DAA therapy. The results provide a valuable basis for drug development and introduction of foreign-origin antiviral drugs in China that targeting the HCV NS5B region.
Collapse
|
|
23
|
Liu CH, Lee MH, Lin JW, Liu CJ, Su TH, Tseng TC, Chen PJ, Chen DS, Kao JH. Evolution of eGFR in chronic HCV patients receiving sofosbuvir-based or sofosbuvir-free direct-acting antivirals. J Hepatol 2020; 72:839-846. [PMID: 31790766 DOI: 10.1016/j.jhep.2019.11.014] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Revised: 11/18/2019] [Accepted: 11/19/2019] [Indexed: 12/28/2022]
Abstract
BACKGROUND & AIMS Data regarding the nephrotoxicity of sofosbuvir (SOF) remain controversial. We compared the evolution of estimated glomerular filtration rate (eGFR) in patients with chronic HCV infection receiving SOF-based or SOF-free direct-acting antivirals (DAAs). METHODS A total of 481 patients with compensated liver diseases and eGFR ≥30 ml/min/1.73m2, receiving SOF-based (n = 308) or SOF-free (n = 173) DAAs for 12 weeks, were prospectively enrolled. The eGFR was assessed from baseline to off-treatment week 24 using the chronic kidney disease (CKD)-epidemiology collaboration equation. Differences in the evolution of eGFR between regimens were compared by a generalized linear mixed-effects model. Multivariate analysis was performed for factors affecting eGFR evolution. RESULTS Patients receiving SOF-based DAAs experienced a significant on-treatment decline in eGFR (adjusted slope coefficient difference: -1.24 ml/min/1.73m2/month; 95% CI -1.35 to -1.13; p <0.001) and a significant off-treatment improvement (adjusted slope coefficient difference: 0.14 ml/min/1.73m2/month; 95% CI 0.08 to 0.21; p = 0.004) compared to patients receiving SOF-free DAAs. Multivariate analysis showed age per 1-year increase (adjusted slope coefficient difference: -0.05 ml/min/1.73m2/month; 95% CI -0.05 to -0.04; p <0.001), SOF-based DAAs (adjusted slope coefficient difference: -0.33 ml/min/1.73m2/month; 95% CI -0.49 to -0.17; p <0.001), and CKD stage (adjusted slope coefficient difference: -1.44 ml/min/1.73m2/month; 95% CI -1.58 to -1.30; p <0.001 for stage 3 vs. 1, and -3.59 ml/min/1.73m2/month; 95% CI -3.88 to -3.30; p <0.001 for stage 2 vs. 1) were independent factors affecting eGFR evolution from baseline to off-treatment week 24. CONCLUSIONS Patients receiving SOF-based DAAs exhibited a quadratic trend, with eGFR worsening on treatment and improving off treatment. Increasing age, SOF-based DAAs, and more advanced baseline CKD stage are independently associated with a decline in eGFR in patients with HCV receiving DAAs. LAY SUMMARY While the efficacy of sofosbuvir for the treatment of hepatitis C virus is clear, data regarding its possible nephrotoxicity are controversial. Herein, we showed that sofosbuvir worsened on-treatment kidney function but led to an off-treatment improvement. Our findings suggest that treating physicians should be alert to risk factors for kidney dysfunction before initiating direct-acting antiviral treatment for patients with hepatitis C virus infection. CLINICAL TRIAL NUMBER NCT04047680.
Collapse
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
| | - Mei-Hsuan Lee
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Jou-Wei Lin
- Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Douliou, Taiwan
| | - Chun-Jen Liu
- 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
| | - Tung-Hung Su
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Tai-Chung Tseng
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- 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
| | - Ding-Shinn Chen
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; Genomics Research Center, Academia Sinica, Taipei, 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.
| |
Collapse
|
|
24
|
Najjar A, Karaman R. Successes, failures, and future prospects of prodrugs and their clinical impact. Expert Opin Drug Discov 2019; 14:199-220. [DOI: 10.1080/17460441.2019.1567487] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Anas Najjar
- Department of Bioorganic & Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Quds University, Jerusalem, Palestine
| | - Rafik Karaman
- Department of Bioorganic & Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Quds University, Jerusalem, Palestine
| |
Collapse
|
|
25
|
Sofia MJ. The Discovery and Early Clinical Evaluation of the HCV NS3/4A Protease Inhibitor Asunaprevir (BMS-650032). TOPICS IN MEDICINAL CHEMISTRY 2019. [PMCID: PMC7123690 DOI: 10.1007/7355_2018_58] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
The discovery of asunaprevir (1) began with the concept of engaging the small and well-defined S1’ pocket of the hepatitis C virus (HCV) NS3/4A protease that was explored in the context of tripeptide carboxylic acid-based inhibitors. A cyclopropyl-acyl sulfonamide moiety was found to be the optimal element at the P1-P1’ interface enhancing the potency of carboxylic acid-based prototypes by 10- to >100-fold, dependent upon the specific background. Optimization for oral bioavailability identified a 1-substituted isoquinoline-based P2* element that conferred a significant exposure advantage in rats compared to the matched 4-substituted quinoline isomer. BMS-605339 (30) was the first cyclopropyl-acyl sulfonamide derivative advanced into clinical trials that demonstrated dose-related reductions in plasma viral RNA in HCV-infected patients. However, 30 was associated with cardiac events observed in a normal healthy volunteer (NHV) and an HCV-infected patient that led to the suspension of the development program. Using a Langendorff rabbit heart model, a limited structure-cardiac liability relationship was quickly established that led to the discovery of 1. This compound, which differs from 30 only by changes in the substitution pattern of the P2* isoquinoline heterocycle and the addition of a single chlorine atom to the molecular formula, gave a dose-dependent reduction in plasma viral RNA following oral administration to HCV-infected patients without the burden of the cardiac events that had been observed with 30. A small clinical trial of the combination of 1 with the HCV NS5A inhibitor daclatasvir (2) established for the first time that a chronic genotype 1 (GT-1) HCV infection could be cured by therapy with two direct-acting antiviral agents in the absence of exogenous immune-stimulating agents. Development of the combination of 1 and 2 was initially focused on Japan where the patient population is predominantly infected with GT-1b virus, culminating in marketing approval which was granted on July 4, 2014. In order to broaden therapy to include GT-1a infections, a fixed dose triple combination of 1, 2, and the allosteric NS5B inhibitor beclabuvir (3) was developed, approved by the Japanese health authorities for the treatment of HCV GT-1 infection on December 20, 2016 and marketed as Ximency®.
Collapse
|
|
26
|
Liu CH, Liu CJ, Su TH, Yang HC, Hong CM, Tseng TC, Chen PJ, Chen DS, Kao JH. Real-world effectiveness and safety of sofosbuvir and ledipasvir with or without ribavirin for patients with hepatitis C virus genotype 1 infection in Taiwan. PLoS One 2018; 13:e0209299. [PMID: 30576344 PMCID: PMC6303025 DOI: 10.1371/journal.pone.0209299] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2018] [Accepted: 12/03/2018] [Indexed: 12/13/2022] Open
Abstract
Background The real-world data for the effectiveness and safety of sofosbuvir/ledipasvir (SOF/LDV) with or without ribavirin (RBV) in patients with hepatitis C virus genotype 1 (HCV-1) infection remain limited in Taiwan. Methods A total of 273 chronic HCV-1 patients receiving 8, 12, or 24 weeks of SOF/LDV with or without RBV were enrolled. The sustained virologic response rate at week 12 off-therapy (SVR12) by evaluable population (EP) and per-protocol population (PP) were assessed for effectiveness. The treatment discontinuation rate due to adverse events (AEs) and serious AE rate were assessed for safety. Baseline patient characteristics and on-treatment HCV viral kinetics associated with SVR12 were analyzed. Results The SVR12 rates by EP and PP analyses were 96.7% (95% confidence interval [CI]: 93.9%-98.3%) and 97.5% (95% CI: 94.8%-98.8%), respectively. The rates of treatment discontinuation due to AE and serious AE were 0.4% and 4.4%, respectively. Seven patients with true virologic failure were relapsers. In 2 patients who were lost-to follow-up, one expired at treatment week 3 due to pneumonia which was considered not related to treatment, and one declined follow-up at off-therapy week 4. The SVR12 rates were comparable in terms of baseline patient characteristics and viral decline at week 4 of treatment. Conclusions SOF/LDV with or without RBV for 8–24 weeks is well tolerated and achieves a high SVR12 rate in patients with HCV-1 infection in Taiwan.
Collapse
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
| | - Chun-Jen Liu
- 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
| | - Tung-Hung Su
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Hung-Chih Yang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chun-Ming Hong
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Tai-Chung Tseng
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- 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
| | - Ding-Shinn Chen
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Genomics Research Center, Academia Sinica, Taipei, 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
- * E-mail:
| |
Collapse
|
|
27
|
Reznik SE, Tiwari AK, Ashby CR. Sofosbuvir: A Potential Treatment for Ebola. Front Pharmacol 2018; 9:1139. [PMID: 30364245 PMCID: PMC6192451 DOI: 10.3389/fphar.2018.01139] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 09/19/2018] [Indexed: 11/13/2022] Open
Affiliation(s)
- Sandra E Reznik
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States.,Departments of Pathology and Obstetrics and Gynecology and Women's Health, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, United States
| | - Amit K Tiwari
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, United States
| | - Charles R Ashby
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States
| |
Collapse
|
|
28
|
Generic sofosbuvir-based interferon-free direct acting antiviral agents for patients with chronic hepatitis C virus infection: a real-world multicenter observational study. Sci Rep 2018; 8:13699. [PMID: 30209349 PMCID: PMC6135833 DOI: 10.1038/s41598-018-32060-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 08/30/2018] [Indexed: 12/14/2022] Open
Abstract
Real-world data regarding the effectiveness and safety of generic sofosbuvir (SOF)-based interferon-free direct acting antiviral agents (DAAs) for patients with chronic hepatitis C virus (HCV) infection remain limited. A total of 517 chronic HCV-infected patients receiving 12 or 24 weeks of SOF-based therapies were retrospectively enrolled in 4 academic centers in Taiwan. The rate of sustained virologic response at week 12 off-therapy (SVR12) and that of treatment completion were assessed. The baseline characteristics and on-treatment HCV viral kinetics to predict SVR12 were analyzed. By evaluable population (EP) analysis, the SVR12 rate was 95.4% (95% confidence interval [CI]: 93.2–96.9%). The SVR12 was achieved in 29 of 34 patients (85.3%, 95% CI: 69.6–93.6%), 130 of 139 patients (93.5%, 95% CI: 88.2–96.6%), 119 of 124 patients (96.0%, 95% CI: 90.9–98.3%) and 215 of 220 patients (97.7%, 95% CI: 94.8–99.0%) who received SOF in combination with ribavirin (RBV), ledipasvir (LDV), daclatasvir (DCV) and velpatasvir (VEL), respectively. Of 517 patients, 514 (99.4%) completed the scheduled treatment. All 15 patients with true virologic failures were relapsers. Two decompensated cirrhotic patients had on-treatment deaths which were not related to DAAs. All 7 patients who were lost to follow-up had undetectable HCV RNA level at the last visit. The SVR12 rates were comparable in terms of baseline patient characteristics and viral decline at week 4 of treatment. In conclusion, generic SOF-based regimens are well tolerated and provide high SVR12 rates in patients with chronic HCV infection.
Collapse
|
|
29
|
Rivero-Juarez A, Brieva T, Frias M, Rivero A. Pharmacodynamic and pharmacokinetic evaluation of the combination of daclatasvir/sofosbuvir/ribavirin in the treatment of chronic hepatitis C. Expert Opin Drug Metab Toxicol 2018; 14:901-910. [PMID: 30058394 DOI: 10.1080/17425255.2018.1506765] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION The combination of daclatasvir (DCV), sofosbuvir (SOF), and ribavirin (RBV) is a direct-acting antiviral (DAA) regimen for the treatment of hepatitis C virus (HCV) infection. The inclusion of newer effective DAAs such as SOF and DCV with high efficacy and excellent tolerance introduced a new scenario in HCV infection therapy: high rates of sustained virological response (SVR), shorter therapies, less toxicity, and interferon-free treatments. This combination was approved for the treatment of HCV in treatment-naive or treatment-experienced patients with chronic HCV genotype 1 or 3 infection. Areas covered: This review summarizes the pharmacokinetics, pharmacodynamics, efficacy, and safety of DCV plus SOF and RBV therapy in the treatment of HCV infection. The topics include data regarding drug absorption, distribution, metabolism, excretion, and antiviral activity strategies, such as clinical dose selection and treatment duration. Expert opinion: This combination, taken orally with or without food, has an excellent pharmacokinetic and pharmacodynamic profile. DAC/SOF/RBV achieves very high rates of SVR in treatment-naive and treatment-experienced patients with chronic HCV infection, including difficult-to-treat patients such as those with compensated cirrhosis, post-transplant recurrence, or HIV-1 co-infection.
Collapse
Affiliation(s)
- Antonio Rivero-Juarez
- a Unidad de Enfermedades Infecciosas, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC) , Hospital Universitario Reina Sofía de Córdoba, Universidad de Córdoba , Cordoba , Spain
| | - Teresa Brieva
- a Unidad de Enfermedades Infecciosas, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC) , Hospital Universitario Reina Sofía de Córdoba, Universidad de Córdoba , Cordoba , Spain
| | - Mario Frias
- a Unidad de Enfermedades Infecciosas, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC) , Hospital Universitario Reina Sofía de Córdoba, Universidad de Córdoba , Cordoba , Spain
| | - Antonio Rivero
- a Unidad de Enfermedades Infecciosas, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC) , Hospital Universitario Reina Sofía de Córdoba, Universidad de Córdoba , Cordoba , Spain
| |
Collapse
|
|
30
|
Nano-magnetite/ionic liquid crystal modifiers of carbon nanotubes composite electrode for ultrasensitive determination of a new anti-hepatitis C drug in human serum. J Electroanal Chem (Lausanne) 2018. [DOI: 10.1016/j.jelechem.2018.06.016] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
|
|
31
|
Hassouna M, Mohamed M. UV-Spectrophotometric and Stability Indicating RP-HPLC Methods for the Determination of the Hepatitis C Virus Inhibitor Sofosbuvir in Tablet Dosage Form. ACTA ACUST UNITED AC 2018. [DOI: 10.1080/22297928.2017.1410441] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Affiliation(s)
- M.E.M. Hassouna
- Chemistry Department, Faculty of Science, Beni-Suef University, 62514, Egypt
| | - M.A. Mohamed
- HIKMA group, Pharmaceutical Company, Beni-Suef, Egypt
| |
Collapse
|
|
32
|
Xavier NM, Gonçalves-Pereira R, Jorda R, Řezníčková E, Kryštof V, Oliveira MC. Synthesis and antiproliferative evaluation of novel azido nucleosides and their phosphoramidate derivatives. PURE APPL CHEM 2017. [DOI: 10.1515/pac-2016-1218] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Abstract:New xylofuranosyl and glucopyranosyl nucleoside phosphoramidates were synthesized as potential mimetics of nucleoside 5′-monophosphates. Their access involved N-glycosylation of uracil and 2-acetamido-6-chloropurine with 5′/6′-azido-1,2-di-O-acetyl glycosyl donors and subsequent Staudinger-phosphite reaction of the resulting azido nucleosides. The coupling of the purine derivative with the pyranosyl donor furnished N9- and N7-linked nucleosides in 1:1 ratio, whereas with the furanosyl donor, the N9-nucleoside was the major regioisomer formed. When using uracil, only 5′/6′-azido N1-linked nucleosides were obtained. The purine 5′/6′-azido nucleosides were converted into corresponding phosphoramidates in good yields. The antiproliferative effects of the nucleoside phosphoramidates and those of the azido counterparts on cancer cells were evaluated. While the nucleoside phosphoramidates did not show significant activities, the purine 5′/6′-azido nucleosides displayed potent effects against K562, MCF-7 and BT474 cell lines. The 5′-azidofuranosyl N9 and N7-linked purine nucleosides exhibited highest activity towards the chronic myeloid leukemia cell line (K562) with GI50 values of 13.6 and 9.7 μM, respectively. Among pyranosyl nucleosides, the N7-linked nucleoside was the most active compound with efficacy towards all cell lines assayed and a highest effect on K562 cells (GI50=6.8 μM). Cell cycle analysis of K562 and MCF-7 cells showed that the most active compounds cause G2/M arrest.
Collapse
Affiliation(s)
- Nuno M. Xavier
- Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, 2/5º Piso, Campo Grande, 1749-016 Lisboa, Portugal
| | - Rita Gonçalves-Pereira
- Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, 2/5º Piso, Campo Grande, 1749-016 Lisboa, Portugal
| | - Radek Jorda
- Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 27, 78371 Olomouc, Czech Republic
| | - Eva Řezníčková
- Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 27, 78371 Olomouc, Czech Republic
| | - Vladimír Kryštof
- Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 27, 78371 Olomouc, Czech Republic
| | - M. Conceição Oliveira
- Centro de Química Estrutural (CQE), Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
| |
Collapse
|
|
33
|
Soriano V, Benítez-Gutiérrez L, Arias A, Carrasco I, Barreiro P, Peña JM, de Mendoza C. Evaluation of sofosbuvir, velpatasvir plus voxilaprevir as fixed-dose co-formulation for treating hepatitis C. Expert Opin Drug Metab Toxicol 2017; 13:1015-1022. [PMID: 28753040 DOI: 10.1080/17425255.2017.1359254] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
INTRODUCTION The fixed-dose combination of three direct-acting antivirals (DAA), namely sofosbuvir, velpatasvir and voxilaprevir is the first pangenotypic, single tablet regimen developed for the treatment of HCV infection. Areas covered: The pharmacokinetics, pharmacodynamics, efficacy and safety of the co-formulation are reviewed. Information on drug absorption, distribution, metabolism and excretion of each of the three antivirals is evaluated. Finally, antiviral activity, safety and potential for drug interactions in phase II/III clinical trials in distinct patient populations are discussed. Expert opinion: The triple co-formulation of sofosbuvir-velpatasvir-voxilaprevir represents a major step towards HCV eradication. It depicts high efficacy even in patients infected with viruses harboring resistance-associated substitutions (RAS), including those selected after DAA failures. Likewise, very high success rates and good tolerance are seen in special patient populations, including decompensated cirrhotics, HIV coinfection, organ transplantation or renal insufficiency. A pill once daily for 8 weeks gives SVR rates above 95%. In prior DAA failures, extending treatment to 12 weeks maximizes SVR rates.
Collapse
Affiliation(s)
- Vicente Soriano
- a Infectious Diseases Unit , La Paz University Hospital & Autonomous University , Madrid , Spain
| | - Laura Benítez-Gutiérrez
- b Department of Internal Medicine , Puerta de Hierro Research Institute , Majadahonda , Spain
| | - Ana Arias
- b Department of Internal Medicine , Puerta de Hierro Research Institute , Majadahonda , Spain
| | - Itziar Carrasco
- b Department of Internal Medicine , Puerta de Hierro Research Institute , Majadahonda , Spain
| | - Pablo Barreiro
- a Infectious Diseases Unit , La Paz University Hospital & Autonomous University , Madrid , Spain
| | - Jose M Peña
- a Infectious Diseases Unit , La Paz University Hospital & Autonomous University , Madrid , Spain
| | - Carmen de Mendoza
- b Department of Internal Medicine , Puerta de Hierro Research Institute , Majadahonda , Spain
| |
Collapse
|
|
34
|
Abstract
The hepatitis C virus (HCV) NS5A replication complex inhibitor daclatasvir (Daklinza(®)) is indicated for use in combination with sofosbuvir, with or without ribavirin, in a pangenotypic all-oral regimen. In patients with chronic HCV genotype 1 or 3 infection without cirrhosis, a 12-week regimen of daclatasvir plus sofosbuvir achieved high sustained virological response rates 12 weeks' post-treatment (SVR12), regardless of prior treatment experience, according to the results of the AI444040 and ALLY-3 trials. In the ALLY-3+ trial, high SVR12 rates were achieved with a 12- or 16-week regimen of daclatasvir plus sofosbuvir and ribavirin in patients with chronic HCV genotype 3 infection and advanced fibrosis or compensated cirrhosis. A daclatasvir plus sofosbuvir-based regimen demonstrated efficacy in patients with chronic HCV genotype 1, 3 or 4 infection and advanced cirrhosis or post-transplant recurrence in the ALLY-1 trial, and in patients co-infected with HCV genotype 1, 3 or 4 and HIV-1 in the ALLY-2 trial. Results of clinical trials were supported by real-world data from early-access programmes that included high numbers of patients who would have been excluded from phase 3 trials because of advanced disease and/or concomitant medical conditions. Daclatasvir plus sofosbuvir with or without ribavirin was generally well tolerated. In conclusion, an all-oral regimen comprising daclatasvir plus sofosbuvir with or without ribavirin is an important option for use in treatment-naive or treatment-experienced patients with chronic HCV genotype 1, 3 or 4 infection, including in patients with advanced liver disease, post-transplant recurrence and HIV-1 co-infection.
Collapse
|
|
35
|
Abstract
A once-daily, single-tablet, pangenotypic regimen comprising the hepatitis C virus (HCV) NS5B polymerase inhibitor sofosbuvir and the HCV NS5A inhibitor velpatasvir (sofosbuvir/velpatasvir; Epclusa®) was recently approved for the treatment of adults with chronic HCV genotype 1, 2, 3, 4, 5 or 6 infection in the USA, EU and Canada. In the phase III ASTRAL trials, once-daily oral sofosbuvir/velpatasvir for 12 weeks provided very high rates of sustained virological response at 12 weeks post treatment (SVR12) in treatment-naive and -experienced patients with chronic HCV genotype 1-6 infection, including those with compensated cirrhosis or HIV-1 co-infection. High SVR12 rates were also observed with sofosbuvir/velpatasvir plus ribavirin for 12 weeks in patients with chronic HCV genotype 1-6 infection and decompensated cirrhosis. Sofosbuvir/velpatasvir was generally well tolerated, with low rates of adverse events. Thus, sofosbuvir/velpatasvir represents a valuable treatment option in adults with chronic HCV genotype 1-6 infection, including those with compensated or decompensated cirrhosis, previous treatment experience or HIV-1 co-infection.
Collapse
Affiliation(s)
- Sarah L Greig
- Springer, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand.
| |
Collapse
|
|
36
|
Brieva T, Rivero A, Rivero-Juarez A. Pharmacokinetic drug evaluation of velpatasvir plus sofosbuvir for the treatment of hepatitis C virus infection. Expert Opin Drug Metab Toxicol 2017; 13:483-490. [PMID: 28165830 DOI: 10.1080/17425255.2017.1292253] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
INTRODUCTION The fixed-dose combination therapy of sofosbuvir (SOF) plus velpatasvir (VEL) is the first pangenotypic, direct-acting antiviral (DAA), single-treatment regimen (STR) for the treatment of hepatitis C virus (HCV) infection to be commercialized. It is approved for the treatment of HCV genotypes 1, 2, 3, 4, 5, and 6. Following approval in 2016, new pharmacokinetic and pharmacodynamic data were reported, which led to important clinical applications. Areas covered: This review provides a summary of the pharmacokinetics, pharmacodynamics, efficacy and safety of SOF/VEL therapy for treatment of HCV infection. The topics covered include data regarding the drug's absorption, distribution, metabolism, excretion and antiviral activity strategies, such as clinical dose selection and treatment duration. Expert opinion: This novel combination therapy containing 400 mg of SOF plus 100 mg of VEL, taken orally, once daily, with or without food, has an excellent pharmacokinetic and pharmacodynamic profile. SOF/VEL achieved very high rates of sustained virological response in treatment-naive and treatment-experienced patients with chronic HCV genotype 1-6 infection, including those with compensated cirrhosis or HIV-1 co-infection.
Collapse
Affiliation(s)
- Teresa Brieva
- a Unidad de Enfermedades Infecciosas , Hospital Universitario Reina Sofía de Córdoba, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba , Cordoba , Spain
| | - Antonio Rivero
- a Unidad de Enfermedades Infecciosas , Hospital Universitario Reina Sofía de Córdoba, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba , Cordoba , Spain
| | - Antonio Rivero-Juarez
- a Unidad de Enfermedades Infecciosas , Hospital Universitario Reina Sofía de Córdoba, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba , Cordoba , Spain
| |
Collapse
|
|
37
|
Durante-Mangoni E, Parrella A, Vitrone M, Rago A, Pafundi PC, Nigro G, Utili R, Russo V. Electrophysiological Adverse Effects of Direct Acting Antivirals in Patients With Chronic Hepatitis C. J Clin Pharmacol 2017; 57:924-930. [PMID: 28117887 DOI: 10.1002/jcph.872] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 12/12/2016] [Indexed: 11/05/2022]
Abstract
Recently, several cases of symptomatic, sometimes fatal bradycardia during the first days of direct-acting antiviral (DAA) (eg, sofosbuvir [SOF]) administration have been reported. We analyzed in detail electrocardiographic (ECG) changes during SOF- or non-SOF-based chronic hepatitis C (CHC) treatment, specifically focusing on bradyarrhythmias. All 39 consecutive patients treated at our center with any interferon-free regimen between June and December 2015 were included in this study (26 SOF-based therapy vs 13 no-SOF interferon-free regimens). ECG tracings were obtained from all patients the first day of treatment and after 7, 14, and 28 days. ECG parameters (P-wave, QRS, QT interval, JT interval, Tapex -Tend interval duration) were compared between the 2 groups at baseline and at the 3 different time points during antiviral therapy. There were no cases of symptomatic bradycardia/syncope. In the SOF group, QTc duration rose after 1 week (from 424.3 to 431.2 milliseconds; P = .013) and returned to baseline during therapy. QT dispersion dropped since week 1 (from 85.6 to 67.2 milliseconds) and remained significantly reduced until the end of the observation period (72.9 msec) (P = .003). JT dispersion reduced up to week 2 (P = .010) and returned to baseline at week 4; in the no-SOF group, QRS dispersion transiently reduced (from 41 to 34.5 milliseconds, day 7). No other significant changes were observed in the remaining parameters. In CHC patients treated with SOF and other DAAs, ECG parameter changes were mild and/or transient and did not translate into clinically significant electrophysiological effects in the absence of amiodarone coadministration.
Collapse
Affiliation(s)
- Emanuele Durante-Mangoni
- Internal Medicine, University of Campania 'Luigi Vanvitelli' and AORN dei Colli-Monaldi Hospital, Naples, Italy
| | - Antonio Parrella
- Internal Medicine, University of Campania 'Luigi Vanvitelli' and AORN dei Colli-Monaldi Hospital, Naples, Italy
| | - Martina Vitrone
- Internal Medicine, University of Campania 'Luigi Vanvitelli' and AORN dei Colli-Monaldi Hospital, Naples, Italy
| | - Anna Rago
- Department of Cardiothoracic Sciences, Cardiology Section, University of Campania 'Luigi Vanvitelli' and AORN dei Colli-Monaldi Hospital, Naples, Italy
| | - Pia Clara Pafundi
- Internal Medicine, University of Campania 'Luigi Vanvitelli' and AORN dei Colli-Monaldi Hospital, Naples, Italy
| | - Gerardo Nigro
- Department of Cardiothoracic Sciences, Cardiology Section, University of Campania 'Luigi Vanvitelli' and AORN dei Colli-Monaldi Hospital, Naples, Italy
| | - Riccardo Utili
- Internal Medicine, University of Campania 'Luigi Vanvitelli' and AORN dei Colli-Monaldi Hospital, Naples, Italy
| | - Vincenzo Russo
- Department of Cardiothoracic Sciences, Cardiology Section, University of Campania 'Luigi Vanvitelli' and AORN dei Colli-Monaldi Hospital, Naples, Italy
| |
Collapse
|
|
38
|
Zeng D, Zhang R, Nie Q, Cao L, Shang L, Yin Z. Discovery of 2'-α-C-Methyl-2'-β-C-fluorouridine Phosphoramidate Prodrugs as Inhibitors of Hepatitis C Virus. ACS Med Chem Lett 2016; 7:1197-1201. [PMID: 27994763 DOI: 10.1021/acsmedchemlett.6b00270] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Accepted: 10/19/2016] [Indexed: 12/22/2022] Open
Abstract
2'-α-C-Methyl-2'-β-C-fluorouridine and its phosphoramidate prodrugs were synthesized and evaluated for their inhibitory activity against HCV. The structure-activity relationship analysis of the phosphoramidate moiety found that 17m, 17q, and 17r exhibit potent activities against HCV, with EC50 values of 1.82 ± 0.19, 0.88 ± 0.12, and 2.24 ± 0.22 μM, respectively. The docking study revealed that the recognition of the 2'-β-F by Arg158, 3'-OH by N291, and the Watson-Crick pairing with the template allowed 23 to form the in-line conformation necessary for its incorporation into the viral RNA chain.
Collapse
Affiliation(s)
- Debin Zeng
- State Key Laboratory of Elemento-Organic Chemistry, College
of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, PR China
| | - Rui Zhang
- State Key Laboratory of Elemento-Organic Chemistry, College
of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, PR China
| | - Quandeng Nie
- State Key Laboratory of Elemento-Organic Chemistry, College
of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, PR China
| | - Lin Cao
- State Key Laboratory of Elemento-Organic Chemistry, College
of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, PR China
| | - Luqing Shang
- State Key Laboratory of Elemento-Organic Chemistry, College
of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, PR China
| | - Zheng Yin
- State Key Laboratory of Elemento-Organic Chemistry, College
of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, PR China
| |
Collapse
|
|
39
|
Gentile I, Maraolo AE, Niola M, Graziano V, Borgia G, Paternoster M. Limiting the access to direct-acting antivirals against HCV: an ethical dilemma. Expert Rev Gastroenterol Hepatol 2016; 10:1227-1234. [PMID: 27607920 DOI: 10.1080/17474124.2016.1234375] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) infection affects about 200 million people worldwide and represents a leading cause of liver-related mortality. Eradication of HCV infection, achieved mainly through direct-acting antivirals (DAA), results in a decrease of mortality and an improvement of quality of life. These drugs have a maximal efficacy and an optimal tolerability. However, their high cost precludes a universal access even in wealthy countries. Areas covered: This article deals with the policies adopted for the use of the new anti-HCV drugs, especially in Europe and most of all in Italy, supposedly the developed country with the highest HCV prevalence. The literature search was performed using Pubmed and Web of Science. Moreover, national regulatory institutional websites were consulted. Expert commentary: The current policy of limitation to the access of the DAA presents a series of ethical issues that makes it non-applicable. A 'treat-all' strategy should resolve all ethical dilemmas, by virtue of the wide benefits of anti-HCV treatment not only for the advanced stage of infection, but also for the initial stages. A reduction in price of the drugs is the actual condition to achieve such a change.
Collapse
Affiliation(s)
- Ivan Gentile
- a Department of Clinical Medicine and Surgery , University of Naples Federico II , Naples , Italy
| | - Alberto E Maraolo
- a Department of Clinical Medicine and Surgery , University of Naples Federico II , Naples , Italy
| | - Massimo Niola
- b Department of Advanced Biomedical Sciences , University of Naples Federico II , Naples , Italy
| | - Vincenzo Graziano
- b Department of Advanced Biomedical Sciences , University of Naples Federico II , Naples , Italy
| | - Guglielmo Borgia
- a Department of Clinical Medicine and Surgery , University of Naples Federico II , Naples , Italy
| | - Mariano Paternoster
- b Department of Advanced Biomedical Sciences , University of Naples Federico II , Naples , Italy
| |
Collapse
|
|
40
|
de Ávila AI, Gallego I, Soria ME, Gregori J, Quer J, Esteban JI, Rice CM, Domingo E, Perales C. Lethal Mutagenesis of Hepatitis C Virus Induced by Favipiravir. PLoS One 2016; 11:e0164691. [PMID: 27755573 PMCID: PMC5068784 DOI: 10.1371/journal.pone.0164691] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Accepted: 09/29/2016] [Indexed: 12/14/2022] Open
Abstract
Lethal mutagenesis is an antiviral approach that consists in extinguishing a virus by an excess of mutations acquired during replication in the presence of a mutagen. Here we show that favipiravir (T-705) is a potent mutagenic agent for hepatitis C virus (HCV) during its replication in human hepatoma cells. T-705 leads to an excess of G → A and C → U transitions in the mutant spectrum of preextinction HCV populations. Infectivity decreased significantly in the presence of concentrations of T-705 which are 2- to 8-fold lower than its cytotoxic concentration 50 (CC50). Passaging the virus five times in the presence of 400 μM T-705 resulted in virus extinction. Since T-705 has undergone advanced clinical trials for approval for human use, the results open a new approach based on lethal mutagenesis to treat hepatitis C virus infections. If proven effective for HCV in vivo, this new anti-HCV agent may be useful in patient groups that fail current therapeutic regimens.
Collapse
Affiliation(s)
- Ana I. de Ávila
- Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, 28049, Madrid, Spain
| | - Isabel Gallego
- Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, 28049, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Maria Eugenia Soria
- Liver Unit, Internal Medicine, Laboratory of Malalties Hepàtiques, Vall d’Hebron Institut de Recerca-Hospital Universitari Vall d´Hebron, (VHIR-HUVH), Universitat Autònoma de Barcelona, 08035, Barcelona, Spain
| | - Josep Gregori
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
- Liver Unit, Internal Medicine, Laboratory of Malalties Hepàtiques, Vall d’Hebron Institut de Recerca-Hospital Universitari Vall d´Hebron, (VHIR-HUVH), Universitat Autònoma de Barcelona, 08035, Barcelona, Spain
- Roche Diagnostics, S.L., Sant Cugat del Vallés, Spain
| | - Josep Quer
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
- Liver Unit, Internal Medicine, Laboratory of Malalties Hepàtiques, Vall d’Hebron Institut de Recerca-Hospital Universitari Vall d´Hebron, (VHIR-HUVH), Universitat Autònoma de Barcelona, 08035, Barcelona, Spain
- Universitat Autónoma de Barcelona, Barcelona, Spain
| | - Juan Ignacio Esteban
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
- Liver Unit, Internal Medicine, Laboratory of Malalties Hepàtiques, Vall d’Hebron Institut de Recerca-Hospital Universitari Vall d´Hebron, (VHIR-HUVH), Universitat Autònoma de Barcelona, 08035, Barcelona, Spain
- Universitat Autónoma de Barcelona, Barcelona, Spain
| | - Charles M. Rice
- Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, United States of America
| | - Esteban Domingo
- Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, 28049, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Celia Perales
- Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, 28049, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
- Liver Unit, Internal Medicine, Laboratory of Malalties Hepàtiques, Vall d’Hebron Institut de Recerca-Hospital Universitari Vall d´Hebron, (VHIR-HUVH), Universitat Autònoma de Barcelona, 08035, Barcelona, Spain
| |
Collapse
|
|
41
|
Abstract
Hepatitis C infection can cause chronic liver disease and liver carcinoma and can necessitate liver transplantation. Of the more than 3 million people infected with hepatitis C, more than two-thirds were born between 1945 and 1965. Many individuals are unaware that they're infected, which can delay treatment and lead to disease progression. Once infection is diagnosed, typical treatment regimens can involve multiple medications and side effects that can make it challenging for some people to complete therapy. In October 2014 the U.S. Food and Drug Administration (FDA) approved Harvoni®, a fixed dose combination pill of ledipasvir/sofosbuvir that provides a new option for treatment.
Collapse
|
|
42
|
Millard DC, Strock CJ, Carlson CB, Aoyama N, Juhasz K, Goetze TA, Stoelzle-Feix S, Becker N, Fertig N, January CT, Anson BD, Ross JD. Identification of Drug-Drug Interactions In Vitro: A Case Study Evaluating the Effects of Sofosbuvir and Amiodarone on hiPSC-Derived Cardiomyocytes. Toxicol Sci 2016; 154:174-182. [PMID: 27503387 DOI: 10.1093/toxsci/kfw153] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Drug-drug interactions pose a difficult drug safety problem, given the increasing number of individuals taking multiple medications and the relative complexity of assessing the potential for interactions. For example, sofosbuvir-based drug treatments have significantly advanced care for hepatitis C virus-infected patients, yet recent reports suggest interactions with amiodarone may cause severe symptomatic bradycardia and thus limit an otherwise extremely effective treatment. Here, we evaluated the ability of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) to recapitulate the interaction between sofosbuvir and amiodarone in vitro, and more generally assessed the feasibility of hiPSC-CMs as a model system for drug-drug interactions. Sofosbuvir alone had negligible effects on cardiomyocyte electrophysiology, whereas the sofosbuvir-amiodarone combination produced dose-dependent effects beyond that of amiodarone alone. By comparison, GS-331007, the primary circulating metabolite of sofosbuvir, had no effect alone or in combination with amiodarone. Further mechanistic studies revealed that the sofosbuvir-amiodarone combination disrupted intracellular calcium (Ca2+) handling and cellular electrophysiology at pharmacologically relevant concentrations, and mechanical activity at supra-pharmacological (30x Cmax) concentrations. These effects were independent of the common mechanisms of direct ion channel block and P-glycoprotein activity. These results support hiPSC-CMs as a comprehensive, yet scalable model system for the identification and evaluation of cardioactive pharmacodynamic drug-drug interactions.
Collapse
Affiliation(s)
| | | | - Coby B Carlson
- Cellular Dynamics International, a Fujifilm Company, Madison, Wisconsin
| | - Natsuyo Aoyama
- Cellular Dynamics International, a Fujifilm Company, Madison, Wisconsin
| | - Krisztina Juhasz
- Nanion Technologies GmbH, Munich, Germany
- Technische Universitat Munchen, Munich, Germany
| | | | | | | | | | - Craig T January
- School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin
| | - Blake D Anson
- Cellular Dynamics International, a Fujifilm Company, Madison, Wisconsin
| | | |
Collapse
|
|
43
|
Chopp S, Vanderwall R, Hult A, Klepser M. Simeprevir and sofosbuvir for treatment of hepatitis C infection. Am J Health Syst Pharm 2016; 72:1445-55. [PMID: 26294237 DOI: 10.2146/ajhp140290] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
PURPOSE The pharmacology, pharmacokinetics, efficacy, safety, costs, and place in therapy of simeprevir and sofosbuvir in the management of hepatitis C virus (HCV) infection are reviewed. SUMMARY Sofosbuvir and simeprevir are classified as direct-acting agents because they target specific proteins essential to the replication of HCV. Phase III trials demonstrated that simeprevir in combination with peginterferon alfa and ribavirin was superior to placebo combined with peginterferon alfa and ribavirin in achieving a sustained virological response in both treatment-naive patients and patients who relapsed after treatment with peginterferon alfa-2a or alfa-2b and ribavirin. Q80K polymorphism substantially decreases the efficacy of simeprevir. Clinical trials revealed that sofosbuvir in combination with ribavirin was superior to peginterferon plus ribavirin against HCV genotype 2 infection and as effective as peginterferon plus ribavirin against HCV genotype 3 infection. These findings were significant because they demonstrated the effectiveness of an anti-HCV regimen that did not include peginterferon alfa. Sofosbuvir has much better adverse-effect and drug interaction profiles than previous hepatitis C antiviral agents. Both simeprevir and sofosbuvir are approved for the treatment of chronic hepatitis C in combination with other antiviral medications. Simeprevir has been approved specifically for patients infected with HCV genotype 1 with compensated liver disease (including cirrhosis) in combination with peginterferon alfa-2a or alfa-2b and ribavirin. Sofosbuvir has shown efficacy in HCV genotypes 1-4. CONCLUSION Simeprevir and sofasbuvir have advantages in response rates and convenient dosage forms and frequency compared with other HCV treatments; however, they are more expensive than previous HCV therapies.
Collapse
Affiliation(s)
- Shelby Chopp
- Shelby Chopp, Pharm.D., is Postgraduate Year 1 (PGY1) Pharmacy Practice Resident, Children's Hospital of Michigan, Detroit; at the time of writing she was Pharm.D. student, Ferris State University College of Pharmacy, Kalamazoo, MI. Rebecca Vanderwall, Pharm.D., is PGY1 Pharmacy Practice Resident, Indiana University Health, Indianapolis, IN; at the time of writing she was Pharm.D. student, Ferris State University College of Pharmacy. Amanda Hult, Pharm.D., is PGY1 Pharmacy Practice Resident, Bronson Methodist Hospital, Kalamazoo, MI; at the time of writing she was Pharm.D. student, Ferris State University College of Pharmacy. Michael Klepser, Pharm.D., FCCP, is Professor, Pharmacy Practice, Ferris State University College of Pharmacy
| | - Rebecca Vanderwall
- Shelby Chopp, Pharm.D., is Postgraduate Year 1 (PGY1) Pharmacy Practice Resident, Children's Hospital of Michigan, Detroit; at the time of writing she was Pharm.D. student, Ferris State University College of Pharmacy, Kalamazoo, MI. Rebecca Vanderwall, Pharm.D., is PGY1 Pharmacy Practice Resident, Indiana University Health, Indianapolis, IN; at the time of writing she was Pharm.D. student, Ferris State University College of Pharmacy. Amanda Hult, Pharm.D., is PGY1 Pharmacy Practice Resident, Bronson Methodist Hospital, Kalamazoo, MI; at the time of writing she was Pharm.D. student, Ferris State University College of Pharmacy. Michael Klepser, Pharm.D., FCCP, is Professor, Pharmacy Practice, Ferris State University College of Pharmacy
| | - Amanda Hult
- Shelby Chopp, Pharm.D., is Postgraduate Year 1 (PGY1) Pharmacy Practice Resident, Children's Hospital of Michigan, Detroit; at the time of writing she was Pharm.D. student, Ferris State University College of Pharmacy, Kalamazoo, MI. Rebecca Vanderwall, Pharm.D., is PGY1 Pharmacy Practice Resident, Indiana University Health, Indianapolis, IN; at the time of writing she was Pharm.D. student, Ferris State University College of Pharmacy. Amanda Hult, Pharm.D., is PGY1 Pharmacy Practice Resident, Bronson Methodist Hospital, Kalamazoo, MI; at the time of writing she was Pharm.D. student, Ferris State University College of Pharmacy. Michael Klepser, Pharm.D., FCCP, is Professor, Pharmacy Practice, Ferris State University College of Pharmacy
| | - Michael Klepser
- Shelby Chopp, Pharm.D., is Postgraduate Year 1 (PGY1) Pharmacy Practice Resident, Children's Hospital of Michigan, Detroit; at the time of writing she was Pharm.D. student, Ferris State University College of Pharmacy, Kalamazoo, MI. Rebecca Vanderwall, Pharm.D., is PGY1 Pharmacy Practice Resident, Indiana University Health, Indianapolis, IN; at the time of writing she was Pharm.D. student, Ferris State University College of Pharmacy. Amanda Hult, Pharm.D., is PGY1 Pharmacy Practice Resident, Bronson Methodist Hospital, Kalamazoo, MI; at the time of writing she was Pharm.D. student, Ferris State University College of Pharmacy. Michael Klepser, Pharm.D., FCCP, is Professor, Pharmacy Practice, Ferris State University College of Pharmacy.
| |
Collapse
|
|
44
|
Banerjee D, Reddy KR. Review article: safety and tolerability of direct-acting anti-viral agents in the new era of hepatitis C therapy. Aliment Pharmacol Ther 2016; 43:674-96. [PMID: 26787287 DOI: 10.1111/apt.13514] [Citation(s) in RCA: 112] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Revised: 10/25/2015] [Accepted: 12/13/2015] [Indexed: 12/15/2022]
Abstract
BACKGROUND Direct-acting anti-virals (DAAs) licensed to treat chronic HCV infection have revolutionised treatment algorithms by drastically mitigating side effects while enhancing efficacy relative to interferon-based therapy. AIM To review adverse events (AEs) uniquely associated with DAA therapy across a broad spectrum of patient populations. METHODS Searches of PubMed and FDA surveillance studies were undertaken to complete an exhaustive review. Search terms included 'DAAs', 'safety', and 'tolerability'. RESULTS While DAAs are remarkably well tolerated, they are accompanied by unique AEs. Simeprevir, an NS3/4A protease inhibitor, has been known, albeit infrequently, to cause mild hyperbilirubinemia and photosensitivity reactions; and paritaprevir boosted with ritonavir causes bilirubin and ALT elevations. Asunaprevir, another protease inhibitor, infrequently causes elevated transaminase levels. NS5A and NS5B inhibitors are well tolerated, although sofosbuvir is contraindicated in patients with severe renal impairment. Ribavirin co-administered in certain treatment regimens has been associated with cough, rash and haemolytic anaemia. CONCLUSIONS With the impending reality of a more tolerable interferon-sparing regimen, the future of DAA therapy offers shorter treatment duration, simplified disease management, and a patient-centred regimen. With advantages come drawbacks, including development of resistance to therapy and accessibility to this expensive treatment. DAA therapy continues to advance at a brisk pace with a promising trend for higher tolerability, even in difficult-to-treat subgroups such as those with cirrhosis, nonresponders to prior therapy, and transplant recipients. Subgroup-specific contraindications and safety-related limitations are active areas of research. Concerted research efforts and continuing advances lend hope to the goal of rendering HCV a routinely curable disease.
Collapse
Affiliation(s)
- D Banerjee
- Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA, USA
| | - K R Reddy
- Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA, USA
| |
Collapse
|
|
45
|
Saeed N, Gurakar A. Tackling HCV-3 in Asia: Breakthroughs for Efficient and Cost-effective Treatment Strategies. Euroasian J Hepatogastroenterol 2016; 6:35-42. [PMID: 29201722 PMCID: PMC5578556 DOI: 10.5005/jp-journals-10018-1163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Accepted: 10/18/2015] [Indexed: 11/23/2022] Open
Abstract
Hepatitis C virus (HCV) is known to cause chronic hepatitis C, and its sequelae of cirrhosis and hepatocellular carcinoma. Hepatitis C genotype 3 (HCV-3) in particular is notorious for causing accelerated liver fibrosis, cardiovascular, and metabolic effects, thus increasing morbidity and mortality. It is the commonest variant in Asian countries like India and Pakistan. It is also one of the hardest-to-treat genotypes, especially among treatment-experienced and cirrhotic patients. Due to limited health care affordability and accessibility in these areas, many patients remain untreated. Until recently, the established therapy for HCV had been a combination of pegylated interferon + ribavirin. However, it was only effective in about half of patients and had severe adverse effects; hence a more efficacious option needed to be found. Recent advances have led to the development of sofosbuvir, an NS5B inhibitor that is fast becoming the standard of care, in combination with other novel drugs. It was initially marketed at $1,000 per pill, a cost that was too high for most. Thus, it has not been utilized as a global therapy as yet. Formulation of effective interferon-free regimens is a huge milestone, and awareness needs to be raised regarding these new highly effective options in both the physician and the patient population. This article discusses the newest drugs and combinations that have been developed in the fight against HCV-3, as a treatment outline for HCV-3-dominant areas. It also highlights recent breakthroughs in cost reductions of these drugs and the effort to make them globally accessible. HOW TO CITE THIS ARTICLE Saeed N, Gurakar A. Tackling HCV-3 in Asia: Breakthroughs for Efficient and Cost-effective Treatment Strategies. Euroasian J Hepato-Gastroenterol 2016;6(1):35-42.
Collapse
Affiliation(s)
- Naba Saeed
- Department of Transplant Hepatology, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Ahmet Gurakar
- Department of Transplant Hepatology, Johns Hopkins University School of Medicine, Division of Gastroenterology and Hepatology, Baltimore Maryland, USA
| |
Collapse
|
|
46
|
Sanford M. Simeprevir: a review of its use in patients with chronic hepatitis C virus infection. Drugs 2015; 75:183-96. [PMID: 25559421 DOI: 10.1007/s40265-014-0341-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Simeprevir (Olysio™; Galexos™; Sovriad®) is an orally-administered NS3/4A protease inhibitor for use in combined drug regimens against chronic hepatitis C virus (HCV) infection. This article reviews studies relevant to the EU simeprevir label. In proof-of-concept studies, simeprevir had potent antiviral activity against all HCV genotypes, except genotype 3. In trials in patients with chronic HCV genotype 1 infection, week-12 sustained virological response (SVR12) rates in treatment-naïve patients and prior relapsers were significantly higher with simeprevir plus peginterferon-α/ribavirin (PR) [79-89 %] than with placebo plus PR (36-62 %). In prior partial/null responders, the SVR12 rate with simeprevir plus PR (54 %) was noninferior to that with telaprevir plus PR (55 %). Simeprevir plus PR was also efficacious in patients with HCV genotype 1/HIV-1 co-infection. In prior null responders without severe liver fibrosis (cohort 1) and treatment-naïve patients with severe liver fibrosis (cohort 2) treated with simeprevir plus sofosbuvir, the SVR12 rate for the two cohorts combined was 92 %. In patients with chronic HCV genotype 4 infection, the SVR12 rates with simeprevir plus PR were 83, 87 and 40 % in treatment-naïve patients, prior relapsers and prior null responders, respectively. Grade 3-4 adverse event, serious adverse event and treatment withdrawal rates with simeprevir plus PR were similar to those with placebo plus PR. Skin rashes with simeprevir were mostly mild or moderate; serious photosensitivity reactions occur, but are rare. Simeprevir is efficacious and generally well tolerated in patients with chronic HCV genotypes 1 and 4 infection. Studies of simeprevir in interferon-free regimens and in other subpopulations with HCV infections will be of interest.
Collapse
Affiliation(s)
- Mark Sanford
- Springer, Private Bag 65901, Mairangi Bay, 0754, Auckland, New Zealand,
| |
Collapse
|
|
47
|
Shi X, Zhu D, Lou J, Zhu B, Hu AR, Gan D. Evaluation of a rapid method for the simultaneous quantification of ribavirin, sofosbuvir and its metabolite in rat plasma by UPLC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci 2015; 1002:353-7. [PMID: 26363369 DOI: 10.1016/j.jchromb.2015.08.038] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Revised: 08/23/2015] [Accepted: 08/25/2015] [Indexed: 01/27/2023]
Abstract
A rapid and sensitive ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the determination of ribavirin, sofosbuvir and its metabolite GS-331007 in rat plasma was established. The analytes and the internal standard (midazolam) were separated on an Acquity UPLC BEH C18 chromatography column (2.1mm×50mm, 1.7μm) using gradient elution with a mobile phase of acetonitrile and 0.1% formic acid in water at a flow rate of 0.4mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode to monitor the precursor-to-product ion transitions of m/z 245.1→113.1 for ribavirin, m/z 530.3→243.1 for sofosbuvir, m/z 261.5→113.1 for GS-331007 and m/z 326.2→291.1 for midazolam (IS) using a positive electrospray ionization interface. The method was validated over a concentration range of 5-1000ng/mL for ribavirin, 10-2000ng/mL for sofosbuvir and 10-2000ng/mL for GS-331007. Total time for each chromatograph was 3.0min. The intra- and inter-day precision and accuracy of the quality control samples at low, medium, and high concentration levels exhibited relative standard deviations (RSD) <10.0% and the accuracy values ranged from -10.6% to 11.6%. The method was successfully applied to a pharmacokinetic study of ribavirin, sofosbuvir and GS-331007 in rats.
Collapse
Affiliation(s)
- Xiaojun Shi
- Department of Hepatopathy, Ningbo No.2 Hospital, Ningbo 315000, China
| | - Dedong Zhu
- Department of Hepatopathy, Ningbo No.2 Hospital, Ningbo 315000, China
| | - Jie Lou
- Digestive Department, Ningbo No.2 Hospital, Ningbo 315000, China
| | - Bo Zhu
- Pharmaceutical Preparation Section, Ningbo No.2 Hospital, Ningbo 315000, China
| | - Ai-rong Hu
- Department of Hepatopathy, Ningbo No.2 Hospital, Ningbo 315000, China.
| | - Dongmei Gan
- Department of Paediatrics, Ningbo Women and Children's Hospital, Ningbo 315000, China.
| |
Collapse
|
|
48
|
Tasleem S, Sood GK. Hepatitis C Associated B-cell Non-Hodgkin Lymphoma: Clinical Features and the Role of Antiviral Therapy. J Clin Transl Hepatol 2015; 3:134-9. [PMID: 26357640 PMCID: PMC4548354 DOI: 10.14218/jcth.2015.00011] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2015] [Revised: 05/16/2015] [Accepted: 05/18/2015] [Indexed: 12/13/2022] Open
Abstract
The link between chronic hepatitis C virus (HCV) infection and a subset of B-cell non-Hodgkin lymphomas (B-NHL) is strongly supported by epidemiological studies. Evidence demonstrating complete regression of lymphoma after antiviral treatments suggests possible chronic antigenic stimulation for the origin of B-NHL and provides evidence for a virus-mediated lymphomagenesis. B-NHL is a heterogeneous group of lymphomas with varied clinical presentation and may be indolent or aggressive. The optimal management of HCV related B-NHL is not clear. Antiviral treatment may be sufficient for low-grade lymphomas, but chemotherapy is necessary in patients with high grade lymphomas. Interferon (IFN)-based antiviral treatment regimens for HCV infection are limited by poor tolerance and suboptimal antiviral response. Recently approved novel direct acting antiviral (DAA) drugs are highly effective and safe. This has opened a new era for the treatment of HCV related B-NHL alone or in conjunction with chemotherapy. Treatment of HCV associated B-NHL should be performed in an interdisciplinary approach in close consultation with hematologist and hepatologist. In this review, we summarize data regarding clinical features and epidemiology of B-NHL and discuss novel therapeutic approaches, including DAAs, that may prove to be effective in the treatment of HCV associated lymphomas.
Collapse
Affiliation(s)
- Syed Tasleem
- Department of Surgery, St. Luke’s Center for Liver Disease, Baylor College of Medicine, Houston, Texas, USA
| | - Gagan K Sood
- Department of Surgery, St. Luke’s Center for Liver Disease, Baylor College of Medicine, Houston, Texas, USA
- Department of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas, USA
- Correspondence to: Gagan K Sood, Department of Surgery, St. Luke’s Center for Liver disease, Baylor College of Medicine, 6620 Main Street, Houston, Texas 77030, USA. Tel: +1-832-355-1400, Fax: +1-713-610-2479, E-mail:
| |
Collapse
|
|
49
|
Li HC, Lo SY. Hepatitis C virus: Virology, diagnosis and treatment. World J Hepatol 2015; 7:1377-1389. [PMID: 26052383 PMCID: PMC4450201 DOI: 10.4254/wjh.v7.i10.1377] [Citation(s) in RCA: 103] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 12/22/2014] [Accepted: 04/02/2015] [Indexed: 02/06/2023] Open
Abstract
More than twenty years of study has provided a better understanding of hepatitis C virus (HCV) life cycle, including the general properties of viral RNA and proteins. This effort facilitates the development of sensitive diagnostic tools and effective antiviral treatments. At present, serologic screening test is recommended to perform on individuals in the high risk groups and nucleic acid tests are recommended to confirm the active HCV infections. Quantization and genotyping of HCV RNAs are important to determine the optimal duration of anti-viral therapy and predict the likelihood of response. In the early 2000s, pegylated interferon plus ribavirin became the standard anti-HCV treatment. However, this therapy is not ideal. To 2014, boceprevir, telaprevir, simeprevir, sofosbuvir and Harvoni are approved by Food and Drug Administration for the treat of HCV infections. It is likely that the new all-oral, interferon-free, pan-genotyping anti-HCV therapy will be available within the next few years. Majority of HCV infections will be cured by these anti-viral treatments. However, not all patients are expected to be cured due to viral resistance and the high cost of antiviral treatments. Thus, an efficient prophylactic vaccine will be the next challenge in the fight against HCV infection.
Collapse
|
|
50
|
Ding HX, Leverett CA, Kyne RE, Liu KKC, Fink SJ, Flick AC, O’Donnell CJ. Synthetic approaches to the 2013 new drugs. Bioorg Med Chem 2015; 23:1895-922. [DOI: 10.1016/j.bmc.2015.02.056] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Revised: 02/20/2015] [Accepted: 02/26/2015] [Indexed: 12/31/2022]
|