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Astha, Agrawal A, Gupta A, Sahu P, Kumar D, Shakya P. Sustained virological response in HCV patients receiving antiviral treatment at a teaching centre of northern India. J Family Med Prim Care 2025; 14:942-946. [PMID: 40256099 PMCID: PMC12007787 DOI: 10.4103/jfmpc.jfmpc_1379_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 10/02/2024] [Accepted: 10/15/2024] [Indexed: 04/22/2025] Open
Abstract
In India, it is estimated that 10-24 million people are living with active HCV infection, with a seroprevalence of 0.09% to 2.02% among the healthy population. The current study evaluates the efficacy of newer pan-genotypic directly acting antiviral drugs for SVR, which is the hallmark of successful HCV therapy. Data were collected on the prevalence of HCV infection, rates of SVR, and associated risk factors. In univariate analysis, serum albumin, AST, and APRI are significant predictors of SVR with P < 0.05. Specifically, a unit increase in serum albumin doubled the chances of achieving SVR (OR: 2.08, CI: 1.02-4.19), while increases in AST and APRI values were associated with reduced chances of SVR (OR: -0.99, CI: 0.98-0.99; OR: -0.79, CI: 0.64-0.98). Non-cirrhotic patients were significantly more likely to achieve SVR compared to decompensated cirrhotic patients (OR: 6.48, CI: 1.46-28.59). In the multivariable logistic regression analysis, taking all variables with a P value < 0.05 in the univariate analysis, such an association was not found, and it established the multifactorial nature of SVR. The present study underlines the importance of early diagnosis and the effectiveness of antiviral drugs against improved treatment outcomes of HCV patients in India. The findings present the challenges and successes in HCV elimination in a diverse and populous country.
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Affiliation(s)
- Astha
- Department of Microbiology, F.H. Medical College, Agra, Uttar Pradesh, India
| | - Arti Agrawal
- Department of Microbiology, Sarojini Naidu Medical College, Agra, Uttar Pradesh, India
| | - Ayushi Gupta
- Department of Liberal Arts and Humanities, Jindal School of Liberal Arts and Humanities, Jindal Global University, Sonipat, Haryana, India
| | - Priyanka Sahu
- Department of Community Medicine, ASMC, Auraiya, Uttar Pradesh, India
| | | | - Pragya Shakya
- Department of Microbiology, Sarojini Naidu Medical College, Agra, Uttar Pradesh, India
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Behery ME, Elghwab A, Tabll AA, Elsayed EH, Abdelrazek MA. Serum collagen IV as a predictor for response to direct-acting antivirals hepatitis C therapy. J Immunoassay Immunochem 2024; 45:539-548. [PMID: 39402774 DOI: 10.1080/15321819.2024.2415882] [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] [Indexed: 11/12/2024]
Abstract
Althoughchronic hepatitis C (CHC) therapies based on direct-acting antiviral (DAA) agents safely improved treatment effectiveness, some cases do not obtain sustained virological response (SVR) and, thus, evaluating factors that may be related to treatment failure is very important. We aimed to evaluate the association of baseline serum collagen IV with DAA treatment failure in Egyptian patients with CHC. A total of 175 CHC patients (100 responders and 75non-responders tosofosbuvir/daclatasvir) were included. Collagen IV was assessed using sensitive chemiluminescent immunoassay. There was distinctly higher (P < 0.0001) collagen IV in non-responders compared to responder patients as the median (interquartile range) were 19.02 (13.4-25.2) vs.9.7 (7.2-12.3) µg/L, respectively. Collagen IV has a good ability for distinguishing nonresponders from responder patients (AUC = 0.890) with sensitivity of 92%, specificity 72%, PPV 71.1%, NPV 92.3% and accuracy of 80.6%. Collagen IV was correlated (p < 0.05) with decreased albumin (r=-0.266), elevated APRI (r = 0.288), and elevated FIB-4 (r = 0.281) scores. In conclusion,these findings suggested the remarkable role of baseline collagen IV in the prediction of HCV DAAs treatment response. Thus, however further studies are needed, its measurement may improve treatment duration and the disease control.
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Affiliation(s)
- Mohammed El Behery
- Chemistry Department, Faculty of Science, Port Said University, Port Said, Egypt
| | - AhmedI Elghwab
- Chemistry Department, Faculty of Science, Port Said University, Port Said, Egypt
| | - Ashraf A Tabll
- Microbial Biotechnology Department, Biotechnology Research Institute, National Research Centre, Giza, Egypt
| | - Elsherbiny H Elsayed
- Chemistry Department, Faculty of Science, Port Said University, Port Said, Egypt
| | - Mohamed A Abdelrazek
- Sherbin Central Hospital, Ministry of Health and Population, Shirbin, Egypt
- Research and Development Department, Biotechnology Research Center, New Damietta, Egypt
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Smolobochkin A, Gazizov A, Appazov N, Sinyashin O, Burilov A. Progress in the Stereoselective Synthesis Methods of Pyrrolidine-Containing Drugs and Their Precursors. Int J Mol Sci 2024; 25:11158. [PMID: 39456938 PMCID: PMC11508981 DOI: 10.3390/ijms252011158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 10/11/2024] [Accepted: 10/12/2024] [Indexed: 10/28/2024] Open
Abstract
The presented review systematizes and summarizes the data on the synthesis of pyrrolidine derivatives, which are precursors for obtaining drugs. Based on the analysis of published data, the most promising directions in the synthesis of biologically active compounds containing a pyrrolidine ring are identified. Stereoselective synthesis methods are classified based on the source of the pyrrolidine ring. The first group includes methods that use a pyrrolidine ring as the starting compound. The second group combines stereoselective methods of cyclization of acyclic starting compounds, which lead to optically pure pyrrolidine derivatives.
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Affiliation(s)
- Andrey Smolobochkin
- Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Arbuzov Str., 8, Kazan 420088, Russia; (A.G.); (O.S.); (A.B.)
| | - Almir Gazizov
- Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Arbuzov Str., 8, Kazan 420088, Russia; (A.G.); (O.S.); (A.B.)
| | - Nurbol Appazov
- Laboratory of Engineering Profile, Department of Engineering Technology, Korkyt Ata Kyzylorda University, Aiteke bi Str., 29A, Kyzylorda 120014, Kazakhstan
| | - Oleg Sinyashin
- Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Arbuzov Str., 8, Kazan 420088, Russia; (A.G.); (O.S.); (A.B.)
| | - Alexander Burilov
- Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Arbuzov Str., 8, Kazan 420088, Russia; (A.G.); (O.S.); (A.B.)
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Fateev IV, Sasmakov SA, Abdurakhmanov JM, Ziyaev AA, Khasanov SS, Eshboev FB, Ashirov ON, Frolova VD, Eletskaya BZ, Smirnova OS, Berzina MY, Arnautova AO, Abramchik YA, Kostromina MA, Kayushin AL, Antonov KV, Paramonov AS, Andronova VL, Galegov GA, Esipov RS, Azimova SS, Miroshnikov AI, Konstantinova ID. Synthesis of Substituted 1,2,4-Triazole-3-Thione Nucleosides Using E. coli Purine Nucleoside Phosphorylase. Biomolecules 2024; 14:745. [PMID: 39062460 PMCID: PMC11274511 DOI: 10.3390/biom14070745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 06/18/2024] [Accepted: 06/19/2024] [Indexed: 07/28/2024] Open
Abstract
1,2,4-Triazole derivatives have a wide range of biological activities. The most well-known drug that contains 1,2,4-triazole as part of its structure is the nucleoside analogue ribavirin, an antiviral drug. Finding new nucleosides based on 1,2,4-triazole is a topical task. The aim of this study was to synthesize ribosides and deoxyribosides of 1,2,4-triazole-3-thione derivatives and test their antiviral activity against herpes simplex viruses. Three compounds from a series of synthesized mono- and disubstituted 1,2,4-triazole-3-thione derivatives were found to be substrates for E. coli purine nucleoside phosphorylase. Of six prepared nucleosides, the riboside and deoxyriboside of 3-phenacylthio-1,2,4-triazole were obtained at good yields. The yields of the disubstituted 1,2,4-triazol-3-thiones were low due to the effect of bulky substituents at the C3 and C5 positions on the selectivity of enzymatic glycosylation for one particular nitrogen atom in the triazole ring. The results of cytotoxic and antiviral studies on acyclovir-sensitive wild-type strain HSV-1/L2(TK+) and acyclovir-resistant strain (HSV-1/L2/RACV) in Vero E6 cell culture showed that the incorporation of a thiobutyl substituent into the C5 position of 3-phenyl-1,2,4-triazole results in a significant increase in the cytotoxicity of the base and antiviral activity. The highest antiviral activity was observed in the 3-phenacylthio-1-(β-D-ribofuranosyl)-1,2,4-triazole and 5-butylthio-1-(2-deoxy-β-D-ribofuranosyl)-3-phenyl-1,2,4-triazole nucleosides, with their selectivity indexes being significantly higher than that of ribavirin. It was also found that with the increasing lipophilicity of the nucleosides, the activity and toxicity of the tested compounds increased.
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Affiliation(s)
- Ilya V. Fateev
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St. 16/10, 117997 Moscow, Russia; (V.D.F.); (B.Z.E.); (O.S.S.); (M.Y.B.); (A.O.A.); (Y.A.A.); (M.A.K.); (A.L.K.); (K.V.A.); (A.S.P.); (R.S.E.); (A.I.M.); (I.D.K.)
| | - Sobirdjan A. Sasmakov
- Acad. S.Yu. Yunusov Institute of the Chemistry of Plant Substances, Academy of Sciences of the Republic of Uzbekistan, Mirzo Ulugbek Str. 77, 100170 Tashkent, Uzbekistan; (J.M.A.); (A.A.Z.); (Sh.Sh.K.); (F.B.E.); (O.N.A.); (S.S.A.)
| | - Jaloliddin M. Abdurakhmanov
- Acad. S.Yu. Yunusov Institute of the Chemistry of Plant Substances, Academy of Sciences of the Republic of Uzbekistan, Mirzo Ulugbek Str. 77, 100170 Tashkent, Uzbekistan; (J.M.A.); (A.A.Z.); (Sh.Sh.K.); (F.B.E.); (O.N.A.); (S.S.A.)
| | - Abdukhakim A. Ziyaev
- Acad. S.Yu. Yunusov Institute of the Chemistry of Plant Substances, Academy of Sciences of the Republic of Uzbekistan, Mirzo Ulugbek Str. 77, 100170 Tashkent, Uzbekistan; (J.M.A.); (A.A.Z.); (Sh.Sh.K.); (F.B.E.); (O.N.A.); (S.S.A.)
| | - Shukhrat Sh. Khasanov
- Acad. S.Yu. Yunusov Institute of the Chemistry of Plant Substances, Academy of Sciences of the Republic of Uzbekistan, Mirzo Ulugbek Str. 77, 100170 Tashkent, Uzbekistan; (J.M.A.); (A.A.Z.); (Sh.Sh.K.); (F.B.E.); (O.N.A.); (S.S.A.)
| | - Farkhod B. Eshboev
- Acad. S.Yu. Yunusov Institute of the Chemistry of Plant Substances, Academy of Sciences of the Republic of Uzbekistan, Mirzo Ulugbek Str. 77, 100170 Tashkent, Uzbekistan; (J.M.A.); (A.A.Z.); (Sh.Sh.K.); (F.B.E.); (O.N.A.); (S.S.A.)
| | - Oybek N. Ashirov
- Acad. S.Yu. Yunusov Institute of the Chemistry of Plant Substances, Academy of Sciences of the Republic of Uzbekistan, Mirzo Ulugbek Str. 77, 100170 Tashkent, Uzbekistan; (J.M.A.); (A.A.Z.); (Sh.Sh.K.); (F.B.E.); (O.N.A.); (S.S.A.)
| | - Valeriya D. Frolova
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St. 16/10, 117997 Moscow, Russia; (V.D.F.); (B.Z.E.); (O.S.S.); (M.Y.B.); (A.O.A.); (Y.A.A.); (M.A.K.); (A.L.K.); (K.V.A.); (A.S.P.); (R.S.E.); (A.I.M.); (I.D.K.)
| | - Barbara Z. Eletskaya
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St. 16/10, 117997 Moscow, Russia; (V.D.F.); (B.Z.E.); (O.S.S.); (M.Y.B.); (A.O.A.); (Y.A.A.); (M.A.K.); (A.L.K.); (K.V.A.); (A.S.P.); (R.S.E.); (A.I.M.); (I.D.K.)
| | - Olga S. Smirnova
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St. 16/10, 117997 Moscow, Russia; (V.D.F.); (B.Z.E.); (O.S.S.); (M.Y.B.); (A.O.A.); (Y.A.A.); (M.A.K.); (A.L.K.); (K.V.A.); (A.S.P.); (R.S.E.); (A.I.M.); (I.D.K.)
| | - Maria Ya. Berzina
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St. 16/10, 117997 Moscow, Russia; (V.D.F.); (B.Z.E.); (O.S.S.); (M.Y.B.); (A.O.A.); (Y.A.A.); (M.A.K.); (A.L.K.); (K.V.A.); (A.S.P.); (R.S.E.); (A.I.M.); (I.D.K.)
| | - Alexandra O. Arnautova
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St. 16/10, 117997 Moscow, Russia; (V.D.F.); (B.Z.E.); (O.S.S.); (M.Y.B.); (A.O.A.); (Y.A.A.); (M.A.K.); (A.L.K.); (K.V.A.); (A.S.P.); (R.S.E.); (A.I.M.); (I.D.K.)
| | - Yulia A. Abramchik
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St. 16/10, 117997 Moscow, Russia; (V.D.F.); (B.Z.E.); (O.S.S.); (M.Y.B.); (A.O.A.); (Y.A.A.); (M.A.K.); (A.L.K.); (K.V.A.); (A.S.P.); (R.S.E.); (A.I.M.); (I.D.K.)
| | - Maria A. Kostromina
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St. 16/10, 117997 Moscow, Russia; (V.D.F.); (B.Z.E.); (O.S.S.); (M.Y.B.); (A.O.A.); (Y.A.A.); (M.A.K.); (A.L.K.); (K.V.A.); (A.S.P.); (R.S.E.); (A.I.M.); (I.D.K.)
| | - Alexey L. Kayushin
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St. 16/10, 117997 Moscow, Russia; (V.D.F.); (B.Z.E.); (O.S.S.); (M.Y.B.); (A.O.A.); (Y.A.A.); (M.A.K.); (A.L.K.); (K.V.A.); (A.S.P.); (R.S.E.); (A.I.M.); (I.D.K.)
| | - Konstantin V. Antonov
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St. 16/10, 117997 Moscow, Russia; (V.D.F.); (B.Z.E.); (O.S.S.); (M.Y.B.); (A.O.A.); (Y.A.A.); (M.A.K.); (A.L.K.); (K.V.A.); (A.S.P.); (R.S.E.); (A.I.M.); (I.D.K.)
| | - Alexander S. Paramonov
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St. 16/10, 117997 Moscow, Russia; (V.D.F.); (B.Z.E.); (O.S.S.); (M.Y.B.); (A.O.A.); (Y.A.A.); (M.A.K.); (A.L.K.); (K.V.A.); (A.S.P.); (R.S.E.); (A.I.M.); (I.D.K.)
| | - Valeria L. Andronova
- D. I. Ivanovsky Institute of Virology (N. F. Gamaleya Research Center of Epidemiology and Microbiology, Ministry of Healthcare of the Russian Federation), Gamaleya St. 18, 123098 Moscow, Russia; (V.L.A.); (G.A.G.)
| | - Georgiy A. Galegov
- D. I. Ivanovsky Institute of Virology (N. F. Gamaleya Research Center of Epidemiology and Microbiology, Ministry of Healthcare of the Russian Federation), Gamaleya St. 18, 123098 Moscow, Russia; (V.L.A.); (G.A.G.)
| | - Roman S. Esipov
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St. 16/10, 117997 Moscow, Russia; (V.D.F.); (B.Z.E.); (O.S.S.); (M.Y.B.); (A.O.A.); (Y.A.A.); (M.A.K.); (A.L.K.); (K.V.A.); (A.S.P.); (R.S.E.); (A.I.M.); (I.D.K.)
| | - Shakhnoz S. Azimova
- Acad. S.Yu. Yunusov Institute of the Chemistry of Plant Substances, Academy of Sciences of the Republic of Uzbekistan, Mirzo Ulugbek Str. 77, 100170 Tashkent, Uzbekistan; (J.M.A.); (A.A.Z.); (Sh.Sh.K.); (F.B.E.); (O.N.A.); (S.S.A.)
| | - Anatoly I. Miroshnikov
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St. 16/10, 117997 Moscow, Russia; (V.D.F.); (B.Z.E.); (O.S.S.); (M.Y.B.); (A.O.A.); (Y.A.A.); (M.A.K.); (A.L.K.); (K.V.A.); (A.S.P.); (R.S.E.); (A.I.M.); (I.D.K.)
| | - Irina D. Konstantinova
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St. 16/10, 117997 Moscow, Russia; (V.D.F.); (B.Z.E.); (O.S.S.); (M.Y.B.); (A.O.A.); (Y.A.A.); (M.A.K.); (A.L.K.); (K.V.A.); (A.S.P.); (R.S.E.); (A.I.M.); (I.D.K.)
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Ivanova Reipold E, Shilton S, Donolato M, Fernandez Suarez M. Molecular Point-of-Care Testing for Hepatitis C: Available Technologies, Pipeline, and Promising Future Directions. J Infect Dis 2024; 229:S342-S349. [PMID: 37897429 PMCID: PMC11078314 DOI: 10.1093/infdis/jiad463] [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: 06/01/2023] [Revised: 10/13/2023] [Accepted: 10/17/2023] [Indexed: 10/30/2023] Open
Abstract
Hepatitis C virus (HCV) remains a major public health problem, despite the availability of effective treatments. In many areas, the ability to diagnose HCV infection at the point of care is key to scaling up access to care and treatment. To achieve this, an accurate, easy-to-use, and affordable diagnostic tool is required-this would enable decentralized testing and the creation of one-stop centers to eliminate gaps in the care cascade, which would help reach the millions of people with undiagnosed HCV infection in low- and middle-income countries and high-risk populations in high-income countries. In this review, we examine the current state of point-of-care molecular technologies, the advantages and limitations of currently available devices (both near- and true-point-of-care), the potential of molecular testing to transform diagnostic medicine in the future, and the challenges that need to be addressed for broader adoption of this technology in routine clinical practice.
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Affiliation(s)
| | | | - Marco Donolato
- FIND, The Global Alliance for Diagnostics, Geneva, Switzerland
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Ragab A, Ibrahim SA, Aboul-Magd DS, Baren MH. One-pot synthesis of pyrazolo[4,3- d]thiazole derivatives containing α-aminophosphonate as potential Mur A inhibitors against MDR pathogens with radiosterilization and molecular modeling simulation. RSC Adv 2023; 13:34756-34771. [PMID: 38035237 PMCID: PMC10685179 DOI: 10.1039/d3ra07040a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 11/14/2023] [Indexed: 12/02/2023] Open
Abstract
The present study involves the synthesis of a new series of α-aminophosphonate derivatives in good yields with a simple workup via the Kabachnik-Fields reaction using lithium perchlorate (LiClO4) as a catalyst to facilitate the reaction. All the newly synthesized compounds were confirmed using various physical, spectroscopic, and analytical data, and the obtained results correlated with the proposed molecular structure. The in vitro antimicrobial activities of each compound were evaluated against different clinical isolates. The results indicated that among these derivatives, two compounds (5a and 5b) were the most active and displayed potent activity with MICs in the range from 0.06 to 0.25 μg mL-1 compared with fosfomycin and fluconazole as standard antibiotics. Moreover, the synthesized phosphonates displayed a broad spectrum of bactericidal and fungicidal activities depending on MICs, MBCs/MFCs, and the time-kill kinetics. In addition, the checkerboard assay showed synergistic and partial synergistic activities between the active compounds combined with fosfomycin and fluconazole. Furthermore, the SEM images showed distinct ruptures of the OM integrity of the FOS-R E. coli at their MICs, which was further indicated by the increased EtBr accumulation within the bacterial cells. Moreover, active derivatives revealed MurA inhibitory activity with IC50 values of 3.8 ± 0.39 and 4.5 ± 0.23 μM compared with fosfomycin (IC50 = 12.7 ± 0.27 μM). To our surprise, exposing 5a and 5b compounds to different gamma radiation doses revealed that 7.0 kGy eradicated the microbial load completely. Finally, the results of quantum chemical study supported the binding mode obtained from the docking study performed inside the active site of MurA (PDB: 1UAE), suggesting that these phosphonates may be promising safe candidates for MDR infection therapy clinical trials with no toxic effects on the normal human cells.
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Affiliation(s)
- Ahmed Ragab
- Chemistry Department, Faculty of Science (Boys), Al-Azhar University Nasr City Cairo 11884 Egypt
| | - Seham A Ibrahim
- Chemistry Department, Faculty of Science, Tanta University Tanta 31527 Egypt
| | - Dina S Aboul-Magd
- Drug Radiation Research Department, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority Egypt
| | - Mohamed H Baren
- Chemistry Department, Faculty of Science, Tanta University Tanta 31527 Egypt
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Izhari MA. Molecular Mechanisms of Resistance to Direct-Acting Antiviral (DAA) Drugs for the Treatment of Hepatitis C Virus Infections. Diagnostics (Basel) 2023; 13:3102. [PMID: 37835845 PMCID: PMC10572573 DOI: 10.3390/diagnostics13193102] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 09/23/2023] [Accepted: 09/28/2023] [Indexed: 10/15/2023] Open
Abstract
Hepatitis C virus (HCV) is a hepatotropic virus that affects millions of human lives worldwide. Direct-acting antiviral (DAA) regimens are the most effective HCV treatment option. However, amino acid substitution-dependent resistance to DAAs has been a major challenge. This study aimed to determine the increasing risk of DAA resistance due to substitutions in DAA target non-structural proteins (NS3/4A, NS5A, and NS5B). Using a Sequence Retrieval System (SRS) at the virus pathogen resource (ViPR/BV-BRC), n = 32763 target protein sequences were retrieved and analyzed for resistance-associated amino acid substitutions (RAASs) by the Sequence Feature Variant Type (SFVT) antiviral-resistance assessment modeling tool. Reference target protein sequences with 100% identity were retried from UniProt following NCBI BLAST. The types and locations of RAASs were identified and visualized by AlphaFold and PyMol. Linux-r-base/R-studio was used for the data presentation. Multi-drug-resistant variants of NS3/4A in genotype 1 (n = 9) and genotype 5 (n = 5) along with DAA-specific NS3/4A, NS5A, and NS5B variants were identified pan-genotypically. A total of 27 variants (RAASs) of all the targets were identified. Fourteen genotype 1-specific substitutions: V1196A, V1158I, D1194A/T/G, R1181K, T1080S, Q1106R, V1062A, S1148G, A1182V, Y2065N, M2000T, and L2003V were identified. The most frequent substitutions were V1062L and L2003M, followed by Q2002H. L2003V, Q2002H, M2000T, Y2065N, and NL2003M of NS5A and L2003M of NS5B conferred resistance to daclatasvir. S2702T NS5B was the sofosbuvir-resistant variant. D1194A NS3/4A was triple DAA (simeprevir, faldaprevir, and asunaprevir) resistant. The double-drug resistant variants R1181K (faldaprevir and asunaprevir), A1182V and Q1106K/R (faldaprevir and simeprevir), T1080S (faldaprevir and telaprevir), and single drug-resistant variants V1062L (telaprevir), D1194E/T (simeprevir), D1194G (asunaprevir), S1148A/G (simeprevir), and Q1106L (Boceprevir) of NS3/4A were determined. The molecular phenomenon of DAA resistance is paramount in the development of HCV drug candidates. RAASs in NS3, NS5A, and NS5B reduce the susceptibility to DAAs; therefore, continuous RAAS-dependent resistance profiling in HCV is recommended to minimize the probability of DAA therapeutic failure.
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Affiliation(s)
- Mohammad Asrar Izhari
- Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Al-Baha University, Al-Baha 65522, Saudi Arabia
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Debzi N, Berkane S, Manouni C, Amani N, Hemmam S, Yousfi M, Taleb A, Guessab N, Moulay Brahim AS, Helal S, Benbitour I, Noual L, Kerbouche R, Cheikh IO, Drir O, Belimi HA, Gourari S, Frigga I, Kassah-laouar A, Khaberi M, Afredj N. Efficacy of Sofosbuvir/Daclatasvir in a Single Tablet for Treating Chronic Viral Hepatitis C. J Clin Pharm Ther 2023; 2023:1-9. [DOI: 10.1155/2023/8297332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Background. Published data regarding the real-life application of the combination sofosbuvir/daclatasvir in Algeria are lacking. Therefore, we conducted an observational study to assess the efficacy and safety of this regimen in Algerian patients with chronic hepatitis C. Methods. We carried out a multicentric, observational, open-label study to assess the efficacy and safety of the generic fixed-dose combination (FDC) sofosbuvir/daclatasvir in patients with chronic hepatitis C. We included 100 patients with all genotypes for 12 or 24 weeks of treatment without ribavirin. The primary outcome was the proportion of patients with a sustained virologic response (SVR) 12 weeks after treatment cessation. The secondary outcome assessed the safety and occurrence of adverse events. This study is registered with ClinicalTrials.gov identifier: NCT05138523. Results. The full analysis set included 99 patients with a mean age of 51.4 ± 14.4 years and a sex ratio of M/F = 0.86. Our patients were infected with HCV genotype 1b (n = 47), 2 (n = 17), 1a (n = 3), 2a/2c (n = 2), 3 (n = 2), and 4 (n = 1). A total of 27 patients had missing genotype data. Most patients were naive noncirrhotic (n = 70) and took 12 weeks of treatment, 19 patients had cirrhosis, of which 68.42% (n = 13) were classified as Child–Pugh A, and 5 patients were treatment-experienced. Both cirrhotic and treatment-experienced patients took 24 weeks of treatment. Efficacy analysis was conducted on 95 patients, and the results showed that 91 patients achieved SVR12 with a response rate of 95.8% (95% CI: 92–100%). Six adverse events occurred and were minor and manageable. Conclusion. Our results demonstrate the efficacy and safety of sofosbuvir/daclatasvir in single tablets in treating Algerian HCV patients without ribavirin for 12 or 24 weeks. The promising results of this study warrant further trials to assess the efficacy and safety of this combination in treating special populations.
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Affiliation(s)
- Nabil Debzi
- Hepatology Department, Centre Hospitalo-Universitaire Mustapha Bacha, Algiers, Algeria
| | - Saadi Berkane
- Gastroenterology Department, Centre Hospitalo-Universitaire Mustapha Bacha, Algiers, Algeria
| | - Chafika Manouni
- Gastroenterology Department, Etablissement Hospitalier Universitaire, Oran, Algeria
| | - Nassima Amani
- Gastroenterology Department, Centre Hospitalo-Universitaire Benaouda Benzerdjeb, Oran, Algeria
| | - Sonia Hemmam
- Internal Medicine Department, Etablissement Public Hospitalier Nouvel Hôpital, Khenchela, Algeria
| | - Mohamed Yousfi
- Infectious Diseases Department, Etablissement Public Hospitalier, Boufarik, Algeria
| | - Ayoub Taleb
- Gastroenterology Department, Centre Hospitalo-Universitaire Mustapha Bacha, Algiers, Algeria
| | - Nawal Guessab
- Hepatology Department, Centre Hospitalo-Universitaire Mustapha Bacha, Algiers, Algeria
| | | | | | | | | | - Rafik Kerbouche
- Hepatology Department, Centre Hospitalo-Universitaire Mustapha Bacha, Algiers, Algeria
| | - Ibtissem Ouled Cheikh
- Hepatology Department, Centre Hospitalo-Universitaire Mustapha Bacha, Algiers, Algeria
| | - Othmane Drir
- Hepatology Department, Centre Hospitalo-Universitaire Mustapha Bacha, Algiers, Algeria
| | - Hibat Allah Belimi
- Hepatology Department, Centre Hospitalo-Universitaire Mustapha Bacha, Algiers, Algeria
| | - Samir Gourari
- Microbiology Department, Centre Hospitalo-Universitaire Mustapha Bacha, Algiers, Algeria
| | - Issam Frigga
- Blood Transfusion Department, Centre Hospitalo-Universitaire Mustapha Bacha, Algiers, Algeria
| | | | | | - Nawal Afredj
- Hepatology Department, Centre Hospitalo-Universitaire Mustapha Bacha, Algiers, Algeria
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9
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El-Mahdy NA, Abou-Saif S, Abd EL hamid MI, Hashem HM, Hammad MA, Abu-Risha SES. Evaluation of the effect of direct-acting antiviral agents on melatonin level and lipid peroxidation in chronic hepatitis C patients. Front Pharmacol 2023; 14:1128016. [PMID: 37614319 PMCID: PMC10442483 DOI: 10.3389/fphar.2023.1128016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 07/25/2023] [Indexed: 08/25/2023] Open
Abstract
Background: Oxidative stress and its end products, such as malondialdehyde (MDA) play a leading role in the pathogenesis of hepatitis C. Melatonin is a hormone that helps regulate circadian rhythms, which likely play a role in infectious diseases in terms of susceptibility, clinical expression, and outcome. Objective: The present study was conducted to assess serum malondialdehyde and melatonin levels in patients with chronic hepatitis C infection before and after the intake of direct-acting antivirals. Method: Forty hepatitis C patients were the subjects of this study. While ten healthy volunteers who matched in age and socioeconomic status served as the control subjects. Malondialdehyde and melatonin were assayed in the serum of the three groups, and the results were statistically analyzed. Results: Hepatitis C patients had significantly higher malondialdehyde (p < 0.001) but significantly lower melatonin (p < 0.001) as compared to the healthy controls. After 12 weeks of treatment with direct-acting antivirals, the malondialdehyde level decreased significantly (p < 0.001) and the melatonin level increased significantly (p < 0.001). A significant negative correlation between malondialdehyde and melatonin was observed. Conclusion: The present findings suggest that treatment of hepatitis C patients with Direct-acting antivirals improves liver function parameters and antioxidant profiles.
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Affiliation(s)
- Nageh Ahmed El-Mahdy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Sabry Abou-Saif
- Department of Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
| | | | - Heba M. Hashem
- Department of Pharmacy Practice, Faculty of Pharmacy, Sinai University, El-Arish, Egypt
| | - Mohamed Anwar Hammad
- Department of Clinical Pharmacy, Faculty of Clinical Pharmacy, Al-Baha University, Al-Baha, Saudi Arabia
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10
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Moustafa AH, Pasha HF, Abas MA, Aboregela AM. The ameliorating role of sofosbuvir and daclatasvir on thioacetamide-induced kidney injury in adult albino rats. Anat Cell Biol 2023; 56:109-121. [PMID: 36543744 PMCID: PMC9989782 DOI: 10.5115/acb.22.200] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/06/2022] [Accepted: 11/21/2022] [Indexed: 12/24/2022] Open
Abstract
Thioacetamide (TAA) exposure and hepatitis C virus infection are usually associated with renal dysfunction. Sofosbuvir (SFV) and daclatasvir (DAC) drugs combination has great value in the treatment of hepatitis C. The study aimed to identify the nephrotoxic effects of TAA and to evaluate the ameliorative role of SFV and DAC in this condition. Forty-eight adult male albino rats were divided into eight groups and received saline (control), SFV, DAC, SFV+DAC, TAA, TAA+SFV, TAA+DAC and TAA+SFV+DAC for eight weeks. Kidney and blood samples were retrieved and processed for histological (Hematoxylin and Eosin and Masson's trichrome), immunohistochemical (α-smooth muscle actin), and biochemical analysis (urea, creatinine, total protein, albumin, malondialdehyde, reduced glutathione, superoxide dismutase, and tumor necrosis factor-α). Examination revealed marked destruction of renal tubules on exposure to TAA with either hypertrophy or atrophy of glomeruli, increase in collagen deposition, and wide expression of α-smooth muscle actin. Also, significant disturbance in kidney functions, oxidative stress markers, and tumor necrosis factor-α. Supplementation with either SFV or DAC produced mild improvement in the tissue and laboratory markers. Moreover, the combination of both drugs greatly refined the pathology induced by TAA at the cellular and laboratory levels. However, there are still significant differences when compared to the control. In conclusion, SFV and DAC combination partially but greatly ameliorated the renal damage induced by TAA which might be enhanced with further supplementations to give new hope for those with nephropathy associated with hepatitis.
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Affiliation(s)
- Ahmed H Moustafa
- Department of Chemistry, Faculty of Science, Zagazig University, Zagazig, Egypt
| | - Heba F Pasha
- Department of Medical Biochemistry and Genetics, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Manar A Abas
- Department of Biochemistry, Faculty of Science, Zagazig University, Zagazig, Egypt
| | - Adel M Aboregela
- Department of Human Anatomy and Embryology, Faculty of Medicine, Zagazig University, Zagazig, Egypt.,Department of Basic Medical Sciences, College of Medicine, University of Bisha, Bisha, Saudi Arabia
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11
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Ibrahim HM, Abdel-Ghaffar FR, Zied AB, El-Ghareeb SH. Assessment of the Sofosbuvir + Daclatasvir (±) Ribavirin Treatment and the Prognostic Efficacy of Interferon-gamma Induced Protein 10, Macrophage Inflammatory-1-Beta, and C-reactive Protein in Hepatitis C Egyptian Patients' Therapy Outcome. BIOMEDICAL AND BIOTECHNOLOGY RESEARCH JOURNAL (BBRJ) 2022; 6:109-116. [DOI: 10.4103/bbrj.bbrj_209_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Background:
Hepatitis C virus (HCV) is the most important virus among the infectious agents as the cause of liver disease in Egypt. The aim of this work was to assess the efficacy and tolerability of the sofosbuvir + daclatasvir (±) ribavirin (SOF + DCV [±] RBV) regimens and to evaluate the association of interferon-gamma induced protein 10 (IP-10) and macrophage inflammatory-1-beta (MIP-1β) and C-reactive protein (CRP) with treatment responses as potential biomarkers for the prognosis of HCV in patients from Kafer EL-Sheikh Province, Egypt.
Methods:
HCV Patients were treated with a combined treatment of SOF plus DCV with or without RBV for 12 weeks. The biochemical, hematological parameters, HCV RNA load, IP-10, MIP-1β, and CRP were detected pre- and post-treatment.
Results:
Both SOF-based regimens improved the liver function, anemia, leukopenia, and thrombocytopenia especially after treatment with SOF, DCV, and RBV. Sustained virological response 12 was slightly higher in the group receiving (SOF and DCV) therapy (99.42%) when compared to (SOF, DCV, and RBV) therapy (98.44%). The most common adverse events were fatigue, headache, anorexia, rash, and nausea. Interestingly, higher levels of the IP-10, MIP-1β, or CRP were observed in the serum of patients with HCV before treatment, and their levels significantly decreased after the treatment of both regimens.
Conclusions:
Our study revealed that SOF-based regimens are efficacious in controlling the HCV load and IP-10, MIP-1β, or CRP have both bioprognostic efficacy and potential role in predicting treatment responses.
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12
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Markby J, Shilton S, Sem X, Chan HK, Md Said R, Siva S, Zainuddin Z, Abu Bakar N, Omar H, Ruiz RJI, Gaeddert M, Tyshkovskiy A, Adee M, Chhatwal J, Kumar S, Piedagnel JM, Mohd Zain R, Menétrey C, Yuswan F, Hairizan Nasir N, Andrieux-Meyer I, Ismail F, Zakaria R, Hasim R, Murad S, Easterbrook P, Hassan MRA. Assessing the impact of simplified HCV care on linkage to care amongst high-risk patients at primary healthcare clinics in Malaysia: a prospective observational study. BMJ Open 2021; 11:e055142. [PMID: 34952885 PMCID: PMC8713014 DOI: 10.1136/bmjopen-2021-055142] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
INTRODUCTION To achieve the elimination of hepatitis C virus (HCV), substantial scale-up in access to testing and treatment is needed. This will require innovation and simplification of the care pathway, through decentralisation of testing and treatment to primary care settings and task-shifting to non-specialists. The objective of this study was to evaluate the feasibility and effectiveness of decentralisation of HCV testing and treatment using rapid diagnostic tests (RDTs) in primary healthcare clinics (PHCs) among high-risk populations, with referral of seropositive patients for confirmatory viral load testing and treatment. METHODS This observational study was conducted between December 2018 and October 2019 at 25 PHCs in three regions in Malaysia. Each PHC was linked to one or more hospitals, for referral of seropositive participants for confirmatory testing and pretreatment evaluation. Treatment was provided in PHCs for non-cirrhotic patients and at hospitals for cirrhotic patients. RESULTS During the study period, a total of 15 366 adults were screened at the 25 PHCs, using RDTs for HCV antibodies. Of the 2020 (13.2%) HCV antibody-positive participants, 1481/2020 (73.3%) had a confirmatory viral load test, 1241/1481 (83.8%) were HCV RNA-positive, 991/1241 (79.9%) completed pretreatment assessment, 632/991 (63.8%) initiated treatment, 518/632 (82.0%) completed treatment, 352/518 (68.0%) were eligible for a sustained virological response (SVR) cure assessment, 209/352 (59.4%) had an SVR cure assessment, and SVR was achieved in 202/209 (96.7%) patients. A significantly higher proportion of patients referred to PHCs initiated treatment compared with those who had treatment initiated at hospitals (71.0% vs 48.8%, p<0.001). CONCLUSIONS This study demonstrated the effectiveness and feasibility of a simplified decentralised HCV testing and treatment model in primary healthcare settings, targeting high-risk groups in Malaysia. There were good outcomes across most steps of the cascade of care when treatment was provided at PHCs compared with hospitals.
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Affiliation(s)
| | | | | | - Huan Keat Chan
- Clinical Research Centre, Hospital Sultanah Bahiyah, Alor Setar, Malaysia
| | | | - Sasikala Siva
- Drugs for Neglected Diseases initiative, Geneva, Switzerland
| | | | | | | | | | - Mary Gaeddert
- Division of Clinical Tropical Medicine, Center of Infectious Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - Alexander Tyshkovskiy
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, Russia
| | - Madeline Adee
- Institute for Technology Assessment, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Jagpreet Chhatwal
- Institute for Technology Assessment, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | | | | | | | | | - Fazidah Yuswan
- Disease Control Division, Ministry of Health, Putrajaya, Malaysia
| | | | | | - Fatanah Ismail
- Family Health Development Division, Ministry of Health, Putrajaya, Malaysia
| | - Rozita Zakaria
- Family Health Development Division, Ministry of Health, Putrajaya, Malaysia
| | - Ruziaton Hasim
- Family Health Development Division, Ministry of Health, Putrajaya, Malaysia
| | - Shahnaz Murad
- Drugs for Neglected Diseases initiative, Geneva, Switzerland
| | - Philippa Easterbrook
- Global HIV, Hepatitis & STI Programmes, World Health Organization, Geneva, Switzerland
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13
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Abbass S, Kamal E, Salama M, Salman T, Sabry A, Abdel-Razek W, Helmy S, Abdelgwad A, Sakr N, Elgazzar M, Einar M, Farouk M, Saif M, Shehab I, El-Hosieny E, Mansour M, Mahdi D, Tharwa ES, Salah M, Elrouby O, Waked I. Efficacy and safety of sofosbuvir plus daclatasvir or ravidasvir in patients with COVID-19: A randomized controlled trial. J Med Virol 2021; 93:6750-6759. [PMID: 34379337 PMCID: PMC8426808 DOI: 10.1002/jmv.27264] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 08/05/2021] [Accepted: 08/08/2021] [Indexed: 12/23/2022]
Abstract
Only a few treatments are approved for coronavirus disease‐2019 (COVID‐19) infections, with continuous debate about their clinical impact. Repurposing antiviral treatments might prove the fastest way to identify effective therapy. This trial aimed to evaluate the efficacy and safety of sofosbuvir (SOF) plus daclatasvir (DCV) or ravidasvir (RDV) added to standard care (SOC) for patients with moderate and severe COVID‐19 infection. Multicentre parallel randomized controlled open‐label trial. One hundred and twenty eligible patients with moderate and severe COVID‐19 infection were randomized to one of the study arms. Ten days of treatment with SOF plus DCV or RDV in addition to the standard of care compared to SOC. Follow up in 7 days. Sum of the counted symptoms at 7 and 10 days, mean change in oxygen saturation level, viral negativity, and rate of intensive care unit (ICU) admission. Compared to SOC, the SOF‐DCV group experienced a significantly lower sum of the counted symptoms (fever, headache, generalized aches, or respiratory distress) combined with no evidence of deterioration (ICU admission and mechanical ventilation) on Days 7 and 10 of treatment. Oxygen saturation also significantly improved among the SOF‐DCV group compared to SOC starting from Day 4. The study also showed positive trends regarding the efficacy of SOF‐DCV with a lower incidence of mortality. On the other hand, adding SOF‐RDV to SOC did not show significant improvements in endpoints. The results support the efficacy and safety of SOF‐DCV as an add‐on to SOC for the treatment of moderate to severe COVID‐19 infections.
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Affiliation(s)
- Sherif Abbass
- National Liver Institute, Shebeen El-Kom, Menoufia, Egypt
| | - Ehab Kamal
- Medical Research Division, National Research Centre, Cairo, Egypt
| | - Mohsen Salama
- National Liver Institute, Shebeen El-Kom, Menoufia, Egypt
| | - Tary Salman
- National Liver Institute, Shebeen El-Kom, Menoufia, Egypt
| | - Alyaa Sabry
- National Liver Institute, Shebeen El-Kom, Menoufia, Egypt
| | | | | | | | - Neamt Sakr
- National Liver Institute, Shebeen El-Kom, Menoufia, Egypt
| | | | | | | | | | | | | | | | | | | | | | | | - Imam Waked
- National Liver Institute, Shebeen El-Kom, Menoufia, Egypt
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14
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Nagaty A, Helmy SH, Abd El-Wahab EW. Sofosbuvir-/Daclatasvir-based therapy for chronic HCV and HCV/hepatitis B virus coinfected patients in Egypt. Trans R Soc Trop Med Hyg 2021; 114:200-212. [PMID: 31722032 DOI: 10.1093/trstmh/trz079] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 03/25/2019] [Accepted: 07/11/2019] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Dramatic advances in hepatitis C virus (HCV) treatment were witnessed with the introduction of direct-acting antivirals (DAAs). Generic DAAs with remarkable efficacy and good safety profiles are currently manufactured by local pharmaceutical companies in Egypt. METHODS In the real-world setting, of a total of 367 patients chronically infected with HCV, 289 (277 treatment-naïve and 12 treatment-experienced) patients were enrolled. Approximately 15% of the patients were coinfected with hepatitis B virus (HBV). Patients were treated with sofosbuvir+daclatasvir with or without ribavirin for 12 or 24 wk as the standard of care. HBV DNA levels were monitored throughout the study. RESULTS A sustained virologic response at 12 wk (SVR12) was achieved in 98.3% of the patients. All non-responders were treatment-naïve and the response rate among treatment-experienced patients was 100.0%. Elevated α-fetoprotein and treatment with sofosbuvir+daclatasvir+ribavirin for 6 mo were predictors of non-response (OR [95% CI] = 1.06 [1.02 to 1.1] and 15.9 [1.8 to 136.2]; p<0.05, respectively). No HBV reactivation was noticed throughout the treatment and follow-up periods in HCV/HBV coinfected patients. CONCLUSION The present real-world findings add to the evidence for the efficacy of generic DAAs for the treatment of patients infected with HCV. HBV reactivation is unlikely to occur in those coinfected with HBV. Although liver cirrhosis affected the outcome, pretreatment liver chemistry did not seem to correlate with the results of treatment.
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Affiliation(s)
- Ahmed Nagaty
- Consultant of Hepatogastroentrology and Infectious Diseases, Ministry of Health and Population, 21568 Alexandria, Egypt
| | - Sherine Ha Helmy
- Medical Consultant, R&D Project Innovations, Pharco Pharamaceutical Corporation, 679 El Horreya Road, 21569 Alexandria, Egypt
| | - Ekram W Abd El-Wahab
- Tropical Health Department, High Institute of Public Health, Alexandria University, 165 El Horreya Road, 21561 Alexandria, Egypt
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15
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Park YJ, Woo HY, Heo J, Park SG, Hong YM, Yoon KT, Kim DU, Kim GH, Kim HH, Song GA, Cho M. Real-Life Effectiveness and Safety of Glecaprevir/Pibrentasvir for Korean Patients with Chronic Hepatitis C at a Single Institution. Gut Liver 2021; 15:440-450. [PMID: 32839365 PMCID: PMC8129668 DOI: 10.5009/gnl19393] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 06/03/2020] [Accepted: 06/21/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND/AIMS Glecaprevir/pibrentasvir (G/P) is a combination of direct-acting antiviral agents that is an approved treatment for chronic infections by all six hepatitis C virus (HCV) genotypes. However, there are limited data on the effect of G/P in Korean patients in actual real-world settings. We evaluated the real-life effectiveness and safety of G/P at a single institution in Korea. METHODS This retrospective, observational, cohort study used sustained virologic response at 12 weeks after treatment completion (SVR12) as the primary effectiveness endpoint. Safety and tolerability were also determined. RESULTS We examined 267 individuals who received G/P for chronic HCV infections. There were 148 females (55.4%), and the overall median age was 63.0 years (range, 25 to 87 years). Eighty-three patients (31.1%) had HCV genotype-1 and 182 (68.2%) had HCV-2. A total of 212 patients (79.4%) were HCV treatment-naïve, 200 (74.9%) received the 8-week treatment, 13 (4.9%) had received prior treatment for hepatocellular carcinoma, 37 (13.7%) had chronic kidney disease stage 3 or higher, and 10 (3.7%) were receiving dialysis. Intention to treat (ITT) analysis indicated that 256 (95.9%) achieved SVR12. A modified ITT analysis indicated that SVR12 was 97.7% (256/262). Six patients failed therapy because of posttreatment relapse. SVR12 was significantly lower in those who received prior sofosbuvir treatment (p=0.002) and those with detectable HCV RNA at week 4 (p=0.027). Seventy patients (26.2%) experienced one or more adverse events, and most of them were mild. CONCLUSIONS These real-life data indicated that G/P treatment was highly effective and well tolerated, regardless of viral genotype or patient comorbidities.
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Affiliation(s)
- Young Joo Park
- Department of Internal Medicine, College of Medicine, Pusan National University, Busan, Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Hyun Young Woo
- Department of Internal Medicine, College of Medicine, Pusan National University, Busan, Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Jeong Heo
- Department of Internal Medicine, College of Medicine, Pusan National University, Busan, Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Sang Gyu Park
- Department of Internal Medicine, Good Samsun Hospital, Busan, Korea
| | - Young Mi Hong
- Department of Internal Medicine, College of Medicine, Pusan National University, Busan, Korea
- Liver Center, Pusan National University Yangsan Hospital, Yangsan, Korea
| | - Ki Tae Yoon
- Department of Internal Medicine, College of Medicine, Pusan National University, Busan, Korea
- Liver Center, Pusan National University Yangsan Hospital, Yangsan, Korea
| | - Dong Uk Kim
- Department of Internal Medicine, College of Medicine, Pusan National University, Busan, Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Gwang Ha Kim
- Department of Internal Medicine, College of Medicine, Pusan National University, Busan, Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Hyung Hoi Kim
- Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
- Department of Laboratory Medicine, College of Medicine, Pusan National University, Busan, Korea
| | - Geun Am Song
- Department of Internal Medicine, College of Medicine, Pusan National University, Busan, Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Mong Cho
- Department of Internal Medicine, College of Medicine, Pusan National University, Busan, Korea
- Liver Center, Pusan National University Yangsan Hospital, Yangsan, Korea
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16
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Ramesh D, Vijayakumar BG, Kannan T. Advances in Nucleoside and Nucleotide Analogues in Tackling Human Immunodeficiency Virus and Hepatitis Virus Infections. ChemMedChem 2021; 16:1403-1419. [PMID: 33427377 DOI: 10.1002/cmdc.202000849] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Indexed: 12/13/2022]
Abstract
Nucleoside and nucleotide analogues are structurally similar antimetabolites and are promising small-molecule chemotherapeutic agents against various infectious DNA and RNA viruses. To date, these analogues have not been documented in-depth as anti-human immunodeficiency virus (HIV) and anti-hepatitis virus agents, these are at various stages of testing ranging from pre-clinical, to those withdrawn from trials, or those that are approved as drugs. Hence, in this review, the importance of these analogues in tackling HIV and hepatitis virus infections is discussed with a focus on the viral genome and the mechanism of action of these analogues, both in a mutually exclusive manner and their role in HIV/hepatitis coinfection. This review encompasses nucleoside and nucleotide analogues from 1987 onwards, starting with the first nucleoside analogue, zidovudine, and going on to those in current clinical trials and even the drugs that have been withdrawn. This review also sheds light on the prospects of these nucleoside analogues in clinical trials as a treatment option for the COVID-19 pandemic.
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Affiliation(s)
- Deepthi Ramesh
- Department of Chemistry, Pondicherry University, Kalapet, Puducherry, 605014, India
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17
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Yu H, Yang H, Shi E, Tang W. Development and Clinical Application of Phosphorus-Containing Drugs. MEDICINE IN DRUG DISCOVERY 2020; 8:100063. [PMID: 32864606 PMCID: PMC7445155 DOI: 10.1016/j.medidd.2020.100063] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Revised: 08/12/2020] [Accepted: 08/13/2020] [Indexed: 12/20/2022] Open
Abstract
Phosphorus-containing drugs belong to an important class of therapeutic agents and are widely applied in daily clinical practices. Structurally, the phosphorus-containing drugs can be classified into phosphotriesters, phosphonates, phosphinates, phosphine oxides, phosphoric amides, bisphosphonates, phosphoric anhydrides, and others; functionally, they are often designed as prodrugs with improved selectivity and bioavailability, reduced side effects and toxicity, or biomolecule analogues with endogenous materials and antagonistic endoenzyme supplements. This review summarized the phosphorus-containing drugs currently on the market as well as a few promising molecules at clinical studies, with particular emphasis on their structural features, biological mechanism, and indications.
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Affiliation(s)
- Hanxiao Yu
- State Key Laboratory of Bio-Organic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, 345 Ling Ling Road, Shanghai 200032, China
| | - He Yang
- Shenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Enxue Shi
- State Key Laboratory of NBC Protection for Civilian, Beijing 102205, China
| | - Wenjun Tang
- State Key Laboratory of Bio-Organic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, 345 Ling Ling Road, Shanghai 200032, China
- School of Chemistry and Material Sciences, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-lane Xiangshan, Hangzhou 310024, China
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18
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Synthesis of Novel 2-Hetarylpyrrolidines via the Reaction of N-(4,4-diethoxybutyl)amidophosphates with C-nucleophiles. Chem Heterocycl Compd (N Y) 2020. [DOI: 10.1007/s10593-020-02823-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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19
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Ramesh D, Vijayakumar BG, Kannan T. Therapeutic potential of uracil and its derivatives in countering pathogenic and physiological disorders. Eur J Med Chem 2020; 207:112801. [PMID: 32927231 DOI: 10.1016/j.ejmech.2020.112801] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 08/21/2020] [Accepted: 08/27/2020] [Indexed: 02/07/2023]
Abstract
Uracil is one of the most notable pharmacophores in medicinal chemistry as the pyrimidine nucleobase forms an integral part of many commercial drugs. Though the name uracil is usually associated with cancer drugs, there are many uracil-based compounds which can treat different diseases when they are employed. So far, there has been no in-depth review concerning uracil drugs in the market, or in the different stages of clinical trials, including those approved or discontinued. The current work focuses on the importance of uracil and its derivatives in treating different diseases. The use of uracil compounds in treating viral infections, cancer, diabetic, thyroid and autosomal recessive disorders are discussed in the review. The mechanism of action of each uracil drug with emphasis on their structure and properties are discussed in detail. The targeted action of these drugs on sites or on the different stages of a disorder/pathogenic life cycle are also discussed. This review encompasses uracil drugs approved as well as those in development from the 1950's onwards. The utility of uracil in drug discovery and its association with a wide range of diseases is brought forth within this review to demonstrate its potential to a wider audience.
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Affiliation(s)
- Deepthi Ramesh
- Department of Chemistry, Pondicherry University, Kalapet, Puducherry, 605014, India
| | | | - Tharanikkarasu Kannan
- Department of Chemistry, Pondicherry University, Kalapet, Puducherry, 605014, India.
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20
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Elsadek HM, Abdelbaser ES, Emara MH, Soliman HH, Farag AA. Morbidity and mortality during hepatitis C treatment using sofosbuvir and daclatasvir with or without ribavirin, in a cohort of Egyptian patients. Eur J Gastroenterol Hepatol 2020; 32:1046-1053. [PMID: 33216478 DOI: 10.1097/meg.0000000000001695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Though direct-acting antiviral agents (DAAs) therapy is associated with a high cure rate of hepatitis C virus infection, a potential risk of serious adverse events (SAEs) exists. The aim of this study was to determine the incidence and predictors of morbidity and mortality related to DAAs therapy. METHODS This prospective study was conducted on a real word cohort of 1562 treatment naïve chronic hepatitis C (CHC) Egyptian patients, who received 12-weeks therapy with sofosbuvir (SOF) plus daclatasvir (DCV) ± ribavirin (RBV). The incidence and predictors of SAEs and mortality during treatment course and over the following 12 weeks were recorded. RESULTS The mean age of study participants was 51.38 ± 9.70 years (55.22%, males). Liver cirrhosis was defined in 72.4% of participants. SAEs were recorded in 120 participants (7.68%), including hepatic decompensation, gastrointestinal bleeding, anemia and hepatocellular carcinoma. Nine patients (0.58%) died and 69 patients (4.42%) discontinued therapy due to SAEs. Severity of cirrhosis was the significant predictor of morbidities and mortality. Hepatic decompensation was predicted by baseline serum albumin [cutoff value: 3.00 g/dL, area under the receiver operating characteristic curve (AUROC): 0.953] and serum bilirubin (cutoff value: 1.75 mg/dL, AUROC: 0.940). CONCLUSION The risk of morbidity and mortality related to SOF/DCV ± RBV therapy in CHC patients is small and is significantly linked to advanced cirrhosis.
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Affiliation(s)
- Hany M Elsadek
- Gastroenterology and Hepatology Unit, Internal Medicine Department
| | | | - Mohamed H Emara
- Hepatology, Gastroenterology and Infectious Diseases Department, Faculty of Medicine, Kafrelsheikh University, Kafrelsheikh
| | - Hanan H Soliman
- Community Medicine Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Alaa A Farag
- Gastroenterology and Hepatology Unit, Internal Medicine Department
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21
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Quinoxaline Derivatives as Antiviral Agents: A Systematic Review. Molecules 2020; 25:molecules25122784. [PMID: 32560203 PMCID: PMC7356203 DOI: 10.3390/molecules25122784] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 06/04/2020] [Accepted: 06/09/2020] [Indexed: 01/26/2023] Open
Abstract
Background: In recent decades, several viruses have jumped from animals to humans, triggering sizable outbreaks. The current unprecedent outbreak SARS-COV-2 is prompting a search for new cost-effective therapies to combat this deadly pathogen. Suitably functionalized polysubstituted quinoxalines show very interesting biological properties (antiviral, anticancer, and antileishmanial), ensuring them a bright future in medicinal chemistry. Objectives: Focusing on the promising development of new quinoxaline derivatives as antiviral drugs, this review forms part of our program on the anti-infectious activity of quinoxaline derivatives. Methods: Study compiles and discusses recently published studies concerning the therapeutic potential of the antiviral activity of quinoxaline derivatives, covering the literature between 2010 and 2020. Results: A final total of 20 studies included in this review. Conclusions: This review points to a growing interest in the development of compounds bearing a quinoxaline moiety for antiviral treatment. This promising moiety with different molecular targets warrants further investigation, which may well yield even more encouraging results regarding this scaffold.
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22
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Nasr JJ, Shalan S. Validated 1H and 19F nuclear magnetic resonance for the quantitative determination of the hepatitis C antiviral drugs sofosbuvir, ledipasvir, and daclatasvir in tablet dosage forms. Microchem J 2020. [DOI: 10.1016/j.microc.2019.104437] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
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23
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Abdelaty LN, Elnaggar AA, Said AA, Hussein RRS. Ledipasvir/Sofosbuvir versus Daclatasvir/Sofosbuvir for the Treatment of Chronic Hepatitis C Genotype 4 Patients. Curr Drug Saf 2020; 15:53-60. [PMID: 31573893 DOI: 10.2174/1574886314666191001151314] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 09/01/2019] [Accepted: 09/02/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND Chronic Hepatitis C (CHC) is a common progressive healthcare challenge that leads to liver cirrhosis, liver failure, and hepatocellular carcinoma. The optimum therapy was a combination of pegylated interferon and ribavirin, which was associated with moderate response and severe side effects. Sofosbuvir revolutionized CHC treatment, especially in combination with other antiviral agents. OBJECTIVE The aim of this study was to compare and evaluate the safety and efficacy of sofosbuvir/ daclatasvir versus sofosbuvir/ledipasvir for the treatment of non-cirrhotic naïve patients with chronic Hepatitis C Virus (HCV) genotype 4 infection for 12 weeks. METHODS One hundred CHC genotype 4 patients (70 females, 30 males) were recruited from the hepatology clinic at the Beni-Suef general hospital. Patients were randomly allocated into two groups that received a 12 weeks treatment of either sofosbuvir 400 mg/daclatasvir 60 mg or sofosbuvir 400 mg/ledipasvir 90 mg. The sustained virological response 12 weeks post-treatment (SVR12) (HCV RNA < Lower Limit of Quantification (LLOQ)) was determined to evaluate efficacy. The clinical laboratory tests and any reported adverse effects starting from the administration of the first dose till 30 days after the last dose were assessed to evaluate safety. The main outcome measure was the assessment of the safety, efficacy and compliance of sofosbuvir/ daclatasvir versus sofosbuvir/ledipasvir for the treatment of non-cirrhotic naïve CHC genotype 4 patients for 12 weeks. RESULTS SVR12 was achieved by 98% and 96% of patients receiving sofosbuvir plus ledipasvir and sofosbuvir plus daclatasvir, respectively. The most common adverse events reported were headache, and fatigue. No patients discontinued treatment due to adverse events. CONCLUSION The findings from this study suggest that the 12 weeks treatment regimens of sofosbuvir plus daclatasvir and sofosbuvir plus ledipasvir were both efficacious and well-tolerated in patients with HCV genotype 4 infection. Impact on Practice: In this paper, we report on the most recent approaches in the treatment of Hepatitis C genotype 4 patients in Egypt. This is significant because this article focuses on comparing the efficacy and tolerability of the most commonly used antiviral drugs in Egypt.
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Affiliation(s)
- Lamiaa N Abdelaty
- Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Ahmed A Elnaggar
- Internal Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Amira A Said
- Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Raghda R S Hussein
- Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
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24
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Saadi G, Kalantar-Zadeh K, Almasio P, Ashuntantang G, Barsoum R, Bruchfeld A, Doss W, ElFishawy H, Raziky ME, El-Serafy M, Fabrizi F, Hafez H, Hassaballa M, Hammady MM, Sheishaa H, Abdelaziz TS, Ulasi I, Zakharova E, Jadoul M. Hepatitis C virus infection and global kidney health: the consensus proceedings of the International Federation of Kidney Foundations. AFRICAN JOURNAL OF NEPHROLOGY 2020; 23:159-168. [PMID: 33354560 PMCID: PMC7751950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/12/2023] Open
Abstract
Hepatitis C virus (HCV) infection is an important cause of major morbidities including chronic liver disease, liver cancer, and acute kidney injury (AKI) as well as chronic kidney disease (CKD). HCV can affect kidney health; among CKD and AKI patients with HCV infection, the clinical outcomes are worse. The prevalence of HCV infection is exceptionally high among dialysis and kidney transplant patients throughout the globe. It is estimated that 5% to 25% or more of dialysis dependent patients are affected by chronic HCV, based on the region of the world. Almost half of all deaths in CKD patients, including HCV-infected patients, are due to cardiovascular disease, and HCV infected patients have higher mortality. Given the importance and impact of the HCV epidemic on CKD and global kidney health, and the status of Egypt as the nation with highest prevalence of HCV infection in the world along with its leading initiatives to eradicate HCV, the International Federation of Kidney Foundations (IFKF) convened a consensus conference in Cairo in December 2017. This article reflects the opinions and recommendations of the contributing experts and reiterates that with the current availability of highly effective and well tolerated pharmacotherapy; CKD patients should be given priority for treatment of HCV, as an important step towards the elimination of viral hepatitis as a public health problem by 2030 according to World Health Organization and IFKF. Every country should have an action plan with the goal to improve kidney health and CKD patient outcomes.
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Affiliation(s)
- Gamal Saadi
- Department of Nephrology, Kasr Al Ainy Hospital, Cairo University, Cairo, Egypt
| | - Kamyar Kalantar-Zadeh
- Division of Nephrology, Hypertension and Kidney Transplantation, University of California, Irvine, California, USA
| | | | - Gloria Ashuntantang
- Department of Internal Medicine and Specialties, University of Yaoundé, Yaoundé, Cameroon
| | - Rashad Barsoum
- Department of Nephrology, Kasr Al Ainy Hospital, Cairo University, Cairo, Egypt
| | - Annette Bruchfeld
- Department of Renal Medicine, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden
| | - Wahid Doss
- National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
| | - Hussein ElFishawy
- Department of Nephrology, Kasr Al Ainy Hospital, Cairo University, Cairo, Egypt
| | - Maissa El Raziky
- Department of Tropical Medicine and Endemic Diseases, Cairo University, Cairo, Egypt
| | - Magdy El-Serafy
- Department of Tropical Medicine and Endemic Diseases, Cairo University, Cairo, Egypt
| | - Fabrizio Fabrizi
- Division of Nephrology, Maggiore Hospital and IRCCS Foundation, Milan, Italy
| | - Hani Hafez
- Department of Nephrology, Kasr Al Ainy Hospital, Cairo University, Cairo, Egypt
| | - May Hassaballa
- Department of Nephrology, Kasr Al Ainy Hospital, Cairo University, Cairo, Egypt
| | - Mona M.R. Hammady
- Department of Nephrology, Kasr Al Ainy Hospital, Cairo University, Cairo, Egypt
| | - Hussein Sheishaa
- Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
| | - Tarek S. Abdelaziz
- Department of Nephrology, Kasr Al Ainy Hospital, Cairo University, Cairo, Egypt
| | - Ifeoma Ulasi
- Renal Unit, Department of Medicine, College of Medicine, University of Nigeria, Ituku-Ozalla, Enugu, Nigeria
| | - Elena Zakharova
- Department of Nephrology, City Hospital of SP Botkin, Moscow, Russia
| | - Michel Jadoul
- Nephrology Department, Cliniques universitaires Saint-Luc and Université catholique de Louvain, Brussels, Belgium
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25
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Hlaing NKT, Nangia G, Tun KT, Lin S, Maung MZ, Myint KT, Kyaw AMM, Maung ST, Sein Win S, Bwa AH, Loza BL, Win KM, Reddy KR. High sustained virologic response in genotypes 3 and 6 with generic NS5A inhibitor and sofosbuvir regimens in chronic HCV in myanmar. J Viral Hepat 2019; 26:1186-1199. [PMID: 31104344 DOI: 10.1111/jvh.13133] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 04/29/2019] [Indexed: 12/11/2022]
Abstract
Exclusive HCV therapy clinical trials with genotype 6 patients in high prevalence areas have been sparse. We analysed the safety and efficacy of two generic, pangenotypic NS5A/NS5B combination oral DAA regimens, primarily in genotypes 3 and 6, in a real-world setting: (a) daclatasvir/sofosbuvir (DCV/SOF) ± ribavirin (RBV) and (b) Velpatasvir/sofosbuvir (VEL/SOF ± RBV). Between December 2015 and November 2017, data from 522 patients were analysed, 311 of whom were treated with DCV/SOF ± RBV for 12/24 weeks (genotype 3: n = 193, genotype 6: n = 89) and 211 were treated with VEL/SOF ± RBV for 12/24 weeks (genotype 3: n = 83, genotype 6: n = 77). Overall SVR rates were high for both DCV/SOF ± RBV (96.1%, n = 299/311) and VEL/SOF ± RBV (95.3%, n = 201/211), and there was a good adverse event profile. Treatment naïve status and inclusion of RBV (in advanced fibrosis/cirrhosis) were significant independent predictors of achieving SVR12, while type of DAA regimen was not predictive. In this large cohort of genotypes 3 (n = 276) and 6 (n = 166; n = 127 unique subtype of 6c-l), high SVR rates of 94.9% (n = 262/276) and 95.2% (n = 158/166), respectively, were noted. In conclusion, generic and pangenotypic DCV/SOF and VEL/SOF ± RBV regimens were highly effective and safe, in genotypes 3 and 6 chronic HCV in Myanmar. These efficacious pangenotypic regimens suggest that baseline genotype testing can be eliminated moving forward. While RBV may still be needed for those with advanced fibrosis/cirrhosis, in a global elimination strategy it would not be practical even if it does compromise SVR in a minority with difficult to treat characteristics.
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Affiliation(s)
| | | | | | - Sithu Lin
- Mandalay General Hospital, Mandalay, Myanmar
| | | | | | | | | | | | | | - Bao-Li Loza
- University of Pennsylvania, Philadelphia, Pennsylvania
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26
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Youssef AA, Magdy N, Hussein LA, El-Kosasy AM. Validated RP-HPLC Method for Simultaneous Determination of Ribavirin, Sofosbuvir and Daclatasvir in Human Plasma: A Treatment Protocol Administered to HCV Patients in Egypt. J Chromatogr Sci 2019; 57:636-643. [PMID: 31063182 DOI: 10.1093/chromsci/bmz038] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 03/11/2019] [Accepted: 04/05/2019] [Indexed: 02/06/2023]
Abstract
Egypt has the highest prevalence of hepatitis C virus (HCV) in the world thus it launched a national program for eliminating HCV aiming to treat 300,000 HCV patients per year. Three anti-HCV co-administered drugs; ribavirin (RBV), sofosbuvir (SF) daclatasvir (DAC) were simultaneously determined in human plasma by a validated, simple and sensitive RP-HPLC method using propyl paraben as an internal standard. Liquid-liquid extraction using ethyl acetate was used for samples extraction. Chromatographic separation was achieved on Scharlau® C18 column (250 × 4.6 mm2, 5 μm). Gradient elution was employed with a mobile phase mixture of water and acetonitrile at a flow rate 1 mL/min. UV detection using photodiode array detector was carried out at 207, 260 and 312 nm for RBV, SF and DAC, respectively. Method validation was performed according to the FDA guidelines for bioanalytical method validation. The calibration curves were linear over the ranges (0.5-80, 0.1-40 and 0.5-80 μg/mL) with average recoveries (100.64-108.28%, 98.48-105.91% and 97.68-101.38%) for RBV, SF and DAC, respectively. The intra-day and inter-day precision and accuracy results were within the acceptable limits. Stability assays revealed that the three studied analytes were stable during sample storage, preparation and injection. The method can be successfully applied in routine analysis of plasma of HCV patients treated with this combination therapy which aids in therapeutic drug monitoring and patients' follow-up especially in Egypt and other developing countries fighting HCV.
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Affiliation(s)
- Aya A Youssef
- Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Organization of African Unity Street, Abassia, Cairo, Egypt
| | - N Magdy
- Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Organization of African Unity Street, Abassia, Cairo, Egypt
| | - Lobna A Hussein
- Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Organization of African Unity Street, Abassia, Cairo, Egypt
| | - A M El-Kosasy
- Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Organization of African Unity Street, Abassia, Cairo, Egypt
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27
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Wang G, Dyatkina N, Prhavc M, Williams C, Serebryany V, Hu Y, Huang Y, Wan J, Wu X, Deval J, Fung A, Jin Z, Tan H, Shaw K, Kang H, Zhang Q, Tam Y, Stoycheva A, Jekle A, Smith DB, Beigelman L. Synthesis and Anti-HCV Activities of 4'-Fluoro-2'-Substituted Uridine Triphosphates and Nucleotide Prodrugs: Discovery of 4'-Fluoro-2'- C-methyluridine 5'-Phosphoramidate Prodrug (AL-335) for the Treatment of Hepatitis C Infection. J Med Chem 2019; 62:4555-4570. [PMID: 30951311 DOI: 10.1021/acs.jmedchem.9b00143] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
We report the synthesis and biological evaluation of a series of 4'-fluoro-2'- C-substituted uridines. Triphosphates of the uridine analogues exhibited a potent inhibition of hepatitis C virus (HCV) NS5B polymerase with IC50 values as low as 27 nM. In an HCV subgenomic replicon assay, the phosphoramidate prodrugs of these uridine analogues demonstrated a very potent activity with EC50 values as low as 20 nM. A lead compound AL-335 (53) demonstrated high levels of the nucleoside triphosphate in vitro in primary human hepatocytes and Huh-7 cells as well as in dog liver following a single oral dose. Compound 53 was selected for the clinical development where it showed promising results in phase 1 and 2 trials.
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Affiliation(s)
- Guangyi Wang
- Janssen BioPharma, Inc. , South San Francisco , California 94080 , United States
| | - Natalia Dyatkina
- Janssen BioPharma, Inc. , South San Francisco , California 94080 , United States
| | - Marija Prhavc
- Janssen BioPharma, Inc. , South San Francisco , California 94080 , United States
| | - Caroline Williams
- Janssen BioPharma, Inc. , South San Francisco , California 94080 , United States
| | - Vladimir Serebryany
- Janssen BioPharma, Inc. , South San Francisco , California 94080 , United States
| | - Yujian Hu
- Department of Medicinal Chemistry , WuXi AppTec , Shanghai 200131 , P. R. China
| | - Yongfei Huang
- Department of Medicinal Chemistry , WuXi AppTec , Shanghai 200131 , P. R. China
| | - Jinqiao Wan
- Department of Medicinal Chemistry , WuXi AppTec , Shanghai 200131 , P. R. China
| | - Xiangyang Wu
- Department of Medicinal Chemistry , WuXi AppTec , Shanghai 200131 , P. R. China
| | - Jerome Deval
- Janssen BioPharma, Inc. , South San Francisco , California 94080 , United States
| | - Amy Fung
- Janssen BioPharma, Inc. , South San Francisco , California 94080 , United States
| | - Zhinan Jin
- Janssen BioPharma, Inc. , South San Francisco , California 94080 , United States
| | - Hua Tan
- Janssen BioPharma, Inc. , South San Francisco , California 94080 , United States
| | - Kenneth Shaw
- Janssen BioPharma, Inc. , South San Francisco , California 94080 , United States
| | - Hyunsoon Kang
- Janssen BioPharma, Inc. , South San Francisco , California 94080 , United States
| | - Qingling Zhang
- Janssen BioPharma, Inc. , South San Francisco , California 94080 , United States
| | - Yuen Tam
- Janssen BioPharma, Inc. , South San Francisco , California 94080 , United States
| | - Antitsa Stoycheva
- Janssen BioPharma, Inc. , South San Francisco , California 94080 , United States
| | - Andreas Jekle
- Janssen BioPharma, Inc. , South San Francisco , California 94080 , United States
| | - David B Smith
- Janssen BioPharma, Inc. , South San Francisco , California 94080 , United States
| | - Leonid Beigelman
- Janssen BioPharma, Inc. , South San Francisco , California 94080 , United States
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28
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Abdel Ghaffar TY, El Naghi S, Abdel Gawad M, Helmy S, Abdel Ghaffar A, Yousef M, Moafy M. Safety and efficacy of combined sofosbuvir/daclatasvir treatment of children and adolescents with chronic hepatitis C Genotype 4. J Viral Hepat 2019; 26:263-270. [PMID: 30380158 DOI: 10.1111/jvh.13032] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Accepted: 10/03/2018] [Indexed: 12/16/2022]
Abstract
Direct-acting antivirals have become available for treating chronic HCV (hepatitis C virus) infection in adults and, recently, in children at least 12 years old. Our aim was to investigate the safety and efficacy of combined sofosbuvir (SOF)/daclatasvir (DCV) for HCV Genotype 4 in children aged 8 to 18 years or weighing 17 kg or more. A total of 40 chronic HCV-infected, treatment-naïve children with well compensated livers were recruited from two sites. Patients received combined therapy of SOF (400 mg/d for patients weighing greater than 45 kg; 200 mg/d for patients weighing 17 to 45 kg) and DCV (60 mg/d for patients weighing greater than 45 kg; 30 mg/d for patients weighing 17 to 45 kg) for 12 weeks. They were followed up regularly by clinical examination and laboratory tests during treatment (weekly in the first month then monthly to the end of treatment), every 3 months for 6 months post-treatment, and at 48 weeks post-treatment. In our cohort, which included 45% of children below the age of 12 years (72.5% genotype 4 and 27.5% mixed genotype 4 and 1), end of treatment response (ETR) was 97.5%. Sustained virologic response for weeks 12 and 24 post-treatment (SVR12 and SVR24) were 97.5% and 95%, respectively, on an intention to treat basis, and 100% and 100% for those who completed the study protocol. Observed side effects were mild and none required drug cessation. Combined SOF/DCV was found to be effective and safe for treating HCV Genotype 4-infected children, 8 years of age and above.
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Affiliation(s)
- Tawhida Y Abdel Ghaffar
- Yassin Abdel Ghaffar Charity Center for Liver Disease and Research, Cairo, Egypt.,Department of Pediatrics, Ain Shams University, Cairo, Egypt
| | - Suzan El Naghi
- Yassin Abdel Ghaffar Charity Center for Liver Disease and Research, Cairo, Egypt.,Department of Pediatrics, National Hepatology & Tropical Medicine Research Institute, Cairo, Egypt
| | | | - Sarah Helmy
- Yassin Abdel Ghaffar Charity Center for Liver Disease and Research, Cairo, Egypt
| | | | | | - Mohamad Moafy
- Department of Pediatrics, Ain Shams University, Cairo, Egypt
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29
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Ahmed M. Era of direct acting anti-viral agents for the treatment of hepatitis C. World J Hepatol 2018; 10:670-684. [PMID: 30386460 PMCID: PMC6206157 DOI: 10.4254/wjh.v10.i10.670] [Citation(s) in RCA: 13] [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: 04/11/2018] [Revised: 05/15/2018] [Accepted: 05/23/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C infection is universal and the most common indication of liver transplantation in the United States. The period of less effective interferon therapy with intolerable side effects has gone. Now we have stepped into the era of direct acting anti-viral agents (DAAs) against hepatitis C virus. Treatment of hepatitis C is now extremely effective, tolerable and requires a short duration of intake of oral agents. Less monitoring is required with the current therapy and drug-drug interactions are less than the previous regimen. The current treatment options of chronic hepatitis C with various DAAs are discussed in this article.
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Affiliation(s)
- Monjur Ahmed
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Thomas Jefferson University, Philadelphia, PA 19107, United States.
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30
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Krol E, Pastuch-Gawolek G, Chaubey B, Brzuska G, Erfurt K, Szewczyk B. Novel Uridine Glycoconjugates, Derivatives of 4-Aminophenyl 1-Thioglycosides, as Potential Antiviral Compounds. Molecules 2018; 23:molecules23061435. [PMID: 29899276 PMCID: PMC6100568 DOI: 10.3390/molecules23061435] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 06/02/2018] [Accepted: 06/10/2018] [Indexed: 01/19/2023] Open
Abstract
A novel series of uridine glycoconjugates, derivatives of 4-aminophenyl 1-thioglycosides, was designed and synthesized. All compounds were evaluated in vitro for their antiviral activity against hepatitis C virus (HCV) and classical swine fever virus (CSFV), two important human and animal viral pathogens for which new or improved therapeutic options are needed. The antiviral activity of all synthesized compounds was confirmed using pseudo-plaque reduction assays in which a significant arrest of CSFV and HCV growth was observed in the presence of these compounds. Two of the synthesized compounds, 9 and 12, displayed a significant inhibitory effect on HCV and CSFV propagation with IC50 values of 4.9 and 13.5 µM for HCV and 4.2 and 4 µM for CSFV, respectively, with low cytotoxicity. Using various infection and replication models, we have shown that both compounds were able to significantly reduce viral genome replication by up to 90% with IC50 values in the low micromolar range. A structure activity analysis of the synthesized compounds showed that the high antiviral activity was attributed to the hydrophobicity of glycoconjugates and the introduction of elements capable to coordinate metal ions into the spacer connecting the sugar and uridine moiety, which can be useful in the development of new antiviral compounds in the future.
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Affiliation(s)
- Ewelina Krol
- Department of Recombinant Vaccines, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Abrahama 58, 80-307 Gdansk, Poland.
| | - Gabriela Pastuch-Gawolek
- Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Faculty of Chemistry, Silesian University of Technology, Krzywoustego 4, 44-100 Gliwice, Poland.
- Biotechnology Center, Silesian University of Technology, Krzywoustego 8, 44-100 Gliwice, Poland.
| | - Binay Chaubey
- Department of Recombinant Vaccines, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Abrahama 58, 80-307 Gdansk, Poland.
- Functional Genomics Lab., Centre for Advanced Study, Department of Botany, University of Calcutta, 35, Ballygunge Circular Road, 700019 Kolkata, India.
| | - Gabriela Brzuska
- Department of Recombinant Vaccines, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Abrahama 58, 80-307 Gdansk, Poland.
| | - Karol Erfurt
- Department of Chemical Organic Technology and Petrochemistry, Faculty of Chemistry, Silesian University of Technology, Krzywoustego 4, 44-100 Gliwice, Poland.
| | - Boguslaw Szewczyk
- Department of Recombinant Vaccines, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Abrahama 58, 80-307 Gdansk, Poland.
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Ahmed OA, Elsebaey MA, Fouad MHA, Elashry H, Elshafie AI, Elhadidy AA, Esheba NE, Elnaggar MH, Soliman S, Abd-Elsalam S. Outcomes and predictors of treatment response with sofosbuvir plus daclatasvir with or without ribavirin in Egyptian patients with genotype 4 hepatitis C virus infection. Infect Drug Resist 2018; 11:441-445. [PMID: 29628768 PMCID: PMC5878661 DOI: 10.2147/idr.s160593] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND AND AIMS Treatment of hepatitis C virus (HCV) changed dramatically with the introduction of oral direct-acting antiviral drugs due to their high antiviral potency and safety profile. Sofosbuvir plus daclatasvir combination therapy was extensively investigated in HCV genotypes 1, 2, and 3, while published data regarding its real-life application in the treatment of genotype 4 is lacking. Therefore, we conducted this study to assess the outcomes and predictors of treatment response with sofosbuvir plus daclatasvir with or without ribavirin in Egyptian patients with genotype 4 hepatitis C virus infection. PATIENTS AND METHODS This prospective study included 300 Egyptian patients with chronic genotype 4 HCV, treated with sofosbuvir plus daclatasvir with or without ribavirin for 12-24 weeks. Primary outcome was the number of patients who achieved sustained virologic response (SVR12), and secondary outcome was the occurrence of adverse events. RESULTS A total of 92.67% of all patients achieved SVR12. SVR12 rates of 96.55% and 84.54% were reported in non-cirrhotic and cirrhotic patients, respectively. SVR12 in treatment-naïve and treatment-experienced patients were 94.12% and 87.01%, respectively. A total of 19.7% of patients experienced mild adverse events. Older age, cirrhosis, and low platelet count were the predictors of treatment non-response. CONCLUSION Based on this multi-center prospective study, sofosbuvir plus daclatasvir with or without ribavirin for 12-24 weeks appears to have favorable outcomes in the treatment of genotype 4 HCV-infected Egyptian patients. Older age, cirrhosis, especially Child-Pugh class B, and low platelet count are independent risk factors of treatment non-response.
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Affiliation(s)
- Ossama A Ahmed
- Department of Internal Medicine, Ain Shams University, Faculty of Medicine, Cairo, Egypt
| | | | - Mohamed Hassan A Fouad
- Department of Internal Medicine, Ain Shams University, Faculty of Medicine, Cairo, Egypt
| | - Heba Elashry
- Department of Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Ahmed I Elshafie
- Department of Internal Medicine, Ain Shams University, Faculty of Medicine, Cairo, Egypt
| | | | - Noha E Esheba
- Department of Internal Medicine, Tanta University, Tanta, Egypt
| | | | - Shaimaa Soliman
- Department of Public Health and Community Medicine, Menoufia University, Shbeen El-koum, Egypt
| | - Sherief Abd-Elsalam
- Department of Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
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Ahmed OA, Safwat E, Khalifa MO, Elshafie AI, Fouad MHA, Salama MM, Naguib GG, Eltabbakh MM, Sherief AF, Abd-Elsalam S. Sofosbuvir Plus Daclatasvir in Treatment of Chronic Hepatitis C Genotype 4 Infection in a Cohort of Egyptian Patients: An Experiment the Size of Egyptian Village. Int J Hepatol 2018; 2018:9616234. [PMID: 29755792 PMCID: PMC5884208 DOI: 10.1155/2018/9616234] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 02/19/2018] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND AND AIMS As indicated by the World Health Organization (WHO), Egypt is positioned as the country with the world's highest prevalence of Hepatitis C virus (HCV). HCV is transmitted through unexamined blood transfusions, different employments of syringes, and poor cleansing, as per the WHO. Our study aimed at screening and management of chronic hepatitis C genotype 4 infected patients in Bardeen village, Sharkeya Governorate, Egypt, with Sofosbuvir plus Daclatasvir, as well as estimating the safety and efficacy of that regimen. METHODS Screening of adult patients in Bardeen village was done from March 2016 till November 2016 using hepatitis C virus antibodies by third-generation ELISA testing. Positive results were confirmed by PCR. Patients eligible for treatment received Sofosbuvir 400 mg and Daclatasvir 60 mg daily for 12 weeks and were assessed for sustained virologic response at 12 weeks following the end of treatment (SVR 12). RESULTS Out of 2047 subjects screened for hepatitis C virus, 249 (12.2%) showed positive results. 221 out of those 249 subjects (88.7%) had detectable RNA by PCR. Treatment of eligible patients (183 patients) with Sofosbuvir plus Daclatasvir for 12 weeks resulted in 96% achievement of sustained virologic response at week 12. Adverse events were tolerable. CONCLUSION Sofosbuvir plus Daclatasvir regimen is safe and effective for treatment of chronic hepatitis C Genotype 4 infected patients with minimal adverse events. HCV eradication program implemented in Egypt can be a model for other countries with HCV and limited resources. The availability of generic drugs in Egypt will help much in eradication of the virus.
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Affiliation(s)
- Ossama Ashraf Ahmed
- Internal Medicine Department, Gastroenterology and Hepatology Unit, Ain Shams University, Cairo, Egypt
| | - Eslam Safwat
- Internal Medicine Department, Gastroenterology and Hepatology Unit, Ain Shams University, Cairo, Egypt
| | | | - Ahmed I. Elshafie
- Internal Medicine Department, Gastroenterology and Hepatology Unit, Ain Shams University, Cairo, Egypt
| | | | - Mohamed Magdy Salama
- Internal Medicine Department, Gastroenterology and Hepatology Unit, Ain Shams University, Cairo, Egypt
| | - Gina Gamal Naguib
- Internal Medicine Department, Gastroenterology and Hepatology Unit, Ain Shams University, Cairo, Egypt
| | | | | | - Sherief Abd-Elsalam
- Tropical Medicine & Infectious Diseases Department, Tanta University, Tanta, Egypt
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Mehta V, Mahajan R, Midha V, Narang V, Kaur K, Singh A, Malhotra A, Parvez A, Sood A. Impact of Direct Acting Antiviral Therapy for Treatment of Hepatitis C Genotypes 1, 3 and 4: A Real Life Experience from India. J Clin Exp Hepatol 2018; 8:7-14. [PMID: 29743791 PMCID: PMC5938329 DOI: 10.1016/j.jceh.2017.06.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Accepted: 06/12/2017] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE To assess impact of Direct Acting Antiviral (DAA) therapies for treatment of Hepatitis C Virus (HCV) genotypes 1, 3 and 4 in a real-world cohort from India. METHODS Adults with chronic HCV infection treated with Sofosbuvir (SOF) and Ledipasvir (LDV) (genotypes 1 and 4) or SOF and Daclatasvir (DCV) (genotype 3), with or without Ribavirin (RBV) between December 2015 and December 2016 were included. The primary endpoint was Sustained Virological Response at Post-treatment Week 12 (SVR12). RESULTS Of the 648 patients, 181 received SOF/LDV (65 with RBV) and 467 received SOF/DCV (135 with RBV). Most patients were males (65.4%), aged 41-60 years (49.4%) and treatment-naïve (92.6%). Genotype 3 (72.1%) was most common, followed by genotypes 1 (22.4%) and 4 (5.6%). Forty two percent patients (n = 271) had cirrhosis (112 patients were decompensated). SVR12 (modified intention-to-treat) was achieved by 98.1% of patients (512/522) (100% in genotypes 1 and 4, and 97.3% (362/372) in genotype 3). On intention to treat analysis, SVR12 was 88.1% (512/581) [genotype 1-96.8% (121/125), genotype 3-85.2%, genotype 4-93.5% (29/31)]. Seventy patients had treatment failure (non response in 6, virological breakthrough in 2, 10 patients relapsed, 2 died and 50 were lost to follow up). High SVR was observed regardless of HCV genotype, presence of cirrhosis or past history of treatment. No major adverse events warranting discontinuation of treatment were noted. CONCLUSIONS DAA therapy for HCV genotypes 1, 3 and 4 achieves high SVR rates in all patients, including those with cirrhosis and previous non-responders.
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Key Words
- DAA, Direct Acting Antiviral
- DCV, Daclatasvir
- EASL, European Association of Study of the Liver (EASL)
- ETR, End of Treatment Response
- HBV, Hepatitis B
- HCC, Hepatocellular Carcinoma
- HCV, Hepatitis C Virus
- HIV, Human Immunedeficiency Virus
- ITT, intention to treat
- LDV, ledipasvir
- RBV, Ribavirin
- RVR, Rapid Virological Response
- SOF, Sofosbuvir
- SVR, Sustained Virological Response
- SVR12, sustained virological response at Post-treatment Week 12
- direct acting antivirals
- hepatitis C
- mITT, modified Intention-to-Treat
- real life experience
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Affiliation(s)
- Varun Mehta
- Department of Gastroenterology, Dayanand Medical College, Ludhiana, Punjab, India
| | - Ramit Mahajan
- Department of Gastroenterology, Dayanand Medical College, Ludhiana, Punjab, India
| | - Vandana Midha
- Department of Internal Medicine, Dayanand Medical College, Ludhiana, Punjab, India
| | - Vikram Narang
- Department of Pathology, Dayanand Medical College, Ludhiana, Punjab, India
| | - Kirandeep Kaur
- Department of Pharmacology, Dayanand Medical College, Ludhiana, Punjab, India
| | - Arshdeep Singh
- Department of Gastroenterology, Dayanand Medical College, Ludhiana, Punjab, India
| | - Anand Malhotra
- Department of Gastroenterology, Dayanand Medical College, Ludhiana, Punjab, India
| | - Aslam Parvez
- Department of Gastroenterology, Dayanand Medical College, Ludhiana, Punjab, India
| | - Ajit Sood
- Department of Gastroenterology, Dayanand Medical College, Ludhiana, Punjab, India,Address for correspondence: Ajit Sood, Professor & Head, Department of Gastroenterology, Dayanand Medical College & Hospital, Ludhiana, Punjab, India.
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Ivanova Reipold E, Easterbrook P, Trianni A, Panneer N, Krakower D, Ongarello S, Roberts T, Miller V, Denkinger C. Optimising diagnosis of viraemic hepatitis C infection: the development of a target product profile. BMC Infect Dis 2017; 17:707. [PMID: 29143620 PMCID: PMC5688443 DOI: 10.1186/s12879-017-2770-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Background The current low access to virological testing to confirm chronic viraemic HCV infection in low- and middle-income countries (LMIC) is limiting the rollout of hepatitis C (HCV) care. Existing tests are complex, costly and require sophisticated laboratory infrastructure. Diagnostic manufacturers need guidance on the optimal characteristics a virological test needs to have to ensure the greatest impact on HCV diagnosis and treatment in LMIC. Our objective was to develop a target product profile (TPP) for diagnosis of HCV viraemia using a global stakeholder consensus-based approach. Methods Based on the standardised process established to develop consensus-based TPPs, we followed five key steps. (i) Identifying key potential global stakeholders for consultation and input into the TPP development process. (ii) Informal priority-setting exercise with key experts to identify the needs that should be the highest priority for the TPP development; (iii) Defining the key TPP domains (scope, performance and operational characteristics and price). (iv) Delphi-like process with larger group of key stakeholder to facilitate feedback on the key TPP criteria and consensus building based on pre-defined consensus criteria. (v) A final consensus-gathering meeting for discussions around disputed criteria. A complementary values and preferences survey helped to assess trade-offs between different key characteristics. Results The following key attributes for the TPP for a test to confirm HCV viraemic infection were identified: The scope defined is for both HCV detection as well as confirmation of cure. The timeline of development for tests envisioned in the TPP is 5 years. The test should be developed for use by health-care workers or laboratory technicians with limited training in countries with a medium to high prevalence of HCV (1.5–3.5% and >3.5%) and in high-risk populations in low prevalence settings (<1.5%). A clinical sensitivity at a minimum of 90% is considered sufficient (analytical sensitivity of the equivalent of 3000 IU/ml), particularly if the test increases access to testing through an affordable price, increase ease-of-use and feasibility on capillary blood. Polyvalency would be optimal (i.e. ability to test for HIV and others). The only characteristic that full agreement could not be achieved on was the price for a virological test. Discussants felt that to reach the optimal target price substantial trade-offs had to be made (e.g. in regards to sensitivity and integration). Conclusion The TPP and V&P survey results define the need for an easy-to-use, low cost test to increase access to diagnosis and linkage to care in LMIC. Electronic supplementary material The online version of this article (10.1186/s12879-017-2770-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
| | - Philippa Easterbrook
- Global Hepatitis Programme, HIV Department, World Health Organization, Geneva, Switzerland
| | | | | | - Douglas Krakower
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | | | | | | | - Claudia Denkinger
- FIND, MSF Access Campaign, Geneva, Switzerland.,Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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Elsharkawy A, Eletreby R, Fouad R, Soliman Z, Abdallah M, Negm M, Mohey M, Esmat G. Impact of different sofosbuvir based treatment regimens on the biochemical profile of chronic hepatitis C genotype 4 patients. Expert Rev Gastroenterol Hepatol 2017; 11:773-778. [PMID: 28480808 DOI: 10.1080/17474124.2017.1326816] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Huge efforts have been made to control chronic HCV in Egypt with introduction of Direct-Acting Antivirals (DAAs). Current study aims at evaluating effect of various DAA regimens on liver biochemical profile and haematological indices during treatment. METHODS 272 patients with chronic HCV genotype 4 treated by different DAA regimens (SOF/RBV, SOF/DAC ± RBV, SOF/SIM) for a duration of 12 or 24 weeks in Kasr Alainy Viral Hepatitis Center, Cairo University were followed up for serum bilirubin (BIL), albumin (ALB), alanine transaminase (ALT), aspartate aminotransferase (AST), prothrombin concentration, international normalized ratio (INR), and CBC at baseline, week-4 and end of treatment. RESULTS Mean age was 54 years. Males comprised 64.7%, 72.4% were treatment-naïve, 39% were cirrhotic. Overall SVR12 rate was (93.4%). With all regimens, ALT and AST declined after treatment. In cirrhotics, there was a rise in BIL and INR; with no change in ALB and a decrease in White blood cells. Drop in Hemoglobin and platelets in cirrhotic patients were noted with SOF/RBV, while SOF/SIM showed rise in BIL. CONCLUSION DAAs are safe and effective in genotype 4 chronic HCV patients. It improves liver necro-inflammatory markers in cirrhotics and non-cirrhotics. Cirrhotic patients require careful observation being more vulnerable for treatment related complications.
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Affiliation(s)
- Aisha Elsharkawy
- a Endemic Medicine and Hepatogastroentrology Department, Faculty of medicine , Cairo University , Cairo , Egypt
| | - Rasha Eletreby
- a Endemic Medicine and Hepatogastroentrology Department, Faculty of medicine , Cairo University , Cairo , Egypt
| | - Rabab Fouad
- a Endemic Medicine and Hepatogastroentrology Department, Faculty of medicine , Cairo University , Cairo , Egypt
| | - Zeinab Soliman
- a Endemic Medicine and Hepatogastroentrology Department, Faculty of medicine , Cairo University , Cairo , Egypt
| | - Mohamed Abdallah
- b Medical research division , National research Centre , Cairo , Egypt
| | - Mohamed Negm
- c Kasr Al-Ainy Viral Hepatitis Center, Faculty of medicine , Cairo University , Cairo , Egypt
| | - Mohammad Mohey
- a Endemic Medicine and Hepatogastroentrology Department, Faculty of medicine , Cairo University , Cairo , Egypt
| | - Gamal Esmat
- a Endemic Medicine and Hepatogastroentrology Department, Faculty of medicine , Cairo University , Cairo , Egypt
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Bielen R, Moreno C, Van Vlierberghe H, Bourgeois S, Mulkay JP, Vanwolleghem T, Verlinden W, Brixko C, Decaestecker J, De Galocsy C, Janssens F, Cool M, Van Overbeke L, Van Steenkiste C, D'heygere F, Cools W, Nevens F, Robaeys G. Belgian experience with direct acting antivirals in people who inject drugs. Drug Alcohol Depend 2017; 177:214-220. [PMID: 28618285 DOI: 10.1016/j.drugalcdep.2017.04.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Revised: 04/04/2017] [Accepted: 04/24/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIM Hepatitis C viral infection (HCV) has become a curable disease due to the development of direct acting antivirals (DAA). The WHO has set a target to eliminate HCV completely. Therefore, people who inject drugs (PWID) also need to be treated. In this study, we compared the real-life uptake and outcome of DAA treatment for HCV in PWID and non-PWID. METHODS We performed a nation-wide, retrospective cohort study in 15 hospitals. All patients who were treated with simeprevir-sofosbuvir, daclatasvir-sofosbuvir, or ombitasvir/paritaprevir ritonavir-dasabuvir between December 2013 and November 2015 were included. RESULTS The study population consisted of 579 patients: 115 PWID (19.9%) and 464 non-PWID (80.1%). Of the PWID 18 were active PWID (15.6%), 35 still received opiate substitution therapy (OST) (30.4%) and 62 were former PWID without OST (53.9%). PWID were more infected with genotype 1a and 3 (p=0.001). There were equal rates of side-effects (44.7% vs. 46.6%; p=0.847), similar rates of treatment completion (95.7% vs 98.1%; p=0.244) and SVR (93.0% vs 94.8%; p=0.430) between PWID and non-PWID, respectively. CONCLUSION PWID, especially active users, are underserved for DAA treatment in real life in Belgium. Reimbursement criteria based on fibrosis stage make it difficult to treat PWID. Treatment adherence is similar in PWID and the general population, even in patients with active abuse. DAA were safe and effective in PWID despite the higher prevalence of difficult-to-treat genotypes. Based on these data more efforts to treat PWID are needed and policy changes are necessary to reach the WHO targets.
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Affiliation(s)
- Rob Bielen
- Faculty of Medicine and Life Sciences, Hasselt University, Department of Gastro-Enterology and Hepatology, Ziekenhuis-Oost Limburg, Genk, Belgium.
| | - Christophe Moreno
- Department of Gastro-Enterology and Hepatopancreatology, Erasme Hospital, Brussels, Belgium
| | - Hans Van Vlierberghe
- Department of Hepatology and Gastro-Enterology, University Hospitals Gent, Belgium
| | - Stefan Bourgeois
- Department of Gastro-Enterology and Hepatology, ZNA Stuivenberg, Antwerp, Belgium
| | - Jean-Pierre Mulkay
- Department of Gastro-Enterology and Hepatology, Hôpital Saint-Pierre, Brussels, Belgium
| | - Thomas Vanwolleghem
- Department of Gastro-Enterology and Hepatology, University Hospitals UZ Antwerpen, Antwerp
| | - Wim Verlinden
- Department of Gastro-Enterology and Hepatology, University Hospitals UZ Antwerpen, Antwerp
| | - Christian Brixko
- Department of Gastroenterology and Digestive Oncology, CHR Citadelle, Liège, Belgium
| | - Jochen Decaestecker
- Department of Gastro-Enterology and Hepatology, AZ Delta, Roeselare, Department of Gastro-Enterology and Hepatology, University Hospitals KULeuven, Leuven, Belgium
| | - Chantal De Galocsy
- Department of Gastro-Enterology and Hepatology, Hôpital HIS Bracops, Brussels, Belgium
| | - Filip Janssens
- Department of Gastro-Enterology and Hepatology, Jessa Hospital, Hasselt, Department of Gastro-Enterology and Hepatology, University Hospitals KULeuven, Leuven, Belgium
| | - Mike Cool
- Department of Gastro-Enterology and Hepatology, AZ Damiaan, Oostende, Department of Gastro-Enterology and Hepatology, University Hospitals KULeuven, Leuven, Belgium
| | - Lode Van Overbeke
- Department of Gastro-Enterology and Hepatology, AZ Sint Maarten, Mechelen, Belgium
| | - Christophe Van Steenkiste
- Department of Gastro-Enterology and Hepatology, AZ Maria Middelares, Gent, Department of Gastro-Enterology and Hepatology, University Hospitals Gent, Belgium
| | - François D'heygere
- Department of Gastro-Enterology and Hepatology, AZ Groeninge, Kortrijk, Department of Gastro-Enterology and Hepatology, University Hospitals KULeuven, Leuven, Belgium
| | - Wilfried Cools
- Faculty of Science, Center for Statistics, Hasselt University, Diepenbeek, Belgium
| | - Frederik Nevens
- Department of Gastro-Enterology and Hepatology, University Hospitals KULeuven, Leuven, Belgium
| | - Geert Robaeys
- Department of Gastro-Enterology and Hepatology, Ziekenhuis-Oost Limburg, Genk, Department of Gastro-Enterology and Hepatology, University Hospitals KULeuven, Leuven, Belgium
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Cacoub P, Comarmond C, Desbois AC, Saadoun D. Rheumatologic Manifestations of Hepatitis C Virus Infection. Clin Liver Dis 2017; 21:455-464. [PMID: 28689585 DOI: 10.1016/j.cld.2017.03.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hepatitis C virus (HCV) infection is associated with a morbidity and mortality due to liver complications. HCV infection is also frequently associated with rheumatic disorders, such as arthralgia, myalgia, cryoglobulinemia vasculitis, and sicca syndrome, as well as the production of autoantibodies. The treatment of HCV infection with interferon alpha (IFN) has been contraindicated for a long time in many rheumatologic autoimmune/inflammatory disorders. New oral IFN-free combinations offer an opportunity for HCV-infected patients with extrahepatic manifestations, including rheumatologic autoimmune/inflammatory disorders, to be cured with a short treatment duration and a low risk of side effects.
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Affiliation(s)
- Patrice Cacoub
- Inflammation-Immunopathology-Biotherapy Department (DHU i2B), UMR 7211, UPMC Université Paris 06, Sorbonne Universités, Paris F-75005, France; INSERM, UMR_S 959, Paris F-75013, France; CNRS, FRE3632, Paris F-75005, France; Department of Internal Medicine and Clinical Immunology, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, 83 boulevard de l'hô pital, Paris F-75013, France.
| | - Cloé Comarmond
- Inflammation-Immunopathology-Biotherapy Department (DHU i2B), UMR 7211, UPMC Université Paris 06, Sorbonne Universités, Paris F-75005, France; INSERM, UMR_S 959, Paris F-75013, France; CNRS, FRE3632, Paris F-75005, France; Department of Internal Medicine and Clinical Immunology, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, 83 boulevard de l'hô pital, Paris F-75013, France
| | - Anne Claire Desbois
- Inflammation-Immunopathology-Biotherapy Department (DHU i2B), UMR 7211, UPMC Université Paris 06, Sorbonne Universités, Paris F-75005, France; INSERM, UMR_S 959, Paris F-75013, France; CNRS, FRE3632, Paris F-75005, France; Department of Internal Medicine and Clinical Immunology, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, 83 boulevard de l'hô pital, Paris F-75013, France
| | - David Saadoun
- Inflammation-Immunopathology-Biotherapy Department (DHU i2B), UMR 7211, UPMC Université Paris 06, Sorbonne Universités, Paris F-75005, France; INSERM, UMR_S 959, Paris F-75013, France; CNRS, FRE3632, Paris F-75005, France; Department of Internal Medicine and Clinical Immunology, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, 83 boulevard de l'hô pital, Paris F-75013, France
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Maistat L, Kravchenko N, Reddy A. Hepatitis C in Eastern Europe and Central Asia: a survey of epidemiology, treatment access and civil society activity in eleven countries. HEPATOLOGY, MEDICINE AND POLICY 2017; 2:9. [PMID: 30288322 PMCID: PMC6171005 DOI: 10.1186/s41124-017-0026-z] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Accepted: 04/13/2017] [Indexed: 01/28/2023]
Abstract
INTRODUCTION The 16 countries of the Eastern Europe and Central Asia (EECA) region are home to 6.6 million people in need of treatment for chronic hepatitis C virus (HCV) infection. Because of transformational change in HCV treatment, global efforts to address HCV are accelerating. Given its large regional burden, the EECA needs to ensure its inclusion in and benefit from any new developments. METHODS Our 2015-16 survey aimed to collect and report on epidemiology, treatment access (including drug registration and prices, national HCV guidelines and treatment program coverage) and pertinent civil society organization (CSO) activities in 11 countries in the EECA. RESULTS Major gaps in epidemiological data exist; reported anti-HCV prevalence ranged from 1.5 to 7.5% for the general population, 22.7 to 70-95% for people who inject drugs (PWID) and 18 to 80% for people living with HIV (PLHIV). Ten countries (91% of the sample) have registered one or more of the second-generation, direct-acting antiviral medications (DAA) for potential interferon-free treatment. However, intellectual property issues and prices limit access to these drugs. In 2014, HCV programs in the surveyed countries covered only 0.15% of the total number of people in need of treatment. CSO-driven, international donor-funded programs are starting to fulfill needs of PWID and PLHIV. CONCLUSIONS As feasible curative HCV treatment is now available, and given the significant regional disease burden, EECA countries need to ensure HCV surveillance and DAA availability at affordable prices in order to expand treatment and prevent the onward transmission of the infection. EECA CSOs have demonstrated their capacity to play a crucial role in advancing HCV issues, and they should continue leveraging these issues for the benefit of individual patients and public health in general.
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Yang YM, Choi EJ. Efficacy and safety outcomes of sofosbuvir-based treatment regimens for hepatitis C virus-infected patients with or without cirrhosis from phase III clinical trials. Ther Clin Risk Manag 2017; 13:477-497. [PMID: 28442915 PMCID: PMC5395279 DOI: 10.2147/tcrm.s134818] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Background With the appearance of oral direct-acting antivirals (DAAs), the field of hepatitis C virus (HCV) treatment has been dramatically changed. This evolution makes possible for all oral treatments to be available for the treatment of HCV-infected patients. The aims of this review were to report the efficacy and safety of sofosbuvir (SOF)-based regimens for the treatment of patients with chronic HCV infection and to provide our clinical perspectives on these regimens. Methods A literature search of clinical studies published in PubMed and posted on ClinicalTrials.gov website was performed to identify studies evaluating the efficacy or safety of SOF-containing treatment regimens. Results A total of 23 clinical trials were examined in the review. The evaluated SOF-based regimens are as follows: SOF/daclatasvir (DCV) ± ribavirin (RBV), SOF/ledipasvir (LDV) ± RBV, SOF/simeprevir (SMV), SOF/velpatasvir (VEL) ± RBV, and SOF/RBV ± peginterferon (peg-IFN). These SOF-based regimens were at least effective and safe for HCV-infected patients with or without cirrhosis. The SOF/VEL ± RBV regimen, a pan-genotypic DAA regimen, was effective for the treatment of patients with HCV genotype 1, 2, 3, 4, 5, or 6 infection. The 24-week SOF/RBV regimen was as effective as the 12-week SOF/RBV/peg-IFN regimen. Patients with HCV genotype 3 infection could have benefits from the use of the 24-week SOF/RBV regimen. For cirrhotic patients with HCV genotype 3 infection, the 12-week SOF/RBV/peg-IFN regimen could be considered as an alternative treatment option when access to SOF-based regimens with other DAAs is limited. In the included studies, significant adverse events due to SOF-based regimens were not reported. Conclusion The clinical trials suggest that SOF-based treatment regimens for HCV-infected patients with or without cirrhosis can be at least effective and safe patient-convenient medications. However, it is necessary to monitor HCV-infected patients, since rare adverse events, drug–drug interactions, and drug–disease interactions can occur in real clinical settings.
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Affiliation(s)
- Young-Mo Yang
- Department of Pharmacy, College of Pharmacy, Chosun University, Gwangju, South Korea
| | - Eun Joo Choi
- Department of Pharmacy, College of Pharmacy, Chosun University, Gwangju, South Korea
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Li YH, Wu ZY, Tang S, Zhang X, Wang YX, Jiang JD, Peng ZG, Song DQ. Evolution of matrinic ethanol derivatives as anti-HCV agents from matrine skeleton. Bioorg Med Chem Lett 2017; 27:1962-1966. [PMID: 28320615 DOI: 10.1016/j.bmcl.2017.03.025] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 03/07/2017] [Accepted: 03/10/2017] [Indexed: 12/12/2022]
Abstract
Twenty-two novel 12N-substituted matrinic ethanol derivatives were synthesized and evaluated for their antiviral activities against HCV taking compound 1 as the lead. The SAR study indicated that the shortening of the 11-butyl chain to ethyl chain did not affect the activity significantly. Out of the target compounds, matrinic ethanol 6a demonstrated a potential anti-HCV effect with an EC50 value of 3.2μM and a SI value of 96.6. The free hydroxyl arm in 6a made it possible as a parent structure to prepare pro-drug for the potential application in HCV treatment. This study provided powerful information on further strategic optimization and development of this kind of compounds into a novel family of anti-HCV agents.
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Affiliation(s)
- Ying-Hong Li
- Beijing Key Laboratory of Anti-infective Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China
| | - Zhou-Yi Wu
- Beijing Key Laboratory of Anti-infective Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China
| | - Sheng Tang
- Beijing Key Laboratory of Anti-infective Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China
| | - Xin Zhang
- Beijing Key Laboratory of Anti-infective Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China
| | - Yan-Xiang Wang
- Beijing Key Laboratory of Anti-infective Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China
| | - Jian-Dong Jiang
- Beijing Key Laboratory of Anti-infective Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China
| | - Zong-Gen Peng
- Beijing Key Laboratory of Anti-infective Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China.
| | - Dan-Qing Song
- Beijing Key Laboratory of Anti-infective Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China.
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Cacoub P, Commarmond C, Sadoun D, Desbois AC. Hepatitis C Virus Infection and Rheumatic Diseases. Rheum Dis Clin North Am 2017; 43:123-132. [PMID: 27890169 DOI: 10.1016/j.rdc.2016.09.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Ivanenkov YA, Aladinskiy VA, Bushkov NA, Ayginin AA, Majouga AG, Ivachtchenko AV. Small-molecule inhibitors of hepatitis C virus (HCV) non-structural protein 5A (NS5A): a patent review (2010-2015). Expert Opin Ther Pat 2017; 27:401-414. [PMID: 27967269 DOI: 10.1080/13543776.2017.1272573] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Non-structural 5A (NS5A) protein has achieved a considerable attention as an attractive target for the treatment of hepatitis C (HCV). A number of novel NS5A inhibitors have been reported to date. Several drugs having favorable ADME properties and mild side effects were launched into the pharmaceutical market. For instance, daclatasvir was launched in 2014, elbasvir is currently undergoing registration, ledipasvir was launched in 2014 as a fixed-dose combination with sofosbuvir (NS5B inhibitor). Areas covered: Thomson integrity database and SciFinder database were used as a valuable source to collect the patents on small-molecule NS5A inhibitors. All the structures were ranked by the date of priority. Patent holder and antiviral activity for each scaffold claimed were summarized and presented in a convenient manner. A particular focus was placed on the best-in-class bis-pyrrolidine-containing NS5A inhibitors. Expert opinion: Several first generation NS5A inhibitors have recently progressed into advanced clinical trials and showed superior efficacy in reducing viral load in infected subjects. Therapy schemes of using these agents in combination with other established antiviral drugs with complementary mechanisms of action can address the emergence of resistance and poor therapeutic outcome frequently attributed to antiviral drugs.
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Affiliation(s)
- Yan A Ivanenkov
- a Department of Biological and Medical Physics , Moscow Institute of Physics and Technology (State University) , Dolgoprudny City , Moscow Region , Russia.,b Department of Computational and Medicinal Chemistry , ChemDiv , San Diego , CA , USA.,c Chemistry Department , Moscow State University , Moscow , Russia
| | - Vladimir A Aladinskiy
- a Department of Biological and Medical Physics , Moscow Institute of Physics and Technology (State University) , Dolgoprudny City , Moscow Region , Russia
| | - Nikolay A Bushkov
- a Department of Biological and Medical Physics , Moscow Institute of Physics and Technology (State University) , Dolgoprudny City , Moscow Region , Russia
| | - Andrey A Ayginin
- a Department of Biological and Medical Physics , Moscow Institute of Physics and Technology (State University) , Dolgoprudny City , Moscow Region , Russia
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The Efficacy of 12 Weeks of Sofosbuvir, Daclatasvir, and Ribavirin in Treating Hepatitis C Patients with Cirrhosis, Genotypes 1 and 3. HEPATITIS MONTHLY 2016. [DOI: 10.5812/hepatmon.44564] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
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