|
1
|
Mohamed Abdelnajid D, Elmowafy AY, Rostaing L, Elrakaiby MT. Prediction of response to sofosbuvir-based therapy using serum interleukin-12 and single nucleotide polymorphism of the interleukin 28B gene as predictive factors in HCV positive genotype-4 patients. Medicine (Baltimore) 2023; 102:e34125. [PMID: 37443472 PMCID: PMC10344568 DOI: 10.1097/md.0000000000034125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 06/07/2023] [Indexed: 07/15/2023] Open
Abstract
Some hepatitis-C virus patients have resistance to direct-acting-antivirals (DAAs). Genetic polymorphisms have been associated with drug resistance. This study aimed to evaluate the role of interleukin (IL)-28B gene polymorphism and IL-12 levels as predictors for a response to sofosbuvir/ribavirin (SOF/RBV) with (triple-therapy) or without (dual-therapy) Peg-alpha-interferon. 92 hepatitis C virus (HCV)/RNA (+)-patients treated with dual (n = 72) or triple (n = 20) therapy. IL28B genetic polymorphism and IL-12 level assessments. 30.4% of the patients were IL28B C/C genotype, 56.5% C/T-genotype, and 13% T/T-genotype. Mean baseline IL-12 levels were 27.5 ± 3.0 pg/mL. Rapid viral response was achieved in 86/92 patients. All patients achieved end-of-treatment virologic response. The 12- and 24-week sustained virologic responses (SVR) were achieved in 76 patients (82.6%), that is, a relapse was found in 16 patients (17.4%). 8 and 12-weeks after antiviral therapy, IL-12 levels decreased significantly, and became comparable to those of the control-group. That drop in IL-12 levels was similar across the dual- and triple-therapy patients. Finally, logistic regression analysis showed that the increase in baseline aspartate aminotransferase (AST) and T/T genotyping had an independent effect on increasing the probability a SVR failing in both dual- and triple-therapy groups (P = .0007 and P = .02, respectively). Single-nucleotide polymorphism (SNP) in IL-28B and IL-12 levels play roles as predictors in DAAs resistance.
Collapse
Affiliation(s)
- Doaa Mohamed Abdelnajid
- Department of Microbiology and Immunology, Military Medical Academy, Cairo, Egypt
- Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Kasr Al-Aini, Cairo, Egypt
| | | | - Lionel Rostaing
- Department of Nephrology, Hemodialysis, Apheresis, and Kidney Transplantation, CHU Grenoble-Alpes, France
- Grenoble Alpes University, Grenoble, France
| | - Marwa T. Elrakaiby
- Department of Microbiology and Immunology, Military Medical Academy, Cairo, Egypt
| |
Collapse
|
|
2
|
Cao Y, Wu X, Wang Z, Huang Y, Wu J, Cao G, Yu J, Wang J, Yang H, Zhang W, Zhang J. Single-Ascending-Dose, Food-Effect, and Multiple-Dose Study of the Safety, Tolerability, and Pharmacokinetics of the Pangenotypic Anti-Hepatitis C Virus Drug Holybuvir in Healthy Chinese Subjects. Antimicrob Agents Chemother 2023; 67:e0129522. [PMID: 36809048 PMCID: PMC10019294 DOI: 10.1128/aac.01295-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Accepted: 12/25/2022] [Indexed: 02/23/2023] Open
Abstract
Holybuvir is a novel pangenotypic hepatitis C virus NS5B inhibitor. This first in-human study aimed to evaluate the pharmacokinetics (PK), safety, and tolerability of holybuvir and its metabolites and the effect of food on the PK of holybuvir and its metabolites in healthy Chinese subjects. A total of 96 subjects were enrolled in this study which included (i) a single-ascending-dose (SAD) study (100 to 1,200 mg), (ii) a food-effect (FE) study (600 mg), and (iii) a multiple-dose (MD) study (400 and 600 mg once daily for 14 days). The results showed that single oral administration of holybuvir at doses up to 1,200 mg was well tolerated. Holybuvir was rapidly absorbed and metabolized in the human body, which was consistent with the characteristics of holybuvir as a prodrug. PK analysis showed that Cmax and area under the curve (AUC) increased with dose in no dose-proportional manner after a single-dose administration (100 to 1,200 mg). Although high-fat meals did change the PK of holybuvir and its metabolites, clinical significance of changes in PK parameters induced by eating a high-fat diet would be further confirmed. Following multiple-dose administration, accumulation of metabolites SH229M4 and SH229M5-sul was observed. The favorable PK and safety results support the further development of holybuvir for patients with HCV. (This study was registered at Chinadrugtrials.org under identifier CTR20170859.).
Collapse
Affiliation(s)
- Yuran Cao
- Phase I Clinical Research Center, Huashan Hospital, Fudan University, Shanghai, China
| | - Xiaojie Wu
- Phase I Clinical Research Center, Huashan Hospital, Fudan University, Shanghai, China
| | - Zhiqiang Wang
- Nanjing Sanhome Pharmaceutical Co., Ltd., Nanjing, Jiangsu, China
| | - Yuxian Huang
- Infectious Disease Department, Huashan Hospital, Fudan University, Shanghai, China
| | - Junzhen Wu
- Phase I Clinical Research Center, Huashan Hospital, Fudan University, Shanghai, China
| | - Guoying Cao
- Phase I Clinical Research Center, Huashan Hospital, Fudan University, Shanghai, China
| | - Jicheng Yu
- Phase I Clinical Research Center, Huashan Hospital, Fudan University, Shanghai, China
| | - Jingjing Wang
- Phase I Clinical Research Center, Huashan Hospital, Fudan University, Shanghai, China
| | - Haijing Yang
- Phase I Clinical Research Center, Huashan Hospital, Fudan University, Shanghai, China
| | - Wenhong Zhang
- Infectious Disease Department, Huashan Hospital, Fudan University, Shanghai, China
| | - Jing Zhang
- Phase I Clinical Research Center, Huashan Hospital, Fudan University, Shanghai, China
- Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China
| |
Collapse
|
|
3
|
AbdElrahman M, Ibrahim MK, Tawfik S, Omran D, Bendary MM, Hassanin SO, Elbatae H. The relation between SNPs in the NME1 gene and response to sofosbuvir in Egyptian patients with chronic HCV. BENI-SUEF UNIVERSITY JOURNAL OF BASIC AND APPLIED SCIENCES 2023. [DOI: 10.1186/s43088-022-00337-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Abstract
Background
Hepatitis C virus (HCV) infection is considered one of the most urgent health problems in the world, with an incidence of approximately 71 million patients and 399,000 deaths per year from related liver diseases. In this study, we examined the association between 2 single nucleotide polymorphisms (SNPs) in the nucleoside diphosphate kinase 1 (NME1) gene (encoding one of the sofosbuvir metabolizing enzymes) and the response to the sofosbuvir plus daclatasvir regimen in Egyptian HCV-infected patients.
Results
Our data showed a similarity in the distribution of the CC, CT, and TT genotypes of NME1 rs2302254 C/T (p = 0.847) and the CC, TC, and TT genotypes of NME1 rs16949649 T/C (p = 0.937) among patients who were either treatment responders or relapsers. Based on the univariate and multivariate logistic regression analyses of the significant predictors for sustained virological response (SVR), five factors showed a robust predictive potency for the treatment outcome: age, fasting blood glucose level, platelets, albumin, and alpha-fetoprotein. Strikingly, there was a significant correlation between the rs16949649T/C polymorphism and serum creatinine (p = 0.023). Higher creatinine levels were observed among the CC carriers than the TC or TT carriers.
Conclusions
The 2 studied SNPs of NME1 had no significant association with SVR in Egyptian HCV-infected patients; however, the noticeable relation between rs16949649T/C and creatinine level might represent a foundation for future studies on the renal extra-hepatic manifestation of HCV and SNPs of NME1 gene.
Collapse
|
|
4
|
Sise ME, McQuaid T, Martin P. Sofosbuvir-based hepatitis C therapies in patients with chronic and end-stage kidney disease. Nephrol Dial Transplant 2022; 37:2327-2334. [PMID: 33848334 DOI: 10.1093/ndt/gfab072] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Indexed: 12/31/2022] Open
Abstract
Sofosbuvir (SOF), a nucleotide inhibitor of the hepatitis C virus (HCV) polymerase, is a component of several all-oral HCV therapies. GS-331007, SOF's predominant metabolite, is renally eliminated and accumulates 5- to 20-fold in patients with advanced chronic kidney disease (CKD) or undergoing hemodialysis (HD), respectively. Preclinical data did not determine whether these exposures represented a risk for toxicity. Therefore subjects with advanced CKD were not included in registrational studies and SOF was not initially approved for use in advanced CKD. Nevertheless, after initial licensing, off-label use of SOF at full or reduced doses was reported in patients with kidney disease. Two clinical trials of SOF-containing therapies were conducted in patients with end-stage kidney disease, demonstrating safety and efficacy. These led to expanded US Food and Drug Administration approval in 2019 for the use of SOF-containing regimens in patients with advanced CKD, including dialysis dependence. Even so, given the availability of protease inhibitor-containing direct-acting antiviral regimens, there was a reluctance by some practitioners to use SOF-containing regimens in moderate to severe kidney disease. Here we review the existing data on SOF's pharmacokinetics, toxicology, efficacy and safety in patients with kidney disease. Data from both clinical trials and real-world practice settings indicate that in patients with moderate to severe kidney disease, full-dose SOF-based regimens have high rates of efficacy and acceptable safety and tolerability profiles, without increased risk for cardiac adverse events or clinically meaningful changes in kidney function. SOF-based regimens are safe and effective in patients who have moderate to severe kidney disease, including those undergoing HD.
Collapse
Affiliation(s)
- Meghan E Sise
- Depertment of Medicine, Massachusetts General Hospital, Harvard University, Boston, MA, USA
| | | | - Paul Martin
- Miller School of Medicine, University of Miami, Miami, FL, USA
| |
Collapse
|
|
5
|
Kamal A, Matta C, Mohsin HA, Elhadidi AS, Ghazy RM, Omar HH, Tahoun M, Mohamed NA. ASSESSING PREDICTORS OF DIRECTLY ACTING ANTIVIRALS' FAILURE AS A FURTHER STEP TOWARDS MORE EFFICIENT HCV ELIMINATION PROGRAMS: IL28B (IFNL4) GENE POLYMORPHISM HAS NO ROLE WHILE HIGHER ESTIMATED CREATININE CLEARANCE IS A FORGOTTEN FACTOR. ARQUIVOS DE GASTROENTEROLOGIA 2022; 59:177-183. [PMID: 35830025 DOI: 10.1590/s0004-2803.202202000-33] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 01/17/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Sustained virologic response (SVR) rates after directly acting antivirals (DAAs) for hepatitis C virus (HCV) exceed 95%. This encouraged policymakers to put plans to achieve HCV elimination by 2030. The remaining percentage of non-SVR12 can affect HCV eradication strategies in the real-world especially the compliance of large numbers of treated persons to follow up for assessment of virologic response cannot be guaranteed. OBJECTIVE We aimed to assess predictors of failure to achieve SVR after receiving sofosbuvir plus NS5A inhibitor as an important step towards achieving better HCV eradication strategies. METHODS During the period from 1st November 2018 to 1st November 2019, 1581 treatment-naive patients received sofosbuvir plus daclatasvir ± ribavirin at our unit and 10 patients were referred to us with HCV relapse after the same regimens. A total of 163 out of the 1581 patients were lost for follow-up before assessment of virologic response and excluded from the analysis. 20 out of the remaining patients failed to achieve SVR12. Data from the 30 patients with non-SVR12 were included in the case-control analysis. RESULTS Every unit increase in estimated creatinine clearance using modification of diet in renal disease study (MDRD) score, total bilirubin, and INR was associated with 1.03, 13.92, and 80.08 times greater odds of non-SVR12 (P<0.001, P=0.0016, P=0.02) respectively. The presence of liver cirrhosis on ultrasonography increases the odds by 10.03. (P=0.009). CONCLUSION Higher MDRD score, INR, total bilirubin, and presence of sonographic features of liver cirrhosis are predictors of failure to achieve SVR12 using sofosbuvir plus NS5A inhibitor.
Collapse
Affiliation(s)
- Ahmed Kamal
- Internal Medicine and Hepatology department. Faculty of Medicine, Alexandria University, Egypt
| | - Cecil Matta
- Developmental Genetics department, Faculty of Science, Alexandria University, Egypt
| | - Heba Akram Mohsin
- Cell biology and genetics fellow, Faculty of Science, Alexandria University, Egypt
- College of pharmacy-Al-Zahraa University for Women, Iraq
| | - Abeer Shawki Elhadidi
- Clinical and chemical pathology department, Faculty of Medicine, Alexandria University, Egypt
| | - Ramy Mohamed Ghazy
- Tropical health department, High Institute of Public Health, Alexandria University, Egypt
| | - Heba Hany Omar
- Clinical Pharmacist at Alexandria Main University hospitals, Alexandria University, Egypt
- Microbiology department, Faculty of Pharmacy, AL Salam University, Egypt
| | - Mona Tahoun
- Clinical and chemical pathology department, Faculty of Medicine, Alexandria University, Egypt
| | | |
Collapse
|
|
6
|
KOCABAŞ F, USLU M. The current state of validated small molecules inhibiting SARS-CoV-2 nonstructural proteins. Turk J Biol 2021; 45:469-483. [PMID: 34803448 PMCID: PMC8573838 DOI: 10.3906/biy-2106-42] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 08/06/2021] [Indexed: 11/03/2022] Open
Abstract
The current COVID-19 outbreak has had a profound influence on public health and daily life. Despite all restrictions and vaccination programs, COVID-19 still can lead to fatality due to a lack of COVID-19-specific treatments. A number of studies have demonstrated the feasibility to develop therapeutics by targeting underlying components of the viral proteome. Here we reviewed recently developed and validated small molecule inhibitors of SARS-CoV-2's nonstructural proteins. We described the validation level of identified compounds specific for SARS-CoV-2 in the presence of in vitro and in vivo supporting data. The mechanisms of pharmacological activity, as well as approaches for developing improved SARS-CoV-2 NSP inhibitors have been emphasized.
Collapse
Affiliation(s)
- Fatih KOCABAŞ
- Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, İstanbulTurkey
| | - Merve USLU
- Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, İstanbulTurkey
| |
Collapse
|
|
7
|
Serpi M, Pertusati F. An overview of ProTide technology and its implications to drug discovery. Expert Opin Drug Discov 2021; 16:1149-1161. [PMID: 33985395 DOI: 10.1080/17460441.2021.1922385] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Introduction: The ProTide technology is a phosphate (or phosphonate) prodrug method devised to deliver nucleoside monophosphate (or monophosphonate) intracellularly bypassing the key challenges of antiviral and anticancer nucleoside analogs. Three new antiviral drugs, exploiting this technology, have been approved by the FDA while others are in clinical studies as anticancer agents.Areas covered: The authors describe the origin and development of this technology and its incredible success in transforming the drug discovery of antiviral and anticancer nucleoside analogues. As evidence, discussion on the antiviral ProTides on the market, and those currently in clinical development are included. The authors focus on how the proven capacity of this technology to generate new drug candidates has stimulated its application to non-nucleoside-based molecules.Expert opinion: The ProTide approach has been extremely successful in delivering blockbuster antiviral medicines and it seems highly promising in oncology. Its application to non-nucleoside-based small molecules is recently emerging and proving effective in other therapeutic areas. However, investigations to explain the lack of activity of certain ProTide series and comprehensive structure activity relationship studies to identify the appropriate phosphoramidate motifs depending on the parent molecule are in our opinion mandatory for the future development of these compounds.
Collapse
Affiliation(s)
| | - Fabrizio Pertusati
- School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK
| |
Collapse
|
|
8
|
Sadeghi A, Ali Asgari A, Norouzi A, Kheiri Z, Anushirvani A, Montazeri M, Hosamirudsai H, Afhami S, Akbarpour E, Aliannejad R, Radmard AR, Davarpanah AH, Levi J, Wentzel H, Qavi A, Garratt A, Simmons B, Hill A, Merat S. Sofosbuvir and daclatasvir compared with standard of care in the treatment of patients admitted to hospital with moderate or severe coronavirus infection (COVID-19): a randomized controlled trial. J Antimicrob Chemother 2020; 75:3379-3385. [PMID: 32812039 PMCID: PMC7454592 DOI: 10.1093/jac/dkaa334] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 07/03/2020] [Indexed: 02/07/2023] Open
Abstract
Background Currently no effective antiviral therapy has been found to treat COVID-19. The aim of this trial was to assess if the addition of sofosbuvir and daclatasvir improved clinical outcomes in patients with moderate or severe COVID-19. Methods This was an open-label, multicentre, randomized controlled clinical trial in adults with moderate or severe COVID-19 admitted to four university hospitals in Iran. Patients were randomized into a treatment arm receiving sofosbuvir and daclatasvir plus standard care, or a control arm receiving standard care alone. The primary endpoint was clinical recovery within 14 days of treatment. The study is registered with IRCT.ir under registration number IRCT20200128046294N2. Results Between 26 March and 26 April 2020, 66 patients were recruited and allocated to either the treatment arm (n = 33) or the control arm (n = 33). Clinical recovery within 14 days was achieved by 29/33 (88%) in the treatment arm and 22/33 (67%) in the control arm (P = 0.076). The treatment arm had a significantly shorter median duration of hospitalization [6 days (IQR 4–8)] than the control group [8 days (IQR 5–13)]; P = 0.029. Cumulative incidence of hospital discharge was significantly higher in the treatment arm versus the control (Gray’s P = 0.041). Three patients died in the treatment arm and five in the control arm. No serious adverse events were reported. Conclusions The addition of sofosbuvir and daclatasvir to standard care significantly reduced the duration of hospital stay compared with standard care alone. Although fewer deaths were observed in the treatment arm, this was not statistically significant. Conducting larger scale trials seems prudent.
Collapse
Affiliation(s)
- Anahita Sadeghi
- Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Ali Asgari
- Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Norouzi
- Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Science, Gorgan, Iran
| | - Zahedin Kheiri
- Department of Internal Medicine, Baharloo hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Anushirvani
- Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahnaz Montazeri
- Department of infectious diseases, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Hadiseh Hosamirudsai
- Department of Infectious Diseases, Baharloo Hospital, Tehran University of Medical Science, Tehran, Iran
| | - Shirin Afhami
- Department of infectious diseases, Shariati Hospital, Tehran University of Medical Science, Tehran, Iran
| | - Elham Akbarpour
- Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Rasoul Aliannejad
- Department of Pulmonary and Critical Care, Shariati Hospital, Thoracic Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Reza Radmard
- Department of Radiology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir H Davarpanah
- Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA, USA
| | - Jacob Levi
- Department of Emergency Medicine, Homerton University Hospital, London, UK
| | - Hannah Wentzel
- School of Public Health, Imperial College London, London, UK
| | - Ambar Qavi
- School of Public Health, Imperial College London, London, UK
| | - Anna Garratt
- Cardiff and Vale University Health Board, Cardiff, UK
| | - Bryony Simmons
- Department of Infectious Disease, Imperial College London, London, UK
| | - Andrew Hill
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK
| | - Shahin Merat
- Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
9
|
Sayan M, Yıldırım FS, Akhan S, Yıldırım AA, Şirin G, Cabalak M, Demir M, Can S, Ersöz G, Altıntaş E, Ensaroğlu F, Akbulut A, Şener A, Deveci A. NS5A resistance - associated substitutions in chronic hepatitis C patients with direct acting antiviral treatment failure in Turkey. Int J Infect Dis 2020; 95:84-89. [PMID: 32302766 DOI: 10.1016/j.ijid.2020.03.061] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Revised: 03/19/2020] [Accepted: 03/24/2020] [Indexed: 02/08/2023] Open
Abstract
OBJECTIVES Chronic hepatitis C (CHC) is now a more curable disease with new direct acting antivirals (DAA). Although high sustained virologic response rates, failures still occur in DAA regimens. Our objective in this study was to characterize the real-life presence of clinically relevant resistance - associated substitutions (RASs) in the HCV NS5A gene in CHC patients whose DAA regimen has failed. METHODS The study enrolled 53 CHC patients who experienced failure with DAA regimen as the prospective longitudinal cohort between 2017-2019. Genotypic resistance testing was performed via the viral population sequencing method and The Geno2pheno HCV tool was used for RAS analysis. RESULTS The most frequent failure category was relapse (88%) followed by non-responder (12%). For a total of 36% of patients, RASs was detected in NS5A, Y93H was the most detected RAS in GT1b infected patients (89%). CONCLUSIONS This study establishes an HCV failure registry for Turkey in which samples were combined with clinical, virologic and molecular data of adult patients whose DAA therapy failed. RASs can occur in CHC patients with DAA treatment failures. Evaluation of RAS after DAA failure is very important before re-treatment is initiated to prevent virologic failure.
Collapse
Affiliation(s)
- Murat Sayan
- Faculty of Medicine, Clinical Laboratory, PCR Unit, University of Kocaeli, Kocaeli, Turkey; Research Center of Experimental Health Sciences, University of Near East, Nicosia, Cyprus.
| | - Figen Sarıgül Yıldırım
- Antalya Education and Research Hospital, Department of Infectious Disease, University of Health Sciences, Antalya, Turkey
| | - Sıla Akhan
- Faculty of Medicine, Department of Infectious Diseases, University of Kocaeli, Kocaeli, Turkey
| | | | - Göktuğ Şirin
- Faculty of Medicine, Department of Gastroenterology, University of Kocaeli, Kocaeli, Turkey
| | - Mehmet Cabalak
- Faculty of Medicine, Department of Infectious Diseases, University of Hatay Mustafa Kemal, Hatay, Turkey
| | - Mehmet Demir
- Faculty of Medicine, Department of Gastroenterology, University of Hatay Mustafa Kemal, Hatay, Turkey
| | - Selver Can
- Konya Education and Research Hospital, Department of Infectious Disease, University of Health Sciences, Konya, Turkey
| | - Gülden Ersöz
- Faculty of Medicine, Department of Infectious Diseases, University of Mersin, Mersin, Turkey
| | - Engin Altıntaş
- Faculty of Medicine, Department of Gastroenterology, University of Mersin, Mersin, Turkey
| | - Fatih Ensaroğlu
- Faculty of Medicine, Department of Gastroenterology, University of İstinye, İstanbul, Turkey
| | - Ayhan Akbulut
- Faculty of Medicine Department of Infectious Disease, University of Fırat, Elazıg, Turkey
| | - Alper Şener
- Faculty of Medicine Department of Infectious Disease, University of Onsekiz Mart, Canakkale, Turkey
| | - Aydın Deveci
- Faculty of Medicine, Department of Infectious Diseases, University of 19 Mayıs, Samsun, Turkey
| |
Collapse
|
|
10
|
Li X, Guo S, Liu Y, Zhang P, Xu B, Li Y, Huang J. Assessment of Bioequivalence and Safety of a Generic Sofosbuvir Product in Healthy Chinese Volunteers under Fasting and Fed Conditions. JOURNAL OF EXPLORATORY RESEARCH IN PHARMACOLOGY 2020; 000:1-7. [DOI: 10.14218/jerp.2020.00003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
|
|
11
|
Tsertsvadze T, Gamkrelidze A, Nasrullah M, Sharvadze L, Morgan J, Shadaker S, Gvinjilia L, Butsashvili M, Metreveli D, Kerashvili V, Ezugbaia M, Chkhartishvili N, Abutidze A, Kvaratskhelia V, Averhoff F. Treatment outcomes of patients with chronic hepatitis C receiving sofosbuvir-based combination therapy within national hepatitis C elimination program in the country of Georgia. BMC Infect Dis 2020; 20:30. [PMID: 31924172 PMCID: PMC6954615 DOI: 10.1186/s12879-019-4741-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 12/27/2019] [Indexed: 12/25/2022] Open
Abstract
Background Georgia has one of the highest HCV prevalence in the world and launched the world’s first national HCV elimination programs in 2015. Georgia set the ambitious target of diagnosing 90% of people living with HCV, treating 95% of those diagnosed and curing 95% of treated patients by 2020. We report outcomes of Sofosbuvir (SOF) based treatment regimens in patients with chronic HCV infection in Georgia. Methods Patients with cirrhosis, advanced liver fibrosis and severe extrahepatic manifestations were enrolled in the treatment program. Initial treatment consisted of SOF plus ribavirin (RBV) with or without pegylated interferon (INF). Sustained virologic response (SVR) was defined as undetectable HCV RNA at least 12 weeks after the end of treatment. SVR were calculated using both per-protocol and modified intent-to-treat (mITT) analysis. Results for patients who completed treatment through 31 October 2018 were analyzed. Results Of the 7342 patients who initiated treatment with SOF-based regimens, 5079 patients were tested for SVR. Total SVR rate was 82.1% in per-protocol analysis and 74.5% in mITT analysis. The lowest response rate was observed among genotype 1 patients (69.5%), intermediate response rate was achieved in genotype 2 patients (81.4%), while the highest response rate was among genotype 3 patients (91.8%). Overall, SOF/RBV regimens achieved lower response rates than IFN/SOF/RBV regimen (72.1% vs 91.3%, P < 0.0001). In multivariate analysis being infected with HCV genotype 2 (RR =1.10, CI [1.05–1.15]) and genotype 3 (RR = 1.14, CI [1.11–1.18]) were associated with higher SVR. Patients with cirrhosis (RR = 0.95, CI [0.93–0.98]), receiving treatment regimens of SOF/RBV 12 weeks, SOF/RBV 20 weeks, SOF/RBV 24 weeks and SOF/RBV 48 weeks (RR = 0.85, CI [0.81–0.91]; RR = 0.86, CI [0.82–0.92]; RR = 0.88, CI [0.85–0.91] and RR = 0.92, CI [0.87–0.98], respectively) were less likely to achieve SVR. Conclusions Georgia’s real world experience resulted in high overall response rates given that most patients had severe liver damage. Our results provide clear evidence that SOF plus IFN and RBV for 12 weeks can be considered a treatment option for eligible patients with all three HCV genotypes. With introduction of next generation DAAs, significantly improved response rates are expected, paving the way for Georgia to achieve HCV elimination goals.
Collapse
Affiliation(s)
- Tengiz Tsertsvadze
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia. .,Ivane Javakhishvili Tbilisi State University, Faculty of Medicine, Tbilisi, Georgia.
| | - Amiran Gamkrelidze
- National Center for Disease control and public health, 99, Kakheti highway, 0198, Tbilisi, Georgia
| | - Muazzam Nasrullah
- Emerging Infections Program, Centers for Disease Control and Prevention (CDC), Division of Viral Hepatitis National Center for HIV, Hepatitis, STD&TB Prevention, Atlanta, USA
| | - Lali Sharvadze
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia.,Ivane Javakhishvili Tbilisi State University, Faculty of Medicine, Tbilisi, Georgia.,Hepatology Clinic HEPA, Tbilisi, Georgia
| | - Juliette Morgan
- Emerging Infections Program, Centers for Disease Control and Prevention (CDC), Division of Viral Hepatitis National Center for HIV, Hepatitis, STD&TB Prevention, Atlanta, USA
| | - Shaun Shadaker
- Emerging Infections Program, Centers for Disease Control and Prevention (CDC), Division of Viral Hepatitis National Center for HIV, Hepatitis, STD&TB Prevention, Atlanta, USA
| | - Lia Gvinjilia
- CDC Foundation, Georgia Hepatitis C Elimination Program, Tbilisi, Georgia
| | | | | | - Vakhtang Kerashvili
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia
| | - Marina Ezugbaia
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia
| | | | - Akaki Abutidze
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia
| | | | - Francisco Averhoff
- Emerging Infections Program, Centers for Disease Control and Prevention (CDC), Division of Viral Hepatitis National Center for HIV, Hepatitis, STD&TB Prevention, Atlanta, USA
| |
Collapse
|
|
12
|
Haqqi A, Munir R, Khalid M, Khurram M, Zaid M, Ali M, Shah ZH, Ahmed H, Afzal MS. Prevalence of Hepatitis C Virus Genotypes in Pakistan: Current Scenario and Review of Literature. Viral Immunol 2019; 32:402-413. [PMID: 31556811 DOI: 10.1089/vim.2019.0058] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is a major public health concern globally, resulting in liver-related complications. Approximately 6% population of Pakistan is infected with HCV. HCV is error prone, due to which it is classified into 7 genotypes and 67 subtypes. HCV genotype determination is critical for treatment and therapy response. In this study, 3,539 samples were collected from 2015 to 2019 from all over Punjab. RNA was extracted from samples using QIA Amp Viral RNA MINI kit (Qiagen, Germany) and viral genotyping was performed. Furthermore, a systemized literature search (2009-2018) was done to analyze the HCV genotype distribution pattern in Pakistan. In Punjab, genotype 3a (86.46%) is most prevalent, followed by untypable (7.17%) and genotype 1a (3.84%) and 3b (1.04%). Mixed genotype constitutes only 0.67% of total infections. Genotype 2a, 2b, 3c, and 4 were found to be rare. Data available from literature review when compiled showed that HCV genotype 3a (58.16%) was predominant in Pakistan, followed by genotypes 3b (9.05%), 2a (6.70%), 1a (6.22%), and 1b (2.39%). The frequency of mixed genotypes was found to be 4% and 12% of untypable HCV variants. This study highlights the HCV genotype distribution pattern in different regions of Pakistan. Therapy response and disease management depend on genotype, so HCV genotype determination is crucial. In Pakistan, the most prevalent genotype is 3a, followed by untypable genotype. Both interferon and sofosbuvir are effective against genotype 3a, but treatment with sofosbuvir has comparatively high sustained virological response, less adverse effects, and more tolerability.
Collapse
Affiliation(s)
- Aleena Haqqi
- Department of Life Sciences, School of Science, University of Management and Technology (UMT), Lahore, Pakistan
| | - Rimsha Munir
- Cancer Biology Lab, MMG, University of the Punjab, Lahore, Pakistan
- Hormone Lab, Lahore, Pakistan
| | | | - Muhammad Khurram
- Department of Life Sciences, School of Science, University of Management and Technology (UMT), Lahore, Pakistan
| | - Muhammad Zaid
- Department of Life Sciences, School of Science, University of Management and Technology (UMT), Lahore, Pakistan
| | - Muhammad Ali
- Department of Life Sciences, School of Science, University of Management and Technology (UMT), Lahore, Pakistan
| | - Zaheer Hussain Shah
- Department of Life Sciences, School of Science, University of Management and Technology (UMT), Lahore, Pakistan
| | - Haroon Ahmed
- Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan
| | - Muhammad Sohail Afzal
- Department of Life Sciences, School of Science, University of Management and Technology (UMT), Lahore, Pakistan
| |
Collapse
|
|
13
|
Han B, Martin R, Xu S, Parvangada A, Svarovskaia ES, Mo H, Dvory-Sobol H. Sofosbuvir susceptibility of genotype 1 to 6 HCV from DAA-naïve subjects. Antiviral Res 2019; 170:104574. [PMID: 31394118 DOI: 10.1016/j.antiviral.2019.104574] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 07/23/2019] [Accepted: 07/26/2019] [Indexed: 12/12/2022]
Abstract
High sequence diversity of HCV may lead to variation in susceptibility to antiviral agents amongst different genotypes and subtypes of the virus. We assessed the susceptibility to sofosbuvir of chimeric replicons carrying the full length NS5B coding region from 479 HCV infected, treatment-naïve patients, including 15 subtypes in 6 genotypes. NS5B replicon vectors with subtype 1b, subtype 4a and subtype 6a backbone were modified to support testing of patient samples. We also evaluated sofosbuvir susceptibility in a panel of 331 replicons containing engineered NS5B inhibitor resistance-associated substitutions. The mean 50% effective sofosbuvir concentration (EC50) amongst different genotypes ranged from 32 (subtype 2a) to 130 nM (genotype 4); while some variation in susceptibility amongst patient isolates was observed, the 95th percentile for any genotype did not exceed 189 nM. Levels of resistance to sofosbuvir in replicons containing S282T were between 2.4 and 18 fold-change in EC50; no other single NS5B resistance-associated substitution demonstrated reduced sofosbuvir susceptibility. These data suggest that S282T is the only known substitution that confers detectable resistance to sofosbuvir in vitro. Sofosbuvir displayed potent antiviral activity across a diverse range of NS5B mutants and HCV clinical isolates in multiple subtypes of genotypes 1 to 6.
Collapse
Affiliation(s)
- Bin Han
- Gilead Sciences, Foster City, CA, USA
| | | | - Simin Xu
- Gilead Sciences, Foster City, CA, USA
| | | | | | | | | |
Collapse
|
|
14
|
Jansen JW, Linneman TW, Powderly GM, Moenster RP, Nayak L. Association Between Baseline Creatinine Clearance and Treatment Failure in Patients With Hepatitis C Virus Treated With Ledipasvir and Sofosbuvir. Open Forum Infect Dis 2019; 6:ofz087. [PMID: 30949530 DOI: 10.1093/ofid/ofz087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 02/15/2019] [Indexed: 11/14/2022] Open
Abstract
Background Hepatitis C remains a major cause of liver disease globally and is responsible for approximately 500 000 deaths annually. Newer direct-acting antivirals achieve cure rates at or above 90% with excellent tolerability for most patients. The literature focusing on identification of predictors of efficacy and safety with specific hepatitis C therapies has been inconclusive and often conflicting. Methods A retrospective, single-center, case-control analysis of all veteran patients aged ≥18 through ≤89 years who completed a treatment course of 8, 12, or 24 weeks with ledipasvir and sofosbuvir (LDV/SOF) combination therapy for hepatitis C infection was conducted. Patients who were identified and met inclusion criteria were assigned to either the case group (SVR12 failure; hepatitis C viral load detectable at least 11 weeks after therapy completion) or the control group (SVR12 success; hepatitis C viral load undetectable at least 11 weeks after therapy completion). Results Twenty-nine SVR12 failures and 411 SVR12 successes were included in the analysis. The overall failure rate was consistent with the current literature, at 6.6% (29/440). Bivariate analysis identified only baseline creatinine clearance >80 mL min-1 (Cockcroft-Gault) as a possible predictor of SVR12 failure (P = .026). In the multivariate analysis, pretreatment creatinine clearance >80 mL min-1 remained independently associated with SVR12 failure (odds ratio, 2.95; 95% confidence interval, 1.17-7.46; P = .023). Conclusions In hepatitis C patients treated with LDV/SOF, a pretreatment creatinine clearance of >80 mL min-1 was associated with SVR12 failure.
Collapse
Affiliation(s)
- Jeffrey W Jansen
- Department of Research, VA Saint Louis Health Care System, St. Louis, Missouri.,Department of Pharmacy, SCL St. Vincent Healthcare, Billings, Montana
| | - Travis W Linneman
- Department of Pharmacy, VA Saint Louis Health Care System, St. Louis, Missouri
| | - Gillian M Powderly
- Department of Pharmacy, VA Saint Louis Health Care System, St. Louis, Missouri
| | - Ryan P Moenster
- Department of Pharmacy, VA Saint Louis Health Care System, St. Louis, Missouri.,Department of Pharmacy Practice, Saint Louis College of Pharmacy, St. Louis, Missouri
| | - Leela Nayak
- Department of Gastroenterology, Southeastern Louisiana Veterans Healthcare System, New Orleans, Louisiana
| |
Collapse
|
|
15
|
Shen Z, Zhu X, Zhang H, Chen H, Niu J, Chen G, Li X, Ding Y. Pharmacokinetic Profile of a Generic Formulation of Sofosbuvir and Its Metabolite GS-331007 in Healthy Chinese Subjects. Clin Pharmacol Drug Dev 2019; 8:1073-1080. [PMID: 30900816 DOI: 10.1002/cpdd.674] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 02/26/2019] [Indexed: 01/08/2023]
Abstract
Sofosbuvir is an NS5B nucleotide inhibitor for the treatment of hepatitis C viral infection. In this study the pharmacokinetics (PK) and safety of single and multiple doses of generic sofosbuvir were investigated in healthy Chinese subjects. Twelve subjects (6 male and 6 female) were enrolled in this study. The PK parameters of sofosbuvir and its metabolite (GS-331007) in both blood and urine samples were analyzed after dosing by the established liquid chromatography tandem mass spectrometry analytical method. The safety/tolerability assessment consisted of documenting adverse events, vital signs, electrocardiogram, and laboratory test results. Sofosbuvir was well tolerated. Major PK parameters of the generic formulation of sofosbuvir were similar to those found in previous reports. These data support further clinical evaluation of this generic formulation of sofosbuvir.
Collapse
Affiliation(s)
- Zhenwei Shen
- Institute of Immunology, Academy of Translational Medicine, The First Hospital of Jilin University, Jilin University, Changchun, People's Republic of China
| | - Xiaoxue Zhu
- Phase I Clinical Trial Unit, China-Frontage USA, The First Hospital of Jilin University, Jilin University, Changchun, People's Republic of China
| | - Hong Zhang
- Phase I Clinical Trial Unit, China-Frontage USA, The First Hospital of Jilin University, Jilin University, Changchun, People's Republic of China
| | - Hong Chen
- Phase I Clinical Trial Unit, China-Frontage USA, The First Hospital of Jilin University, Jilin University, Changchun, People's Republic of China
| | - Junqi Niu
- Phase I Clinical Trial Unit, China-Frontage USA, The First Hospital of Jilin University, Jilin University, Changchun, People's Republic of China
| | - Guiling Chen
- Phase I Clinical Trial Unit, China-Frontage USA, The First Hospital of Jilin University, Jilin University, Changchun, People's Republic of China
| | - Xiaojiao Li
- Phase I Clinical Trial Unit, China-Frontage USA, The First Hospital of Jilin University, Jilin University, Changchun, People's Republic of China
| | - Yanhua Ding
- Phase I Clinical Trial Unit, China-Frontage USA, The First Hospital of Jilin University, Jilin University, Changchun, People's Republic of China
| |
Collapse
|
|
16
|
Evaluation of Direct Acting Antivirals Efficiency in Turkish Patients with Chronic Hepatitis C Under Strict Rules. HEPATITIS MONTHLY 2019. [DOI: 10.5812/hepatmon.62390] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
|
|
17
|
Abdel-Moneim A, Abood A, Abdel-Gabaar M, Zanaty MI, Ramadan M. Effectiveness of sofosbuvir/pegylated-interferon plus ribavirin in treatment of hepatitis C virus genotype 4 patients. Clin Exp Hepatol 2018; 4:191-196. [PMID: 30324144 PMCID: PMC6185926 DOI: 10.5114/ceh.2018.78123] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 03/12/2018] [Indexed: 12/22/2022] Open
Abstract
INTRODUCTION New regimens involving direct-acting antiviral agents (DAAs) have recently been approved for the treatment of hepatitis C virus (HCV) genotype 4 (GT4). The current study aims to assess the efficacy and safety of sofosbuvir (SOF) with pegylated interferon (PegINF)/ribavirin (RBV) for chronic HCV GT4 patients at the beginning of the interferon-free era. MATERIAL AND METHODS Between March 2015 and November 2015, 99 patients (59 naïve and 40 experienced) infected with HCV GT4 were enrolled in the study. Eligible patients received daily oral 400 mg SOF, RBV (body weight: < 75 kg, 1000 mg; < 75 kg, 1200 mg), the dose modified according to patient tolerability, plus 180 μg PegINFα-2 once weekly for 12 weeks. RESULTS Among the patient cohort, sustained virological response 12 weeks after the end of treatment (SVR12) was achieved by 88% (87/99) of all patients, by 93% (55/59) of naïve patients and by 80% (32/40) of experienced patients. Regarding treatment failure, the data recorded 12% (12/99) of patients (4 null responses and 8 relapsers). Otherwise, the most common adverse events observed during the study included headache, nausea, fatigue, dyspnea, influenza-like illness, anemia, and leukopenia. CONCLUSIONS SOF combination-based therapies were considered promising choice regimens for chronic HCV infection. The present findings suggest that the combination of the SOF/PegINF/RBV regimen was effective for Egyptian patients with HCV GT4. The recorded adverse events and viral outcome revealed the high need for further efforts to minimize the side effects of the current regimen and/or replace PegINF with additional potent DAA(s) to increase SVR12 to achieve 100%.
Collapse
Affiliation(s)
- Adel Abdel-Moneim
- Molecular Physiology Division, Faculty of Science, Beni-Suef University, Egypt
| | - Alaa Abood
- Tropical Medicine Department, Faculty of Medicine, Beni-Suef University, Egypt
| | - Mohamed Abdel-Gabaar
- Biochemistry Division, Chemistry Department, Faculty of Science, Beni-Suef University, Egypt
| | - Mohamed I. Zanaty
- Biotechnology Department, Postgraduate Studies for Advanced Science, Beni-Suef University, Egypt
| | - Mohamed Ramadan
- Biochemistry Division, Chemistry Department, Faculty of Science, Beni-Suef University, Egypt
| |
Collapse
|
|
18
|
Rezk MR, Basalious EB, Badr KA. Novel determination of sofosbuvir and velpatasvir in human plasma by UPLC-MS/MS method: Application to a bioequivalence study. Biomed Chromatogr 2018; 32:e4347. [PMID: 30047564 DOI: 10.1002/bmc.4347] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 06/09/2018] [Accepted: 07/17/2018] [Indexed: 11/08/2022]
Abstract
A novel and sensitive LC-MS/MS method was developed, optimized and validated for quantification of sofosbuvir (SOF) and velpatasvir (VEL) in human plasma using ledipasvir as an internal standard (IS). Sample preparation was done using acetonitrile for precipitation of plasma proteins. Chromatographic analysis was done on an Acquity UPLC BEH C18 column using 0.1% formic acid and acetonitrile as a mobile phase. The Xevo TQD LC-MS/MS system was run with electrospray ionization mode. The developed method was optimized and then validated according to the US Food and Drug Administration guidelines. Linearity was found to be in the range of 0.25-3500 ng/mL for SOF and 1-1000 ng/mL for VEL. A short run time of 1.5 min allows swift analysis of many plasma samples per day. The developed method was successfully utilized for estimating both SOF and VEL in the plasma of healthy human volunteers participated in a bioequivalence study.
Collapse
Affiliation(s)
- Mamdouh R Rezk
- Analytical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Emad B Basalious
- Pharmaceutics and Industrial Pharmacy Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Kamal A Badr
- Pharmaceutics Department, Faculty of Pharmacy, Deraya University, Egypt.,Advanced Research Center, Nasr City, Cairo, Egypt
| |
Collapse
|
|
19
|
Drug Interchangeability of Generic and Brand Products of Fixed Dose Combination Tablets of Sofosbuvir and Ledipasvir (400/90 mg): Employment of Reference Scaled Average Bioequivalence Study on Healthy Egyptian Volunteers. Clin Drug Investig 2018; 38:439-448. [PMID: 29417463 DOI: 10.1007/s40261-018-0622-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND OBJECTIVES The purpose of this study was to apply the reference-scaled average bioequivalence (RSABE) approach to evaluate the bioequivalence and to investigate the pharmacokinetic properties of two formulations of fixed dose combination (FDC) tablet of sofosbuvir (SOF) and ledipasvir (LED) (400/90 mg) in 36 healthy Egyptian volunteers. METHODS The study was performed in single-dose, randomized-sequence, open-label, reference-replicated, 3-period crossover design (RTR, TRR, RRT), with a washout period of 2 weeks. A rapid and simple LC-MS/MS method was developed and validated for the simultaneous estimation of SOF and LED using eplerenone as an internal standard (IS). RESULTS The results showed that the 90% confidence intervals (CIs) for natural log-transformed ratios of Cmax, AUClast and AUC∞ of SOF (89.95-115.31, 98.77-109.75 and 98.79-109.75) were within the RSABE acceptance limits. The 90% CIs for natural log-transformed ratios of Cmax and AUClast of LED (87.33-115.15 and 83.82-112.26) were within the FDA bioequivalence limits (80.00-125.00). In addition, the in vitro dissolution study was done and both formulations released > 85% of drug within 15 min in the proposed dissolution medium. CONCLUSIONS In conclusion, bioequivalence between the two fixed-dose combination products was demonstrated for both active ingredients.
Collapse
|
|
20
|
Removal of the C6 Vaccinia Virus Interferon-β Inhibitor in the Hepatitis C Vaccine Candidate MVA-HCV Elicited in Mice High Immunogenicity in Spite of Reduced Host Gene Expression. Viruses 2018; 10:v10080414. [PMID: 30096846 PMCID: PMC6116028 DOI: 10.3390/v10080414] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 08/03/2018] [Accepted: 08/07/2018] [Indexed: 12/19/2022] Open
Abstract
Hepatitis C virus (HCV) represents a major global health problem for which a vaccine is not available. Modified vaccinia virus Ankara (MVA)-HCV is a unique HCV vaccine candidate based in the modified vaccinia virus Ankara (MVA) vector expressing the nearly full-length genome of HCV genotype 1a that elicits CD8⁺ T-cell responses in mice. With the aim to improve the immune response of MVA-HCV and because of the importance of interferon (IFN) in HCV infection, we deleted in MVA-HCV the vaccinia virus (VACV) C6L gene, encoding an inhibitor of IFN-β that prevents activation of the interferon regulatory factors 3 and 7 (IRF3 and IRF7). The resulting vaccine candidate (MVA-HCV ΔC6L) expresses all HCV antigens and deletion of C6L had no effect on viral growth in permissive chicken cells. In human monocyte-derived dendritic cells, infection with MVA-HCV ΔC6L triggered severe down-regulation of IFN-β, IFN-β-induced genes, and cytokines in a manner similar to MVA-HCV, as defined by real-time polymerase chain reaction (PCR) and microarray analysis. In infected mice, both vectors had a similar profile of recruited immune cells and induced comparable levels of adaptive and memory HCV-specific CD8⁺ T-cells, mainly against p7 + NS2 and NS3 HCV proteins, with a T cell effector memory (TEM) phenotype. Furthermore, antibodies against E2 were also induced. Overall, our findings showed that while these vectors had a profound inhibitory effect on gene expression of the host, they strongly elicited CD8⁺ T cell and humoral responses against HCV antigens and to the virus vector. These observations add support to the consideration of these vectors as potential vaccine candidates against HCV.
Collapse
|
|
21
|
Rattanavipapong W, Anothaisintawee T, Teerawattananon Y. Revisiting policy on chronic HCV treatment under the Thai Universal Health Coverage: An economic evaluation and budget impact analysis. PLoS One 2018; 13:e0193112. [PMID: 29466415 PMCID: PMC5821370 DOI: 10.1371/journal.pone.0193112] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 02/05/2018] [Indexed: 12/15/2022] Open
Abstract
Thailand is encountering challenges to introduce the high-cost sofosbuvir for chronic hepatitis C treatment as part of the Universal Health Care's benefit package. This study was conducted in respond to policy demand from the Thai government to assess the value for money and budget impact of introducing sofosbuvir-based regimens in the tax-based health insurance scheme. The Markov model was constructed to assess costs and benefits of the four treatment options that include: (i) current practice-peginterferon alfa (PEG) and ribavirin (RBV) for 24 weeks in genotype 3 and 48 weeks for other genotypes; (ii) Sofosbuvir plus peginterferon alfa and ribavirin (SOF+PEG-RBV) for 12 weeks; (iii) Sofosbuvir and daclatasvir (SOF+DCV) for 12 weeks; (iv) Sofosbuvir and ledipasvir (SOF+LDV) for 12 weeks for non-3 genotypes and SOF+PEG-RBV for 12 weeks for genotype 3 infection. Given that policy options (ii) and (iii) are for pan-genotypic infection, the cost of genotype testing was applied only for policy options (i) and (iv). Results reveal that all sofosbuvir-based regimens had greater quality adjusted life years (QALY) gains compared with the current treatment, therefore associated with lower lifetime costs and more favourable health outcomes. Additionally, among the three regimens of sofosbuvir, SOF+PEG-RBV for genotype 3 and SOF+LDV for non-3 genotype are the most cost-effective treatment option with the threshold of 160,000 THB per QALY gained. The results of this study had been used in policy discussion which resulted in the recent inclusion of SOF+PEG-RBV for genotype 3 and SOF+LDV for non-3 genotype in the Thailand's benefit package.
Collapse
Affiliation(s)
- Waranya Rattanavipapong
- Health Intervention and Technology Assessment Program (HITAP), Department of Health, Ministry of Public Health, Nonthaburi, Thailand
| | - Thunyarat Anothaisintawee
- Health Intervention and Technology Assessment Program (HITAP), Department of Health, Ministry of Public Health, Nonthaburi, Thailand
- Department of Family Medicine, Faculty of Medicine, Ramathibodi Hospital, Bangkok, Thailand
| | - Yot Teerawattananon
- Health Intervention and Technology Assessment Program (HITAP), Department of Health, Ministry of Public Health, Nonthaburi, Thailand
| |
Collapse
|
|
22
|
Slusarczyk M, Serpi M, Pertusati F. Phosphoramidates and phosphonamidates (ProTides) with antiviral activity. Antivir Chem Chemother 2018; 26:2040206618775243. [PMID: 29792071 PMCID: PMC5971382 DOI: 10.1177/2040206618775243] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Accepted: 04/09/2018] [Indexed: 12/15/2022] Open
Abstract
Following the first report on the nucleoside phosphoramidate (ProTide) prodrug approach in 1990 by Chris McGuigan, the extensive investigation of ProTide technology has begun in many laboratories. Designed with aim to overcome limitations and the key resistance mechanisms associated with nucleoside analogues used in the clinic (poor cellular uptake, poor conversion to the 5'-monophosphate form), the ProTide approach has been successfully applied to a vast number of nucleoside analogues with antiviral and anticancer activity. ProTides consist of a 5'-nucleoside monophosphate in which the two hydroxyl groups are masked with an amino acid ester and an aryloxy component which once in the cell is enzymatically metabolized to deliver free 5'-monophosphate, which is further transformed to the active 5'-triphosphate form of the nucleoside analogue. In this review, the seminal contribution of Chris McGuigan's research to this field is presented. His technology proved to be extremely successful in drug discovery and has led to two Food and Drug Administration-approved antiviral agents.
Collapse
Affiliation(s)
| | - Michaela Serpi
- School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK
| | - Fabrizio Pertusati
- School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK
| |
Collapse
|
|
23
|
Gewaid H, Mesalam AA, Ibrahim AA, Abdel Shafy DN, Abdel Shafy RN, Emara N, Hamdy SM, Gewaid M, Bahgat MM. Establishment of a platform for molecular and immunological characterization of the RNA-dependent-RNA-polymerase NS5B of an Egyptian HCV isolate. J Med Virol 2017; 90:545-558. [PMID: 29064582 DOI: 10.1002/jmv.24977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2017] [Accepted: 10/16/2017] [Indexed: 11/09/2022]
Abstract
The present work aimed at establishing a platform to enable frequent characterization of the HCV RNA-dependent-RNA-polymerase from Egyptian clinical isolates. Subjecting amplified HCV-NS5B coding gene from Egyptian patient's serum to sequencing, multiple alignment, and phylogenetic analysis confirmed its subtype 4a origin. Nucleotide sequence analysis revealed presence of an additional start codon at the beginning of the NS5B gene. Peptide sequence alignment demonstrated presence of unique amino acid residues in our 4a-NS5B sequence distinct from the JFH-1-NS5B sequence as well as unique amino acids compared to other genotypes. The distinct molecular structure of the herein characterized 4a-NS5B from the 2a-JFH-1-NS5B was further demonstrated both in the built 3D models and the Ramachandran plots corresponding to each structure. Both the unique amino acid residues and 3D structure of the 4a-NS5B may influence both genotype 4a replication rate and response to therapy in comparison to other genotypes. Many resistance mutations to polymerase inhibitors were found both in ours and other genotypes' sequences. The presence of the required amino acid motifs for the RNA dependent RNA polymerase activity encouraged to clone the NS5B570-encoding sequence downstream CMV promotor in a mammalian expression vector. Such construct was used for both prokaryotic expression in bacteria and for DNA immunization. Successful mammalian expression and induction of specific immune response were demonstrated by ELISA and Western blotting. The potential of both the raised antibodies and the expressed NS5B to differentiate between HCV-infected and control human sera were demonstrated which reflect their diagnostic value.
Collapse
Affiliation(s)
- Hossam Gewaid
- Research Group Immune- and Bio-markers for Infection, the Center of Excellence for Advanced Sciences, the National Research Center, Cairo, Egypt.,Therapeutic Chemistry Department, the National Research Center, Cairo, Egypt
| | - Ahmed A Mesalam
- Research Group Immune- and Bio-markers for Infection, the Center of Excellence for Advanced Sciences, the National Research Center, Cairo, Egypt.,Therapeutic Chemistry Department, the National Research Center, Cairo, Egypt
| | - Ahmed A Ibrahim
- Research Group Immune- and Bio-markers for Infection, the Center of Excellence for Advanced Sciences, the National Research Center, Cairo, Egypt.,Therapeutic Chemistry Department, the National Research Center, Cairo, Egypt
| | - Dina N Abdel Shafy
- Research Group Immune- and Bio-markers for Infection, the Center of Excellence for Advanced Sciences, the National Research Center, Cairo, Egypt.,Water Pollution Research Department, the National Research Center, Cairo, Egypt
| | - Rola N Abdel Shafy
- Research Group Immune- and Bio-markers for Infection, the Center of Excellence for Advanced Sciences, the National Research Center, Cairo, Egypt.,Therapeutic Chemistry Department, the National Research Center, Cairo, Egypt
| | - Nahed Emara
- Clinical and Chemical Pathology Department, the National Research Center, Cairo, Egypt
| | - Soha M Hamdy
- Division of Biochemistry, Faculty of Science, Fayoum University, Cairo, Egypt
| | | | - Mahmoud M Bahgat
- Research Group Immune- and Bio-markers for Infection, the Center of Excellence for Advanced Sciences, the National Research Center, Cairo, Egypt.,Therapeutic Chemistry Department, the National Research Center, Cairo, Egypt
| |
Collapse
|
|
24
|
Jakobsen JC, Nielsen EE, Feinberg J, Katakam KK, Fobian K, Hauser G, Poropat G, Djurisic S, Weiss KH, Bjelakovic M, Bjelakovic G, Klingenberg SL, Liu JP, Nikolova D, Koretz RL, Gluud C. Direct-acting antivirals for chronic hepatitis C. Cochrane Database Syst Rev 2017; 9:CD012143. [PMID: 28922704 PMCID: PMC6484376 DOI: 10.1002/14651858.cd012143.pub3] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Millions of people worldwide suffer from hepatitis C, which can lead to severe liver disease, liver cancer, and death. Direct-acting antivirals (DAAs), e.g. sofosbuvir, are relatively new and expensive interventions for chronic hepatitis C, and preliminary results suggest that DAAs may eradicate hepatitis C virus (HCV) from the blood (sustained virological response). Sustained virological response (SVR) is used by investigators and regulatory agencies as a surrogate outcome for morbidity and mortality, based solely on observational evidence. However, there have been no randomised trials that have validated that usage. OBJECTIVES To assess the benefits and harms of DAAs in people with chronic HCV. SEARCH METHODS We searched for all published and unpublished trials in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, LILACS, and BIOSIS; the Chinese Biomedical Literature Database (CBM), China Network Knowledge Information (CNKI), the Chinese Science Journal Database (VIP), Google Scholar, The Turning Research into Practice (TRIP) Database, ClinicalTrials.gov, European Medicines Agency (EMA) (www.ema.europa.eu/ema/), WHO International Clinical Trials Registry Platform (www.who.int/ictrp), the Food and Drug Administration (FDA) (www.fda.gov), and pharmaceutical company sources for ongoing or unpublished trials. Searches were last run in October 2016. SELECTION CRITERIA Randomised clinical trials comparing DAAs versus no intervention or placebo, alone or with co-interventions, in adults with chronic HCV. We included trials irrespective of publication type, publication status, and language. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. Our primary outcomes were hepatitis C-related morbidity, serious adverse events, and health-related quality of life. Our secondary outcomes were all-cause mortality, ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, hepatocellular carcinoma, non-serious adverse events (each reported separately), and SVR. We systematically assessed risks of bias, performed Trial Sequential Analysis, and followed an eight-step procedure to assess thresholds for statistical and clinical significance. We evaluated the overall quality of the evidence, using GRADE. MAIN RESULTS We included a total of 138 trials randomising a total of 25,232 participants. The trials were generally short-term trials and designed primarily to assess the effect of treatment on SVR. The trials evaluated 51 different DAAs. Of these, 128 trials employed matching placebo in the control group. All included trials were at high risk of bias. Eighty-four trials involved DAAs on the market or under development (13,466 participants). Fifty-seven trials administered DAAs that were discontinued or withdrawn from the market. Study populations were treatment-naive in 95 trials, had been exposed to treatment in 17 trials, and comprised both treatment-naive and treatment-experienced individuals in 24 trials. The HCV genotypes were genotype 1 (119 trials), genotype 2 (eight trials), genotype 3 (six trials), genotype 4 (nine trials), and genotype 6 (one trial). We identified two ongoing trials.We could not reliably determine the effect of DAAs on the market or under development on our primary outcome of hepatitis C-related morbidity or all-cause mortality. There were no data on hepatitis C-related morbidity and only limited data on mortality from 11 trials (DAA 15/2377 (0.63%) versus control 1/617 (0.16%); OR 3.72, 95% CI 0.53 to 26.18, very low-quality evidence). We did not perform Trial Sequential Analysis on this outcome.There is very low quality evidence that DAAs on the market or under development do not influence serious adverse events (DAA 5.2% versus control 5.6%; OR 0.93, 95% CI 0.75 to 1.15 , 15,817 participants, 43 trials). The Trial Sequential Analysis showed that there was sufficient information to rule out that DAAs reduce the relative risk of a serious adverse event by 20% when compared with placebo. The only DAA that showed a lower risk of serious adverse events when meta-analysed separately was simeprevir (OR 0.62, 95% CI 0.45 to 0.86). However, Trial Sequential Analysis showed that there was not enough information to confirm or reject a relative risk reduction of 20%, and when one trial with an extreme result was excluded, the meta-analysis result showed no evidence of a difference.DAAs on the market or under development may reduce the risk of no SVR from 54.1% in untreated people to 23.8% in people treated with DAA (RR 0.44, 95% CI 0.37 to 0.52, 6886 participants, 32 trials, low quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.Only 1/84 trials on the market or under development assessed the effects of DAAs on health-related quality of life (SF-36 mental score and SF-36 physical score).There was insufficient evidence from trials on withdrawn or discontinued DAAs to determine their effect on hepatitis C-related morbidity and all-cause mortality (OR 0.64, 95% CI 0.23 to 1.79; 5 trials, very low-quality evidence). However, these DAAs seemed to increase the risk of serious adverse events (OR 1.45, 95% CI 1.22 to 1.73; 29 trials, very low-quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.None of the 138 trials provided useful data to assess the effects of DAAs on the remaining secondary outcomes (ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, and hepatocellular carcinoma). AUTHORS' CONCLUSIONS The evidence for our main outcomes of interest come from short-term trials, and we are unable to determine the effect of long-term treatment with DAAs. The rates of hepatitis C morbidity and mortality observed in the trials are relatively low and we are uncertain as to how DAAs affect this outcome. Overall, there is very low quality evidence that DAAs on the market or under development do not influence serious adverse events. There is insufficient evidence to judge if DAAs have beneficial or harmful effects on other clinical outcomes for chronic HCV. Simeprevir may have beneficial effects on risk of serious adverse event. In all remaining analyses, we could neither confirm nor reject that DAAs had any clinical effects. DAAs may reduce the number of people with detectable virus in their blood, but we do not have sufficient evidence from randomised trials that enables us to understand how SVR affects long-term clinical outcomes. SVR is still an outcome that needs proper validation in randomised clinical trials.
Collapse
Affiliation(s)
- Janus C Jakobsen
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenSjællandDenmarkDK‐2100
- Holbaek HospitalDepartment of CardiologyHolbaekDenmark4300
| | - Emil Eik Nielsen
- Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention ResearchBlegdamsvej 9CopenhagenDenmark2100
| | - Joshua Feinberg
- Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812Blegdamsvej 9CopenhagenDenmark2100
| | - Kiran Kumar Katakam
- Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812Blegdamsvej 9CopenhagenDenmark2100
| | - Kristina Fobian
- Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention ResearchBlegdamsvej 9CopenhagenDenmark2100
| | - Goran Hauser
- Clinical Hospital Centre RijekaDepartment of GastroenterologyKresimirova 42RijekaCroatia51 000
| | - Goran Poropat
- Clinical Hospital Centre RijekaDepartment of GastroenterologyKresimirova 42RijekaCroatia51 000
| | - Snezana Djurisic
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagenDenmark
| | - Karl Heinz Weiss
- Heidelberg University HospitalInternal Medicine IV: Gastroenterology, Infectious Diseases, ToxicologyIm Neuenheimer Feld 410HeidelbergGermanyD‐69120
| | - Milica Bjelakovic
- University of NisMedical FacultyBoulevard Dr Zorana Djindjica 81NisSerbia18000
| | - Goran Bjelakovic
- Medical Faculty, University of NisDepartment of Internal MedicineZorana Djindjica 81NisSerbia18000
| | - Sarah Louise Klingenberg
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenSjællandDenmarkDK‐2100
| | - Jian Ping Liu
- Beijing University of Chinese MedicineCentre for Evidence‐Based Chinese Medicine11 Bei San Huan Dong Lu, Chaoyang DistrictBeijingChina100029
| | - Dimitrinka Nikolova
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenSjællandDenmarkDK‐2100
| | | | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenSjællandDenmarkDK‐2100
| | | |
Collapse
|
|
25
|
Jakobsen JC, Nielsen EE, Feinberg J, Katakam KK, Fobian K, Hauser G, Poropat G, Djurisic S, Weiss KH, Bjelakovic M, Bjelakovic G, Klingenberg SL, Liu JP, Nikolova D, Koretz RL, Gluud C. Direct-acting antivirals for chronic hepatitis C. Cochrane Database Syst Rev 2017; 9:CD012143. [PMID: 28922704 PMCID: PMC6484383 DOI: 10.1002/14651858.cd012143.pub2] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Millions of people worldwide suffer from hepatitis C, which can lead to severe liver disease, liver cancer, and death. Direct-acting antivirals (DAAs), e.g. sofosbuvir, are relatively new and expensive interventions for chronic hepatitis C, and preliminary results suggest that DAAs may eradicate hepatitis C virus (HCV) from the blood (sustained virological response). Sustained virological response (SVR) is used by investigators and regulatory agencies as a surrogate outcome for morbidity and mortality, based solely on observational evidence. However, there have been no randomised trials that have validated that usage. OBJECTIVES To assess the benefits and harms of DAAs in people with chronic HCV. SEARCH METHODS We searched for all published and unpublished trials in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, LILACS, and BIOSIS; the Chinese Biomedical Literature Database (CBM), China Network Knowledge Information (CNKI), the Chinese Science Journal Database (VIP), Google Scholar, The Turning Research into Practice (TRIP) Database, ClinicalTrials.gov, European Medicines Agency (EMA) (www.ema.europa.eu/ema/), WHO International Clinical Trials Registry Platform (www.who.int/ictrp), the Food and Drug Administration (FDA) (www.fda.gov), and pharmaceutical company sources for ongoing or unpublished trials. Searches were last run in October 2016. SELECTION CRITERIA Randomised clinical trials comparing DAAs versus no intervention or placebo, alone or with co-interventions, in adults with chronic HCV. We included trials irrespective of publication type, publication status, and language. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. Our primary outcomes were hepatitis C-related morbidity, serious adverse events, and health-related quality of life. Our secondary outcomes were all-cause mortality, ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, hepatocellular carcinoma, non-serious adverse events (each reported separately), and SVR. We systematically assessed risks of bias, performed Trial Sequential Analysis, and followed an eight-step procedure to assess thresholds for statistical and clinical significance. We evaluated the overall quality of the evidence, using GRADE. MAIN RESULTS We included a total of 138 trials randomising a total of 25,232 participants. The trials were generally short-term trials and designed primarily to assess the effect of treatment on SVR. The trials evaluated 51 different DAAs. Of these, 128 trials employed matching placebo in the control group. All included trials were at high risk of bias. Eighty-four trials involved DAAs on the market or under development (13,466 participants). Fifty-seven trials administered DAAs that were discontinued or withdrawn from the market. Study populations were treatment-naive in 95 trials, had been exposed to treatment in 17 trials, and comprised both treatment-naive and treatment-experienced individuals in 24 trials. The HCV genotypes were genotype 1 (119 trials), genotype 2 (eight trials), genotype 3 (six trials), genotype 4 (nine trials), and genotype 6 (one trial). We identified two ongoing trials.We could not reliably determine the effect of DAAs on the market or under development on our primary outcome of hepatitis C-related morbidity or all-cause mortality. There were no data on hepatitis C-related morbidity and only limited data on mortality from 11 trials (DAA 15/2377 (0.63%) versus control 1/617 (0.16%); OR 3.72, 95% CI 0.53 to 26.18, very low-quality evidence). We did not perform Trial Sequential Analysis on this outcome.There is very low quality evidence that DAAs on the market or under development do not influence serious adverse events (DAA 5.2% versus control 5.6%; OR 0.93, 95% CI 0.75 to 1.15 , 15,817 participants, 43 trials). The Trial Sequential Analysis showed that there was sufficient information to rule out that DAAs reduce the relative risk of a serious adverse event by 20% when compared with placebo. The only DAA that showed a lower risk of serious adverse events when meta-analysed separately was simeprevir (OR 0.62, 95% CI 0.45 to 0.86). However, Trial Sequential Analysis showed that there was not enough information to confirm or reject a relative risk reduction of 20%, and when one trial with an extreme result was excluded, the meta-analysis result showed no evidence of a difference.DAAs on the market or under development may reduce the risk of no SVR from 54.1% in untreated people to 23.8% in people treated with DAA (RR 0.44, 95% CI 0.37 to 0.52, 6886 participants, 32 trials, low quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.Only 1/84 trials on the market or under development assessed the effects of DAAs on health-related quality of life (SF-36 mental score and SF-36 physical score).There was insufficient evidence from trials on withdrawn or discontinued DAAs to determine their effect on hepatitis C-related morbidity and all-cause mortality (OR 0.64, 95% CI 0.23 to 1.79; 5 trials, very low-quality evidence). However, these DAAs seemed to increase the risk of serious adverse events (OR 1.45, 95% CI 1.22 to 1.73; 29 trials, very low-quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.None of the 138 trials provided useful data to assess the effects of DAAs on the remaining secondary outcomes (ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, and hepatocellular carcinoma). AUTHORS' CONCLUSIONS The evidence for our main outcomes of interest come from short-term trials, and we are unable to determine the effect of long-term treatment with DAAs. The rates of hepatitis C morbidity and mortality observed in the trials are relatively low and we are uncertain as to how DAAs affect this outcome. Overall, there is very low quality evidence that DAAs on the market or under development do not influence serious adverse events. There is insufficient evidence to judge if DAAs have beneficial or harmful effects on other clinical outcomes for chronic HCV. Simeprevir may have beneficial effects on risk of serious adverse event. In all remaining analyses, we could neither confirm nor reject that DAAs had any clinical effects. DAAs may reduce the number of people with detectable virus in their blood, but we do not have sufficient evidence from randomised trials that enables us to understand how SVR affects long-term clinical outcomes. SVR is still an outcome that needs proper validation in randomised clinical trials.
Collapse
Affiliation(s)
| | - Emil Eik Nielsen
- Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention ResearchBlegdamsvej 9CopenhagenDenmark2100
| | - Joshua Feinberg
- Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention ResearchBlegdamsvej 9CopenhagenDenmark2100
| | - Kiran Kumar Katakam
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalBlegdamsvej 9CopenhagenDenmark2100
| | - Kristina Fobian
- Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention ResearchBlegdamsvej 9CopenhagenDenmark2100
| | - Goran Hauser
- Clinical Hospital Centre RijekaDepartment of GastroenterologyKresimirova 42RijekaCroatia51 000
| | - Goran Poropat
- Clinical Hospital Centre RijekaDepartment of GastroenterologyKresimirova 42RijekaCroatia51 000
| | - Snezana Djurisic
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalBlegdamsvej 9CopenhagenDenmark2100
| | - Karl Heinz Weiss
- Heidelberg University HospitalInternal Medicine IV: Gastroenterology, Infectious Diseases, ToxicologyIm Neuenheimer Feld 410HeidelbergGermanyD‐69120
| | - Milica Bjelakovic
- University of NisMedical FacultyBoulevard Dr Zorana Djindjica 81NisSerbia18000
| | - Goran Bjelakovic
- Medical Faculty, University of NisDepartment of Internal MedicineZorana Djindjica 81NisSerbia18000
| | - Sarah Louise Klingenberg
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | - Jian Ping Liu
- Beijing University of Chinese MedicineCentre for Evidence‐Based Chinese Medicine11 Bei San Huan Dong Lu, Chaoyang DistrictBeijingChina100029
| | - Dimitrinka Nikolova
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | | | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
| |
Collapse
|
|
26
|
German P, Mathias A, Brainard D, Kearney BP. Clinical Pharmacokinetics and Pharmacodynamics of Ledipasvir/Sofosbuvir, a Fixed-Dose Combination Tablet for the Treatment of Hepatitis C. Clin Pharmacokinet 2017; 55:1337-1351. [PMID: 27193156 DOI: 10.1007/s40262-016-0397-0] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Ledipasvir/sofosbuvir (Harvoni®), a fixed-dose combination tablet of an NS5A inhibitor ledipasvir and an NS5B polymerase inhibitor sofosbuvir, is approved in the US, European Union, Canada, and other regions for the treatment of chronic hepatitis C virus infection in adults. Following absorption, ledipasvir reaches maximum plasma concentrations (T max) 4-4.5 h post-dose and is eliminated with a terminal half-life (t 1/2) of 47 h. Sofosbuvir undergoes intracellular activation to an active triphosphate GS-461203 (not detected in plasma) and ultimately to GS-331007, a predominant circulating metabolite, which is the primary analyte of interest in clinical pharmacology studies. Sofosbuvir is rapidly absorbed and eliminated from plasma (T max: 0.8-1 h; t 1/2: 0.5 h). The peak plasma concentrations for GS-331007 are achieved between 3.5 and 4 h post-dose; the elimination t 1/2 for GS-331007 is 27 h. Ledipasvir/sofosbuvir exhibits a favorable clinical pharmacology profile; it can be administered once daily without regard to food and does not require dose modification in hepatitis C virus-infected patients with any degree of hepatic impairment or mild to moderate renal impairment. The pharmacokinetic profiles of ledipasvir, sofosbuvir, and GS-331007 (predominant circulating metabolite of sofosbuvir) are not significantly affected by demographic variables; pharmacokinetic/pharmacodynamic analyses reveal no exposure-response relationships for efficacy or safety. The review summarizes the clinical pharmacokinetics, pharmacodynamics, and pharmacokinetic/pharmacodynamic analyses for ledipasvir/sofosbuvir.
Collapse
Affiliation(s)
- Polina German
- Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA.
| | - Anita Mathias
- Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA
| | - Diana Brainard
- Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA
| | - Brian P Kearney
- Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA
| |
Collapse
|
|
27
|
Abstract
The ProTide technology is a prodrug approach developed for the efficient intracellular delivery of nucleoside analogue monophosphates and monophosphonates. In this approach, the hydroxyls of the monophosphate or monophosphonate groups are masked by an aromatic group and an amino acid ester moiety, which are enzymatically cleaved-off inside cells to release the free nucleoside monophosphate and monophosphonate species. Structurally, this represents the current end-point of an extensive medicinal chemistry endeavor that spans almost three decades. It started from the masking of nucleoside monophosphate and monophosphonate groups by simple alkyl groups and evolved into the sophisticated ProTide system as known today. This technology has been extensively employed in drug discovery, and it has already led to the discovery of two FDA-approved (antiviral) ProTides. In this work, we will review the development of the ProTide technology, its application in drug discovery, and its role in the improvement of drug delivery and efficacy.
Collapse
Affiliation(s)
- Youcef Mehellou
- School of Pharmacy and Pharmaceutical Sciences , Cardiff University , Redwood Building , Cardiff CF10 3NB , U.K
| | - Hardeep S Rattan
- School of Pharmacy, College of Medical and Dental Sciences , University of Birmingham , Edgbaston , Birmingham B15 2TT , U.K
| | - Jan Balzarini
- Laboratory of Virology and Chemotherapy , Rega Institute for Medical Research , Herestraat 49 , 3000 Leuven , Belgium
| |
Collapse
|
|
28
|
Dolatimehr F, Karimi-Sari H, Rezaee-Zavareh MS, Alavian SM, Behnava B, Gholami-Fesharaki M, Sharafi H. Combination of sofosbuvir, pegylated-interferon and ribavirin for treatment of hepatitis C virus genotype 1 infection: a systematic review and meta-analysis. Daru 2017; 25:11. [PMID: 28427463 PMCID: PMC5397824 DOI: 10.1186/s40199-017-0177-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2016] [Accepted: 04/11/2017] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Hepatitis C virus (HCV) infection is an important cause of chronic liver disease which has been affected 3% of world's population. Some studies have shown that adding Sofosbuvir (SOF), an HCV polymerase inhibitor to the conventional therapy of Pegylated-interferon (PegIFN) plus Ribavirin (RBV) can increase the rate of sustained virologic response (SVR) among HCV-infected patients. This study was conducted to determine the effect of combination therapy with PegIFN and RBV plus SOF for chronic hepatitis C genotype 1 infection using systematic review with meta-analysis. METHODS In this study, electronic databases including PubMed, Scopus, Science Direct, and Web of Science were comprehensively searched using appropriate strategies containing all related keywords of "hepatitis C", "PegIFN", "RBV" and "SOF". Studies assessed the efficacy of combination therapy with PegIFN and RBV plus SOF for chronic hepatitis C genotype 1 infection were included in the meta-analysis. RESULTS After screening of 757 records, we included five articles with total sample size of 411 to the meta-analysis. Based on the fixed-effect model (χ 2 = 5.29, P = 0.26 and I2 = 24.4%), pooled SVR rate for treatment regimen of PegIFN and RBV plus SOF was calculated as 88.54% (95% CI = 85.77%-91.32%). CONCLUSIONS Combination therapy with PegIFN and RBV plus SOF results in high treatment response in patients with HCV genotype 1 infection.
Collapse
Affiliation(s)
- Fardin Dolatimehr
- Student Research Committee, Baqiyatallah University of Medical Sciences, Tehran, Iran
- Meta-analysis Study Group, Iran Hepatitis Network, Tehran, Iran
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, Iran
- Middle East Liver Disease (MELD) Center, Tehran, Iran
| | - Hamidreza Karimi-Sari
- Student Research Committee, Baqiyatallah University of Medical Sciences, Tehran, Iran
- Meta-analysis Study Group, Iran Hepatitis Network, Tehran, Iran
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, Iran
- Middle East Liver Disease (MELD) Center, Tehran, Iran
| | - Mohammad Saeid Rezaee-Zavareh
- Student Research Committee, Baqiyatallah University of Medical Sciences, Tehran, Iran
- Meta-analysis Study Group, Iran Hepatitis Network, Tehran, Iran
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, Iran
- Middle East Liver Disease (MELD) Center, Tehran, Iran
| | - Seyed Moayed Alavian
- Meta-analysis Study Group, Iran Hepatitis Network, Tehran, Iran
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, Iran
- Middle East Liver Disease (MELD) Center, Tehran, Iran
| | - Bita Behnava
- Meta-analysis Study Group, Iran Hepatitis Network, Tehran, Iran
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, Iran
- Middle East Liver Disease (MELD) Center, Tehran, Iran
| | | | - Heidar Sharafi
- Meta-analysis Study Group, Iran Hepatitis Network, Tehran, Iran
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, Iran
- Middle East Liver Disease (MELD) Center, Tehran, Iran
| |
Collapse
|
|
29
|
Geddawy A, Ibrahim YF, Elbahie NM, Ibrahim MA. Direct Acting Anti-hepatitis C Virus Drugs: Clinical Pharmacology and Future Direction. J Transl Int Med 2017; 5:8-17. [PMID: 28680834 DOI: 10.1515/jtim-2017-0007] [Citation(s) in RCA: 130] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The introduction of direct acting antiviral agents (DAAs) for its treatment represents a major advance in terms of sustained virologic response (SVR) rates and adverse effect profiles. Mechanistically, DAAs inhibit specific HCV non-structural proteins (NS) that are vital for its replication. Boceprevir, telaprevir, simeprevir, asunaprevir, grazoprevir and paritaprevir are NS3/4A inhibitors. Ombitasvir, ledipasvir, daclatasvir, elbasvir and velpatasvir are NS5A inhibitors. Sofosbuvir and dasabuvir are NS5B inhibitors. Currently, a combination of two or more DAAs is the corner stone for the treatment of HCV infection. However, the success of DAA therapy is facing several challenges, including the potential of drug-drug interactions and resistant variance. Moreover, the shortage of relevant clinical pharmacological data and drug interaction regarding DAA is a clinical concern. The present review discusses the clinical pharmacology of DAAs with special emphasis on drug-drug interaction.
Collapse
Affiliation(s)
- Ayman Geddawy
- Department of Pharmacology, Faculty of Medicine, Minia University, El- Minia 61519, Egypt
| | - Yasmine F Ibrahim
- Department of Pharmacology, Faculty of Medicine, Minia University, El- Minia 61519, Egypt
| | - Nabil M Elbahie
- Department of Pharmacology, Faculty of Medicine, Alexandria UniversityEgypt
| | - Mohammad A Ibrahim
- Department of Pharmacology, Faculty of Medicine, Minia University, El- Minia 61519, Egypt
| |
Collapse
|
|
30
|
Jansen JW, Powderly GM, Linneman TW. Identification of Predictors for Treatment Failure in Hepatitis C Virus Patients Treated With Ledipasvir and Sofosbuvir. Ann Pharmacother 2017; 51:543-547. [PMID: 28193102 DOI: 10.1177/1060028017693348] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND New hepatitis C virus (HCV) therapies report cure rates of ~90% but are expensive. Identification of predictors for treatment failure could help decrease health care costs, limit unnecessary drug exposure and adverse events, and prevent drug-drug interactions. Failure to achieve rapid viral response (RVR), defined as detectable viral load at 4 weeks, has previously been identified as a predictor of treatment failure with some previous HCV therapies. OBJECTIVE To evaluate RVR, and other potential variables, as predictors of treatment failure in patients treated with ledipasvir and sofosbuvir (LDV/SOF). METHODS A retrospective, case-control analysis of adult veterans treated with LDV/SOF was conducted. Included patients had a viral load obtained between weeks 3 and 6 of therapy (RVR) and between weeks 12 and 16 after the end of therapy for sustained viral response (SVR12) evaluation. Identified SVR12 failures (viral load detectable) constituted the case population. The control population was randomly selected in a 1:4 case: control ratio from all identified SVR12 successes. RESULTS In all, 12 SVR12 failures were identified; 48 of 144 SVR12 successes were randomly selected for inclusion. Overall failure rate was 7.7% (12/156). Univariate analysis identified histamine-2 receptor antagonist, previous treatment failure, and pretreatment creatinine clearance (CrCl; Cockcroft-Gault) >90 mL/min as potential predictors of SVR12 failure; these variables were included in the regression model with RVR per protocol. In multivariate analysis, pretreatment CrCl >90 mL/min was independently associated with SVR12 failure (odds ratio = 7.27; 95% CI = 1.33 to 39.72; P = 0.022). CONCLUSIONS Patients with pretreatment CrCl >90 mL/min were more likely to fail SVR12 than patients with CrCl <90 mL/min.
Collapse
|
|
31
|
Sarrazin C, Isakov V, Svarovskaia E, Hedskog C, Martin R, Chodavarapu K, Brainard DM, Miller MD, Mo H, Molina JM, Sulkowski MS. Late Relapse Versus Hepatitis C Virus Reinfection in Patients With Sustained Virologic Response After Sofosbuvir-Based Therapies. Clin Infect Dis 2017; 64:44-52. [PMID: 27737953 PMCID: PMC6394130 DOI: 10.1093/cid/ciw676] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Accepted: 09/22/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The development of direct-acting antivirals in recent years has dramatically enhanced rates of viral eradication to >90% in patients with chronic hepatitis C virus (HCV) infection. To determine true treatment efficacy and define the most appropriate retreatment, it is important to distinguish virologic relapse from reinfection when patients in whom HCV is eradicated during treatment become infected with a new HCV strain after treatment. METHODS We investigated the prevalence of late recurrent viremia (patients with sustained virologic response 12 weeks after the end of treatment but detectable HCV RNA at follow-up week 24) and used refined phylogenetic analysis of multiple HCV genes to distinguish virologic relapse from reinfection. RESULTS Across 11 phase 3 clinical trials of ledipasvir-sofosbuvir (SOF) and SOF, only 12 of 3004 patients had detectable HCV RNA following sustained virologic response 12 weeks after the end of treatment. Of these 12 patients with late recurrent viremia, 11 had the same HCV genotype/subtype at baseline and at recurrence. Phylogenetic analysis demonstrated that 58% (7 of 12) of these patients were successfully treated with the SOF-based regimen, with HCV eradication achieved, but became reinfected with a different HCV strain after treatment. The remaining 5 patients with late recurrent viremia had virologic relapse in which the HCV present at baseline persisted in the liver or another compartment and reemerged in the blood 24 weeks after treatment. CONCLUSIONS The incidence of late recurrent viremia was low. Distinguishing reinfection from virologic relapse has implications for determining true treatment efficiency and selecting optimal retreatment strategies.
Collapse
Affiliation(s)
| | | | | | | | - Ross Martin
- Gilead Sciences, Inc., Foster City, California, USA
| | | | | | | | - Hongmei Mo
- Gilead Sciences, Inc., Foster City, California, USA
| | | | - Mark S. Sulkowski
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| |
Collapse
|
|
32
|
Azam Z, Shoaib M, Javed M, Sarwar MA, Shaikh H, Khokhar N. Initial results of efficacy and safety of Sofosbuvir among Pakistani Population: A real life trial - Hepatitis Eradication Accuracy Trial of Sofosbuvir (HEATS). Pak J Med Sci 2017; 33:48-52. [PMID: 28367171 PMCID: PMC5368328 DOI: 10.12669/pjms.331.12352] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Revised: 01/03/2017] [Accepted: 02/08/2017] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVE The uridine nucleotide analogue sofosbuvir is a selective inhibitor of hepatitis C virus (HCV) NS5B polymerase approved for the treatment of chronic HCV infection with genotypes 1 - 4. The objective of the study was to evaluate the interim results of efficacy and safety of regimens containing Sofosbuvir (Zoval) among Pakistani population with the rapid virologic response (RVR2/4 weeks) with HCV infections. METHODS This is a multicenter open label prospective observational study. Patients suffering from chronic Hepatitis C infection received Sofosbuvir (Zoval) 400 mg plus ribavirin (with or without peg interferon) for 12/24 weeks. The interim results of this study were rapid virological response on week 4. Data was analyzed using SPSS version 21 for descriptive statistics. RESULTS A total of 573 patients with HCV infection were included in the study. The mean age of patients was 46.07 ± 11.41 years. Out of 573 patients 535 (93.3%) were treatment naive, 26 (4.5%) were relapser, 7 (1.2%) were non-responders and 5 (1.0%) were partial responders. A rapid virologic response was reported in 563(98.2%) of patients with HCV infection after four weeks of treatment. The treatment was generally well tolerated. CONCLUSION Sofosbuvir (Zoval) is effective and well tolerated in combination with ribavirin in HCV infected patients.
Collapse
Affiliation(s)
- Zahid Azam
- Prof. Zahid Azam, FCPS (Gastro); FCPS (Med); M.Sc (Clinical Research). Professor of Medicine & Gastroenterology, Gastroinstinal and Liver Practice (GILP) and Dow University of Health Sciences, Karachi, Pakistan
| | - Muhammad Shoaib
- Dr. Muhammad Shoaib, FCPS (Gastroenterology). Consultant Gastroenterologist, Memom Medical Institute Hospital, Karachi, Pakistan
| | - Masood Javed
- Dr. Masood Javed, FCPS, Associate Professor, Punjab Medical Collage Faisalabad, Pakistan
| | - Muhammad Adnan Sarwar
- Dr. Muhammad Adnan Sarwar, FCPS(Medicine), Senior Registrar DHQ Hospital Faisalabad, Pakistan
| | - Hafeezullah Shaikh
- Dr. Hafeezullah Shaikh, FCPS (Gastroenterology). Assistant Professor of Gastroenterology, National Institute of liver & GI Diseases (NILGID), Dow University Hospital, Karachi, Pakistan
| | - Nasir Khokhar
- Prof. Dr. Nasir Khokhar, MD, FACG. Professor of Medicine, Shifa International Hospital and Shifa Tameer e Millat University, Islamabad, Pakistan
| |
Collapse
|
|
33
|
Hashem MB, Elbaz T, El-kassas M, Esmat G. Management of Hepatitis C Virus—Genotypes 4, 5, and 6 Using Direct Antiviral Agents: Review of Current Status. CURRENT TREATMENT OPTIONS IN INFECTIOUS DISEASES 2016. [DOI: 10.1007/s40506-016-0094-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
|
|
34
|
Bullard-Feibelman KM, Govero J, Zhu Z, Salazar V, Veselinovic M, Diamond MS, Geiss BJ. The FDA-approved drug sofosbuvir inhibits Zika virus infection. Antiviral Res 2016; 137:134-140. [PMID: 27902933 DOI: 10.1016/j.antiviral.2016.11.023] [Citation(s) in RCA: 179] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Revised: 11/24/2016] [Accepted: 11/24/2016] [Indexed: 01/08/2023]
Abstract
The rapidly expanding Zika virus (ZIKV) epidemic has affected thousands of individuals with severe cases causing Guillain-Barré syndrome, congenital malformations, and microcephaly. Currently, there is no available vaccine or therapy to prevent or treat ZIKV infection. We evaluated whether sofosbuvir, an FDA-approved nucleotide polymerase inhibitor for the distantly related hepatitis C virus, could have antiviral activity against ZIKV infection. Cell culture studies established that sofosbuvir efficiently inhibits replication and infection of several ZIKV strains in multiple human tumor cell lines and isolated human fetal-derived neuronal stem cells. Moreover, oral treatment with sofosbuvir protected against ZIKV-induced death in mice. These results suggest that sofosbuvir may be a candidate for further evaluation as a therapy against ZIKV infection in humans.
Collapse
Affiliation(s)
| | - Jennifer Govero
- Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA
| | - Zhe Zhu
- Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Vanessa Salazar
- Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA
| | - Milena Veselinovic
- Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO, USA
| | - Michael S Diamond
- Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA; Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA; Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO, USA; The Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, Saint Louis, MO, USA
| | - Brian J Geiss
- Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO, USA; School of Biomedical Engineering, Colorado State University, Fort Collins, CO, USA.
| |
Collapse
|
|
35
|
Cuenca-Lopez F, Rivero A, Rivero-Juárez A. Pharmacokinetics and pharmacodynamics of sofosbuvir and ledipasvir for the treatment of hepatitis C. Expert Opin Drug Metab Toxicol 2016; 13:105-112. [PMID: 27797596 DOI: 10.1080/17425255.2017.1255725] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
INTRODUCTION The sofosbuvir (SOF) plus ledipasvir (LDV) fixed dose combination is the first direct action antiviral (DAA) single-treatment regimen (STR) to be commercialized. It is approved for the treatment of Hepatitis C virus (HCV) genotypes 1,3,4,5 and 6. Following approval in 2014, new pharmacokinetics and pharmacodynamics data were reported, which led to important clinical applications. Areas covered: This article reviews the pharmacokinetic and pharmacodynamic properties of the SOF/LDV fixed dose combination for the treatment of HCV. The topics covered include data regarding the drug´s absorption, distribution, metabolism and excretion and antiviral activity strategies such as the clinical dose selection and treatment duration. Expert opinion: The SOF/LDV fixed dose combination has good pharmacological properties that lead to a high sustained virological response after 12 or 24 weeks of treatment; there is minimal interference with other drugs or associated renal or hepatic impairment, such that dose adjustment is not necessary.
Collapse
Affiliation(s)
- Francisca Cuenca-Lopez
- a Infectious Diseases Unit, Hospital Universitario Reina Sofía de Córdoba, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC) , Universidad de Córdoba , Córdoba , Spain
| | - Antonio Rivero
- a Infectious Diseases Unit, Hospital Universitario Reina Sofía de Córdoba, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC) , Universidad de Córdoba , Córdoba , Spain
| | - Antonio Rivero-Juárez
- a Infectious Diseases Unit, Hospital Universitario Reina Sofía de Córdoba, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC) , Universidad de Córdoba , Córdoba , Spain
| |
Collapse
|
|
36
|
Mo H, Hedskog C, Svarovskaia E, Sun SC, Jacobson IM, Brainard DM, McHutchison JG, Miller MD. Antiviral response and resistance analysis of treatment-naïve HCV-infected patients receiving single and multiple doses of GS-9190. J Viral Hepat 2016; 23:644-51. [PMID: 27004425 DOI: 10.1111/jvh.12536] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Accepted: 02/17/2016] [Indexed: 01/03/2023]
Abstract
GS-9190 is a NS5B non-nucleoside analogue with demonstrated effectiveness in a Phase 1 monotherapy study and in combination with other DAAs for treatment of chronic HCV infection. Here, the resistance profile of GS-9190 monotherapy in a Phase 1b study was investigated. Resistance analysis was performed by population sequencing and allele-specific PCR (AS-PCR) for Y448H with an assay cut-off of 0.5%. Phenotypic susceptibility analyses were performed on patient isolates as well as site-directed mutagenesis of mutations selected during monotherapy. No resistance-associated variants were observed in patients before or after receiving single doses of GS-9190 by population sequencing. In contrast, in patients who received GS-9190 for 8 days, mutations Y448H and Y452H in NS5B were observed by population sequencing in 21/36 (58%) and 2/36 (5.6%) patients, respectively, at Day 8 or Day 14. Among the remaining 15 patients who had no detectable Y448H at Day 8 or Day 14 by population sequencing, low frequencies of Y448H ranging from 1.3 to 9.7% were detected in 14 of 15 patients by AS-PCR. By AS-PCR, Y448H remained detectable at reduced frequency in the majority of patients analysed through 4-6 months of follow-up. Chimeric HCV replicons constructed with the NS5B sequence from patients with Y448H and Y448H + Y452H/Y demonstrated 27-fold and 78.5-fold reduced susceptibility to GS-9190. In conclusion, Y448H was rapidly selected in the majority of patients receiving multiple doses of GS-9190 as monotherapy, despite undetectable levels in pretreatment samples. Y448H confers reduced susceptibility to GS-9190 and other NNIs and persisted in most patients for months post-treatment.
Collapse
Affiliation(s)
- H Mo
- Gilead Sciences Inc, Foster City, CA, USA
| | - C Hedskog
- Gilead Sciences Inc, Foster City, CA, USA
| | | | - S-C Sun
- Gilead Sciences Inc, Foster City, CA, USA
| | - I M Jacobson
- Mount Sinai Beth Israel Medical Center, New York, NY, USA
| | | | | | - M D Miller
- Gilead Sciences Inc, Foster City, CA, USA
| |
Collapse
|
|
37
|
Rezk MR, Bendas ER, Basalious EB, Karim IA. Quantification of sofosbuvir and ledipasvir in human plasma by UPLC-MS/MS method: Application to fasting and fed bioequivalence studies. J Chromatogr B Analyt Technol Biomed Life Sci 2016; 1028:63-70. [PMID: 27322631 DOI: 10.1016/j.jchromb.2016.06.004] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Revised: 06/01/2016] [Accepted: 06/03/2016] [Indexed: 12/18/2022]
Abstract
A rapid and sensitive LC-MS/MS method was developed, optimized and validated for quantification of sofosbuvir (SF) and ledipasvir (LD) in human plasma using eplerenone as an internal standard (IS). Analytes and IS were extracted from plasma by simple liquid-liquid extraction technique using methyl tertiary butyl ether. The prepared samples were chromatographed on Acquity UPLC BEH C18 column. Separation was done using a mobile phase formed of 0.1% formic acid and acetonitrile (50:50, v/v) in an isocratic mode at a flow rate of 0.4ml/min. The Xevo TQD LC-MS/MS was operated under the multiple-reaction monitoring mode using electrospray ionization. A full validation of the method was performed according to the FDA guidelines. Linearity was found to be in the range of 0.25-3500ng/ml for SF and 5-2000ng/ml for LD. The intra-day and inter-day precision and accuracy results were within the acceptable limits. A short run time of 2min allows analysis of more than 400 plasma samples per day. The developed method was successfully applied to both fasting and fed bioequivalence studies in healthy human volunteers.
Collapse
Affiliation(s)
- Mamdouh R Rezk
- Analytical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, 11562, Cairo, Egypt.
| | - Ehab R Bendas
- Clinical Pharmacy Department, Faculty of Pharmaceutical Sciences & Pharmaceutical Industries, Future University in Egypt, Egypt
| | - Emad B Basalious
- Pharmaceutics and Industrial Pharmacy Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, 11562, Cairo, Egypt
| | - Iman A Karim
- Advanced Research Center (ARC), Nasr City, Cairo, Egypt
| |
Collapse
|
|
38
|
Li W, Zhao W, Liu X, Huang X, Lopez OD, Leet JE, Fancher RM, Nguyen V, Goodrich J, Easter J, Hong Y, Caceres-Cortes J, Chang SY, Ma L, Belema M, Hamann LG, Gao M, Zhu M, Shu YZ, Humphreys WG, Johnson BM. Biotransformation of Daclatasvir In Vitro and in Nonclinical Species: Formation of the Main Metabolite by Pyrrolidine δ-Oxidation and Rearrangement. Drug Metab Dispos 2016; 44:809-20. [PMID: 27029743 DOI: 10.1124/dmd.115.068866] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Accepted: 03/28/2016] [Indexed: 01/05/2023] Open
Abstract
Daclatasvir is a first-in-class, potent, and selective inhibitor of the hepatitis C virus nonstructural protein 5A replication complex. In support of nonclinical studies during discovery and exploratory development, liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance were used in connection with synthetic and radiosynthetic approaches to investigate the biotransformation of daclatasvir in vitro and in cynomolgus monkeys, dogs, mice, and rats. The results of these studies indicated that disposition of daclatasvir was accomplished mainly by the release of unchanged daclatasvir into bile and feces and, secondarily, by oxidative metabolism. Cytochrome P450s were the main enzymes involved in the metabolism of daclatasvir. Oxidative pathways included δ-oxidation of the pyrrolidine moiety, resulting in ring opening to an aminoaldehyde intermediate followed by an intramolecular reaction between the aldehyde and the proximal imidazole nitrogen atom. Despite robust formation of the resulting metabolite in multiple systems, rates of covalent binding to protein associated with metabolism of daclatasvir were modest (55.2-67.8 pmol/mg/h) in nicotinamide adenine dinucleotide phosphate (reduced form)-supplemented liver microsomes (human, monkey, rat), suggesting that intramolecular rearrangement was favored over intermolecular binding in the formation of this metabolite. This biotransformation profile supported the continued development of daclatasvir, which is now marketed for the treatment of chronic hepatitis C virus infection.
Collapse
Affiliation(s)
- Wenying Li
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Weiping Zhao
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Xiaohong Liu
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Xiaohua Huang
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Omar D Lopez
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - John E Leet
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - R Marcus Fancher
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Van Nguyen
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Jason Goodrich
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - John Easter
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Yang Hong
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Janet Caceres-Cortes
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Shu Y Chang
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Li Ma
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Makonen Belema
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Lawrence G Hamann
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Min Gao
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Mingshe Zhu
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Yue-Zhong Shu
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - W Griffith Humphreys
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Benjamin M Johnson
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| |
Collapse
|
|
39
|
Zhu GQ, Zou ZL, Zheng JN, Chen DZ, Zou TT, Shi KQ, Zheng MH. Systematic Review and Network Meta-Analysis of Randomized Controlled Trials: Comparative Effectiveness and Safety of Direct-Acting Antiviral Agents for Treatment-Naive Hepatitis C Genotype 1. Medicine (Baltimore) 2016; 95:e3004. [PMID: 26945424 PMCID: PMC4782908 DOI: 10.1097/md.0000000000003004] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2015] [Revised: 01/22/2016] [Accepted: 02/11/2016] [Indexed: 12/18/2022] Open
Abstract
All possible direct-acting antiviral agent (DAA) regimens for treatment-naive hepatitis C genotype 1 were evaluated by many randomized controlled trials (RCTs). However, the optimum regimen remains inconclusive. We aim to compare interventions in terms of sustained virological response at 12 (SVR12) and 24 (SVR24) weeks after the end of treatment and adverse effects (AEs) (fatigue, headache, nausea, insomnia). PubMed, Embase, and the Cochrane Library were searched for RCTs until July 31, 2015. We estimated odds ratios (ORs) between treatments on clinical outcomes. Twenty-two eligible RCTs were included. Compared with peginterferon-ribavirin (PR), daclatasvir plus PR (OR 8.90, P < 0.001), faldaprevir plus PR (OR 3.72, P < 0.001), simeprevir plus PR (OR 3.59, P < 0.001), sofosbuvir plus PR (OR 4.69, P < 0.001) yield a significant effect in improving SVR12. Consistently, simeprevir plus PR (OR 3.49, P < 0.001), sofosbuvir plus PR (OR 4.51, P < 0.001), daclatasvir plus PR (OR 4.77, P < 0.001) also improved the rates of SVR24 significantly compared with PR. With respect to AEs, compared with PR, ledipasvir plus sofosbuvir plus PR (OR 2.13, P < 0.001) confer a significant AE in nausea, whereas daclatasvir plus PR (OR 0.20, P < 0.001 and OR 0.18, P < 0.001, respectively) lowered the incidence of fatigue and nausea significantly when compared with ledipasvir plus sofosbuvir plus PR. Daclatasvir plus PR was the most effective in SVR12 and SVR24, but caused an increased AEs profile (headache and insomnia). Combined ledipasvir with sofosbuvir or combination of PR was associated with higher incidence of fatigue and nausea.
Collapse
Affiliation(s)
- Gui-Qi Zhu
- From the Department of Infection and Liver Diseases, Liver Research Center, the First Affiliated Hospital of Wenzhou Medical University (G-QZ, J-NZ, D-ZC, T-TZ, K-QS, M-HZ), School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou (G-QZ, J-NZ, T-TZ), Department of Infection Diseases, the First Hospital of Jiaxing, Jiaxing (Z-LZ), Queen Mary Hospital, University of Hong Kong, Hong Kong (D-ZC), and Institute of Hepatology (K-QS, M-HZ), Wenzhou Medical University, Wenzhou, China
| | | | | | | | | | | | | |
Collapse
|
|
40
|
Kirby BJ, Symonds WT, Kearney BP, Mathias AA. Pharmacokinetic, Pharmacodynamic, and Drug-Interaction Profile of the Hepatitis C Virus NS5B Polymerase Inhibitor Sofosbuvir. Clin Pharmacokinet 2016; 54:677-90. [PMID: 25822283 DOI: 10.1007/s40262-015-0261-7] [Citation(s) in RCA: 194] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Sofosbuvir (SOVALDI(®)), a potent, once-daily, orally administered nucleotide analog prodrug inhibitor of the hepatitis C virus (HCV) NS5B polymerase is approved in the USA, EU, Canada, and other regions for the treatment of HCV infection as a component of an antiviral treatment regimen. Sofosbuvir undergoes intracellular activation to form GS-461203 (active triphosphate, not detected in plasma), and ultimately the inactive, renally eliminated metabolite GS-331007. GS-331007 was identified as the primary analyte of interest for clinical pharmacology studies as it accounted for >90 % of systemic drug-related material exposure, and provided comparable exposure-response relationships for viral kinetics as observed for sofosbuvir. GS-331007 and sofosbuvir exhibit linear pharmacokinetics with minimal accumulation upon multiple dosing. Compared to healthy subjects, HCV-infected patients had modestly lower (39 %) GS-331007 area under the plasma concentration-time curve (AUC) and higher sofosbuvir AUC (60 %). Sofosbuvir can be administered without dose modification in HCV-infected patients with any degree of hepatic impairment or mild to moderate renal impairment. Sofosbuvir has a low propensity for clinically significant drug interactions with common concomitant medications used by HCV-infected patients. Clinically significant alterations in GS-331007 or sofosbuvir exposures are limited to potent inducers of intestinal P-glycoprotein that may lower exposure. In HCV-infected patients, demographic variables do not significantly influence GS-331007 and sofosbuvir exposures and no consistent exposure-response relationships were observed for efficacy or safety. This review focuses on the clinical pharmacokinetics, pharmacodynamics, and pharmacokinetic-pharmacodynamic relationships of sofosbuvir, and summarizes a number of drug interaction studies with important concomitant medications commonly used by HCV-infected patients.
Collapse
Affiliation(s)
- Brian J Kirby
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA
| | | | | | | |
Collapse
|
|
41
|
Novo-Veleiro I, Alvela-Suárez L, Chamorro AJ, González-Sarmiento R, Laso FJ, Marcos M. Alcoholic liver disease and hepatitis C virus infection. World J Gastroenterol 2016. [PMID: 26819510 DOI: 10.3748/wjg.v22.i4.141] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Alcohol consumption and hepatitis C virus (HCV) infection have a synergic hepatotoxic effect, and the coexistence of these factors increases the risk of advanced liver disease. The main mechanisms of this effect are increased viral replication and altered immune response, although genetic predisposition may also play an important role. Traditionally, HCV prevalence has been considered to be higher (up to 50%) in alcoholic patients than in the general population. However, the presence of advanced alcoholic liver disease (ALD) or intravenous drug use (IDU) may have confounded the results of previous studies, and the real prevalence of HCV infection in alcoholic patients without ALD or prior IDU has been shown to be lower. Due to the toxic combined effect of HCV and alcohol, patients with HCV infection should be screened for excessive ethanol intake. Patients starting treatment for HCV infection should be specifically advised to stop or reduce alcohol consumption because of its potential impact on treatment efficacy and adherence and may benefit from additional support during antiviral therapy. This recommendation might be extended to all currently recommended drugs for HCV treatment. Patients with alcohol dependence and HCV infection, can be treated with acamprosate, nalmefene, topiramate, and disulfiram, although baclofen is the only drug specifically tested for this purpose in patients with ALD and/or HCV infection.
Collapse
Affiliation(s)
- Ignacio Novo-Veleiro
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| | - Lucía Alvela-Suárez
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| | - Antonio-Javier Chamorro
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| | - Rogelio González-Sarmiento
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| | - Francisco-Javier Laso
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| | - Miguel Marcos
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| |
Collapse
|
|
42
|
Novo-Veleiro I, Alvela-Suárez L, Chamorro AJ, González-Sarmiento R, Laso FJ, Marcos M. Alcoholic liver disease and hepatitis C virus infection. World J Gastroenterol 2016; 22:1411-1420. [PMID: 26819510 PMCID: PMC4721976 DOI: 10.3748/wjg.v22.i4.1411] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 10/01/2015] [Accepted: 12/01/2015] [Indexed: 02/06/2023] Open
Abstract
Alcohol consumption and hepatitis C virus (HCV) infection have a synergic hepatotoxic effect, and the coexistence of these factors increases the risk of advanced liver disease. The main mechanisms of this effect are increased viral replication and altered immune response, although genetic predisposition may also play an important role. Traditionally, HCV prevalence has been considered to be higher (up to 50%) in alcoholic patients than in the general population. However, the presence of advanced alcoholic liver disease (ALD) or intravenous drug use (IDU) may have confounded the results of previous studies, and the real prevalence of HCV infection in alcoholic patients without ALD or prior IDU has been shown to be lower. Due to the toxic combined effect of HCV and alcohol, patients with HCV infection should be screened for excessive ethanol intake. Patients starting treatment for HCV infection should be specifically advised to stop or reduce alcohol consumption because of its potential impact on treatment efficacy and adherence and may benefit from additional support during antiviral therapy. This recommendation might be extended to all currently recommended drugs for HCV treatment. Patients with alcohol dependence and HCV infection, can be treated with acamprosate, nalmefene, topiramate, and disulfiram, although baclofen is the only drug specifically tested for this purpose in patients with ALD and/or HCV infection.
Collapse
|
|
43
|
Pozzato G, Mazzaro C, Dal Maso L, Mauro E, Zorat F, Moratelli G, Bulian P, Serraino D, Gattei V. Hepatitis C virus and non-Hodgkin’s lymphomas: Meta-analysis of epidemiology data and therapy options. World J Hepatol 2016; 8:107-116. [PMID: 26807206 PMCID: PMC4716526 DOI: 10.4254/wjh.v8.i2.107] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Revised: 07/24/2015] [Accepted: 12/08/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is a global health problem affecting a large fraction of the world’s population: This virus is able to determine both hepatic and extrahepatic diseases. Mixed cryoglobulinemia, a B-cell “benign” lymphoproliferative disorders, represents the most closely related as well as the most investigated HCV-related extrahepatic disorder. Since this virus is able to determine extrahepatic [non-Hodgkin’s lymphoma (NHL)] as well as hepatic malignancies (hepatocellular carcinoma), HCV has been included among human cancer viruses. The most common histological types of HCV-associated NHL are the marginal zone, the lymphoplasmacytic and diffuse large cell lymphomas. The role of the HCV in the pathogenesis of the B-cell lymphoproliferative disorders is confirmed also by the responsiveness of the NHL to antiviral therapy. The purpose of this review is to provide an overview of the recent literature and a meta analysis of the epidemiology data, to explain the role of HCV in the development of NHL’s lymphoma. Furthermore, the possibility to treat these HCV-related NHL with the antiviral therapy or with other therapeutic options, like chemotherapy, is also discussed.
Collapse
|
|
44
|
Bertino G, Ardiri A, Proiti M, Rigano G, Frazzetto E, Demma S, Ruggeri MI, Scuderi L, Malaguarnera G, Bertino N, Rapisarda V, Di Carlo I, Toro A, Salomone F, Malaguarnera M, Bertino E, Malaguarnera M. Chronic hepatitis C: This and the new era of treatment. World J Hepatol 2016; 8:92-106. [PMID: 26807205 PMCID: PMC4716531 DOI: 10.4254/wjh.v8.i2.92] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Revised: 09/29/2015] [Accepted: 12/18/2015] [Indexed: 02/06/2023] Open
Abstract
Over the last years it has started a real revolution in the treatment of chronic hepatitis C. This occurred for the availability of direct-acting antiviral agents that allow to reach sustained virologic response in approximately 90% of cases. In the near future further progress will be achieved with the use of pan-genotypic drugs with high efficacy but without side effects.
Collapse
|
|
45
|
Pérez-Pitarch A, Guglieri-López B, Ferriols-Lisart R, Merino-Sanjuán M. A model-based meta-analysis of sofosbuvir-based treatments in chronic hepatitis C patients. Int J Antimicrob Agents 2016; 47:184-94. [PMID: 26915476 DOI: 10.1016/j.ijantimicag.2015.12.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Revised: 10/13/2015] [Accepted: 12/21/2015] [Indexed: 12/20/2022]
Abstract
The objective of this study was to compare the efficacy of sofosbuvir-based treatments in patients with chronic hepatitis C virus (HCV) infection using a model-based meta-analysis (MBMA). A bibliographic search was performed to identify clinical trials involving sofosbuvir as a unique direct-acting antiviral (DAA) agent or together with daclatasvir, ledipasvir or simeprevir for the treatment of diagnosed HCV infection. The time course of the virological response (VR) was modelled to estimate the effect of treatment and the influence of population characteristics on the longitudinal efficacy profile. The model was validated and simulations of 10 different treatment schedules were performed. Data from 19 clinical trials were included in the analysis. According to the developed model, therapy with sofosbuvir+ledipasvir is the most effective therapy in all scenarios, but it does not differ greatly in terms of sustained VR with respect to other combinations of DAA treatments. In conclusion, this MBMA generates knowledge regarding hypothetical head-to-head trials that have not been conducted previously. Therapies with sofosbuvir+ledipasvir are probably the most effective sofosbuvir-based treatments.
Collapse
Affiliation(s)
- Alejandro Pérez-Pitarch
- Pharmacy Department, University Clinical Hospital of Valencia, Avda. Blasco Ibañez 17, Valencia 46010, Spain; Pharmacy and Pharmaceutical Technology Department, University of Valencia, Valencia, Spain.
| | - Beatriz Guglieri-López
- Pharmacy and Pharmaceutical Technology Department, University of Valencia, Valencia, Spain; Pharmacy Department, Doctor Peset University Hospital, Valencia, Spain
| | - Rafael Ferriols-Lisart
- Pharmacy Department, University Clinical Hospital of Valencia, Avda. Blasco Ibañez 17, Valencia 46010, Spain; Pharmacy and Pharmaceutical Technology Department, University of Valencia, Valencia, Spain
| | - Matilde Merino-Sanjuán
- Pharmacy and Pharmaceutical Technology Department, University of Valencia, Valencia, Spain
| |
Collapse
|
|
46
|
McConachie SM, Wilhelm SM, Kale-Pradhan PB. New direct-acting antivirals in hepatitis C therapy: a review of sofosbuvir, ledipasvir, daclatasvir, simeprevir, paritaprevir, ombitasvir and dasabuvir. Expert Rev Clin Pharmacol 2016; 9:287-302. [DOI: 10.1586/17512433.2016.1129272] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
|
|
47
|
Abstract
Unlike human immunodeficiency virus (HIV) and hepatitis B virus (HBV), hepatitis C virus (HCV) infection is a curable disease. Current direct antiviral agent (DAA) targets are focused on HCV NS3/4A protein (protease), NS5B protein (polymerase) and NS5A protein. The first generation of DAAs includes boceprevir and telaprevir, which are protease inhibitors and were approved for clinical use in 2011. The cure rate for genotype 1 patients increased from 45% to 70% when boceprevir or telaprevir was added to standard PEG-IFN/ribavirin. More effective and less toxic second generation DAAs supplanted these drugs by 2013. The second generation of DAAs includes sofosbuvir (Sovaldi), simeprevir (Olysio), and fixed combination medicines Harvoni and Viekira Pak. These drugs increase cure rates to over 90% without the need for interferon and effectively treat all HCV genotypes. With these drugs the “cure HCV” goal has become a reality. Concerns remain about drug resistance mutations and the high cost of these drugs. The investigation of new HCV drugs is progressing rapidly; fixed dose combination medicines in phase III clinical trials include Viekirax, asunaprevir+daclatasvir+beclabuvir, grazoprevir+elbasvir and others.
Collapse
|
|
48
|
Suwanthawornkul T, Anothaisintawee T, Sobhonslidsuk A, Thakkinstian A, Teerawattananon Y. Efficacy of Second Generation Direct-Acting Antiviral Agents for Treatment Naïve Hepatitis C Genotype 1: A Systematic Review and Network Meta-Analysis. PLoS One 2015; 10:e0145953. [PMID: 26720298 PMCID: PMC4701000 DOI: 10.1371/journal.pone.0145953] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Accepted: 12/10/2015] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND The treatment of hepatitis C (HCV) infections has significantly changed in the past few years due to the introduction of direct-acting antiviral agents (DAAs). DAAs could improve the sustained virological response compared to pegylated interferon with ribavirin (PR). However, there has been no evidence from randomized controlled trials (RCTs) that directly compare the efficacy among the different regimens of DAAs. AIM Therefore, we performed a systematic review and network meta-analysis aiming to compare the treatment efficacy between different DAA regimens for treatment naïve HCV genotype 1. METHODS Medline and Scopus were searched up to 25th May 2015. RCTs investigating the efficacy of second generation DAA regimens for treatment naïve HCV genotype 1 were eligible for the review. Due to the lower efficacy and more side effects of first generation DAAs, this review included only second generation DAAs approved by the US or EU Food and Drug Administration, that comprised of simeprevir (SMV), sofosbuvir (SOF), daclatasvir (DCV), ledipasvir (LDV), and paritaprevir/ritonavir/ombitasvir plus dasabuvir (PrOD). Primary outcomes were sustained virological response at weeks 12 (SVR12) and 24 (SVR24) after the end of treatment and adverse drug events (i.e. serious adverse events, anemia, and fatigue). Efficacy of all treatment regimens were compared by applying a multivariate random effect meta-analysis. Incidence rates of SVR12 and SVR24, and adverse drug events of each treatment regimen were pooled using 'pmeta' command in STATA program. RESULTS Overall, 869 studies were reviewed and 16 studies were eligible for this study. Compared with the PR regimen, SOF plus PR, SMV plus PR, and DVC plus PR regimens yielded significantly higher probability of having SVR24 with pooled risk ratios (RR) of 1.98 (95% CI 1.24, 3.14), 1.46 (95% CI: 1.22, 1.75), and 1.68 (95% CI: 1.14, 2.46), respectively. Pooled incidence rates of SVR12 and SVR24 in all treatment regimens without PR, i.e. SOF plus LDV with/without ribavirin, SOF plus SMV with/without ribavirin, SOF plus DCV with/without ribavirin, and PrOD with/without ribavirin, (pooled incidence of SVR12 ranging from 93% to 100%, and pooled incidence of SVR24 ranging from 89% to 96%) were much higher than the pooled incidence rates of SVR12 (51%) and SVR24 (48%) in PR alone. In comparing SOF plus LDV with ribavirin and SOF plus LDV without ribavirin, the chance of having SVR12 was not significantly different between these two regimens, with the pooled RR of 0.99 (95% CI: 0.97, 1.01). Regarding adverse drug events, risk of serious adverse drug events, anemia and fatigue were relatively higher in treatment regimens with PR than the treatment regimens without PR. The main limitation of our study is that a subgroup analysis according to dosages and duration of treatment could not be performed. Therefore, the dose and duration of recommended treatment have been suggested in range and not in definite value. CONCLUSIONS Both DAA plus PR and dual DAA regimens should be included in the first line drug for treatment naïve HCV genotype 1 because of the significant clinical benefits over PR alone. However, due to high drug costs, an economic evaluation should be conducted in order to assess the value of the investment when making coverage decisions.
Collapse
Affiliation(s)
- Thanthima Suwanthawornkul
- Health Intervention and Technology Assessment Program, Ministry of Public Health, Nonthaburi, Thailand
| | - Thunyarat Anothaisintawee
- Department of Family Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Abhasnee Sobhonslidsuk
- Department of Medicine, Division of Gastroenterology and Hepatology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Ammarin Thakkinstian
- Section for Clinical Epidemiology and Biostatistics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Yot Teerawattananon
- Health Intervention and Technology Assessment Program, Ministry of Public Health, Nonthaburi, Thailand
| |
Collapse
|
|
49
|
Neuman MG, Malnick S, Maor Y, Nanau RM, Melzer E, Ferenci P, Seitz HK, Mueller S, Mell H, Samuel D, Cohen LB, Kharbanda KK, Osna NA, Ganesan M, Thompson KJ, McKillop IH, Bautista A, Bataller R, French SW. Alcoholic liver disease: Clinical and translational research. Exp Mol Pathol 2015; 99:596-610. [PMID: 26342547 DOI: 10.1016/j.yexmp.2015.09.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Accepted: 09/01/2015] [Indexed: 02/05/2023]
Abstract
The present review spans a broad spectrum of topics dealing with alcoholic liver disease (ALD), including clinical research, translational research, pathogenesis and therapies. A special accent is placed on alcohol misuse, as alcohol is a legally commercialized and taxable product. Drinking alcohol, particularly from a young age, is a major health problem. Alcoholism is known to contribute to morbidity and mortality. A systematic literature search was performed in order to obtain updated data (2008-2015). The review is focused on genetic polymorphisms of alcohol metabolizing enzymes and the role of cytochrome p450 2E1 and iron in ALD. Alcohol-mediated hepatocarcinogenesis is also discussed in the presence or absence of co-morbidities such as viral hepatitis C as well as therapeutic the role of innate immunity in ALD-HCV. Moreover, emphasis was placed on alcohol and drug interactions, as well as liver transplantation for end-stage ALD. Finally, the time came to eradicate alcohol-induced liver and intestinal damage by using betaine.
Collapse
Affiliation(s)
- Manuela G Neuman
- In Vitro Drug Safety and Biotechnology, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
| | - Stephen Malnick
- Division of Gastroenterology, Kaplan Health Sciences Centre, Department of Medicine, Faculty of Medicine, Hebrew University, Rehovot, Israel
| | - Yaakov Maor
- Division of Gastroenterology, Kaplan Health Sciences Centre, Department of Medicine, Faculty of Medicine, Hebrew University, Rehovot, Israel
| | - Radu M Nanau
- In Vitro Drug Safety and Biotechnology, Toronto, Ontario, Canada
| | - Ehud Melzer
- Division of Gastroenterology, Kaplan Health Sciences Centre, Department of Medicine, Faculty of Medicine, Hebrew University, Rehovot, Israel
| | | | - Helmut K Seitz
- University of Heidelberg, Heidelberg, Germany; Department of Medicine, Gastroenterology and Hepatology, Centre for Alcohol Research, Salem Medical Centre, Heidelberg, Germany
| | - Sebastian Mueller
- University of Heidelberg, Heidelberg, Germany; Department of Medicine, Gastroenterology and Hepatology, Centre for Alcohol Research, Salem Medical Centre, Heidelberg, Germany
| | - Haim Mell
- Israel Antidrug and Alcohol Authority, Jerusalem, Israel
| | - Didier Samuel
- Liver Transplant Unit, Research Inserm-Paris XI Unit 785, Centre Hepatobiliaire, Hopital Paul Brousse, Villejuif, Paris, France
| | - Lawrence B Cohen
- Division of Gastroenterology, Sunnybrook Health Sciences Centre and Department of Internal Medicine, University of Toronto, Toronto, Canada
| | - Kusum K Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Internal Medicine, Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Natalia A Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Internal Medicine, Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Internal Medicine, Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Kyle J Thompson
- Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, USA
| | - Iain H McKillop
- Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, USA
| | - Abraham Bautista
- Office of Extramural Activities, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD, USA
| | - Ramon Bataller
- Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | | |
Collapse
|
|
50
|
Svarovskaia ES, Gane E, Dvory-Sobol H, Martin R, Doehle B, Hedskog C, Jacobson IM, Nelson DR, Lawitz E, Brainard DM, McHutchison JG, Miller MD, Mo H. L159F and V321A Sofosbuvir-Associated Hepatitis C Virus NS5B Substitutions. J Infect Dis 2015; 213:1240-7. [PMID: 26603202 DOI: 10.1093/infdis/jiv564] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Accepted: 11/09/2015] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Sofosbuvir (SOF) exhibits a high barrier to resistance, with no S282T NS5B substitution or phenotypic resistance detected in phase 3 registration studies. METHODS Here, emergence of the NS5B variants L159F and V321A and possible association with resistance was evaluated in 8 studies of SOF (NEUTRINO, FISSION, POSITRON, FUSION, VALENCE, PHOTON-1, PHOTON-2, and P7977-2025) and 5 studies of combination ledipasvir (LDV) and SOF (LDV/SOF; LONESTAR, ELECTRON [LDV/SOF arms], ION1, ION2, and ION3), using deep sequencing. RESULTS Deep sequencing detected L159F in 15% (53 of 353) and V321A in 5% (17 of 353) of patients with virologic failure in the SOF studies. Intensification of SOF treatment with LDV reduced the emergence of L159F or V321A to 2% (1 of 50 each) at virologic failure. L159F and V321A did not influence the outcome of retreatment with SOF, ribavirin, and pegylated interferon. At baseline, L159F was detected only in genotype 1-infected patients (1%) and was only associated with increased virologic failure in patients treated for short durations with SOF and ribavirin. CONCLUSIONS Deep-sequencing analysis confirmed that NS5B variants L159F and V321A emerged in a subset of patients treated with SOF at virologic failure. These variants had no impact on retreatment outcome with SOF, ribavirin, and pegylated interferon. Baseline L159F in genotype 1 did not affect the treatment outcome with LDV/SOF.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | - Eric Lawitz
- Texas Liver Institute, University of Texas Health Science Center, San Antonio
| | | | | | | | - Hongmei Mo
- Gilead Sciences, Foster City, California
| |
Collapse
|