DOCSLIB.ORG

Epclusa, INN-Sofosbuvir/Velpatasvir

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Epclusa, INN-Sofosbuvir/Velpatasvir 26 May 2016 EMA/399285/2016 Committee for Medicinal Products for Human Use (CHMP) Assessment report Epclusa International non-proprietary name: sofosbuvir / velpatasvir Procedure No. EMEA/H/C/004210/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact An agency of the European Union © European Medicines Agency, 2016. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure .............................................. 7 1.1. Submission of the dossier ...................................................................................... 7 1.2. Steps taken for the assessment of the product ......................................................... 8 2. Scientific discussion ................................................................................ 9 2.1. Introduction......................................................................................................... 9 2.2. Quality aspects .................................................................................................. 10 2.2.1. Introduction .................................................................................................... 10 2.2.2. Active substance ............................................................................................ 10 2.2.3. Finished medicinal product ................................................................................ 15 2.2.4. Discussion on chemical, and pharmaceutical aspects ............................................ 18 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 18 2.2.6. Recommendation for future quality development ................................................. 18 2.3. Non-clinical aspects ............................................................................................ 19 2.3.1. Introduction .................................................................................................... 19 2.3.2. Pharmacology ................................................................................................. 20 2.3.3. Pharmacokinetics............................................................................................. 25 2.3.4. Toxicology ...................................................................................................... 37 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 47 2.3.6. Discussion on non-clinical aspects...................................................................... 50 2.3.7. Conclusion on the non-clinical aspects ................................................................ 50 2.4. Clinical aspects .................................................................................................. 51 2.4.1. Introduction .................................................................................................... 51 2.4.2. Pharmacokinetics............................................................................................. 53 2.4.3. Discussion on clinical pharmacology ................................................................... 66 2.4.4. Conclusions on clinical pharmacology ................................................................. 70 2.5. Clinical efficacy .................................................................................................. 70 2.5.1. Dose response studies...................................................................................... 71 2.5.2. Main studies ................................................................................................... 73 2.5.3. Discussion on clinical efficacy ............................................................................ 87 2.5.4. Conclusions on the clinical efficacy ..................................................................... 89 2.6. Clinical safety .................................................................................................... 89 2.6.1. Discussion on clinical safety ............................................................................ 101 2.6.2. Conclusions on the clinical safety ..................................................................... 102 2.7. Risk Management Plan ...................................................................................... 102 2.8. Pharmacovigilance ............................................................................................ 108 2.9. Product information .......................................................................................... 108 2.9.1. User consultation ........................................................................................... 108 2.9.2. Additional monitoring ..................................................................................... 108 Assessment report EMA/399285/2016 Page 2/112 3. Benefit-Risk Balance............................................................................ 108 4. Recommendations ............................................................................... 111 Assessment report EMA/399285/2016 Page 3/112 List of abbreviations ALT alanine aminotransferase APRI AST to Platelet Ratio Index ARV antiretroviral AST aspartate aminotransferase ATV atazanavir AUC area under the plasma/serum concentration vs. time curve AUCtau area under the plasma/serum concentration vs. time curve over the dosing interval CatA cathepsin A CL/F apparent oral clearance after administration of the drug: Cmax maximum observed plasma/serum concentration of drug Ctau observed drug concentration at the end of the dosing interval BCRP breast cancer resistance protein BCS Biopharmaceutics Classification System BSEP bile salt export pump CLcr creatinine clearance COBI, cobicistat (Tybost) CPT Child-Pugh-Turcotte CsA cyclosporine (cyclosporin A) DAA direct-acting antiviral DCV daclatasvir (BMS-790052) DDI drug-drug interaction DILI drug-induced liver injury DRV darunavir DSC Differential Scanning Calorimetry DTG dolutegravir EC European Commission EC50 concentration of a compound inhibiting virus replication by 50% E/C/F/TAF elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (coformulated) eGFR estimated glomerular filtration rate EFV efavirenz EU European Union EVG elvitegravir (Vitekta) EVG/COBI/FTC/TDF elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (coformulated; Stribild) FDC fixed-dose combination FTC, emtricitabine FTC/RPV/TDF emtricitabine/rilpivirine/tenofovir disoproxil fumarate (coformulated; Complera/Eviplera) FTC/TDF emtricitabine/tenofovir disoproxil fumarate (coformulated; Truvada) GC Gas Chromatography GT genotype GVS Gravimetric vapour sorption Assessment report EMA/399285/2016 Page 4/112 H2RA H2-receptor antagonist HBV hepatitis B virus HCV hepatitis C virus HDPE high-density polyethylene HIV, HIV-1 human immunodeficiency virus, type 1 HMG-CoA 3-hydroxy-3-methylglutaryl-coenzyme A HPLC High performance liquid chromatography IC50 concentration that results in 50% inhibition ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use ICP-OES Inductively coupled plasma-optical emission spectroscopy IFN interferon IFN-α interferon-alpha IR Infrared Ka apparent first-order absorption rate constant LDV ledipasvir LDV/SOF ledipasvir/sofosbuvir (coformulated; Harvoni) LLOQ lower limit of quantitation LPV lopinavir MATE1 multidrug and toxin extrusion 1 MELD model for end-stage liver disease MRP2 multidrug resistance-associated protein 2 NMR Nuclear Magnetic Resonance NOAEL no observed adverse effect level NOEL no observed effect level NOR Normal Operating Range NS (3/4A/5A/5B) nonstructural protein (3/4A/5A/5B) NTCP sodium-taurocholate cotransporter protein OAT organic anion transporter OATP organic anion transporter polypeptide OCT organic cation transporter PAR Proven Acceptable Range PDE Permitted Daily Exposure Peg-IFN pegylated interferon Ph. Eur. European Pharmacopoeia P-gp P-glycoprotein PMI Potentially mutagenic impurities PPI proton pump inhibitor /r boosted with ritonavir QbD Quality by design RAL raltegravir Assessment report EMA/399285/2016 Page 5/112 RAV resistance-associated variant RBV ribavirin RH Relative Humidity ROI Residue on ignition RPV rilpivirine RTV ritonavir SmPC Summary of Product Characteristics SOF sofosbuvir (GS-7977; Sovaldi) SOF/VEL sofosbuvir/velpatasvir (coformulated) SVR, SVRxx sustained virologic response, sustained virologic response, sustained virologic response at “xx” weeks following completion of all treatment TAF tenofovir alafenamide TDF tenofovir disoproxil fumarate TE treatment experienced TFV tenofovir TN treatment naïve TSE Transmissible Spongiform Encephalopathy UGT1A1 uridine disphosphate glucuronosyltransferase 1A1 ULN upper limit of normal range UPLC ultra-high performance liquid chromatography UV Ultraviolet VEL velpatasvir (GS-5816) Assessment report EMA/399285/2016 Page 6/112 1. Background information on the procedure 1.1. Submission of the dossier The applicant Gilead Sciences International Ltd submitted on 14 November 2015 an application for Marketing Authorisation to the European Medicines Agency (EMA) for Epclusa, through the centralised procedure falling within the Article 3(1) and point 3 of Annex
Load more

Recommended publications
  • Sofosbuvir-Based and Elbasvir/Grazoprevir Treatment Fai
    Sofosbuvir-Based and Elbasvir/Grazoprevir Treatment Fai... From www.HCVGuidance.org on September 27, 2021 Sofosbuvir-Based and Elbasvir/Grazoprevir Treatment Failures In general, persons who have experienced treatment failure with a sofosbuvir-based regimen should be retreated with 12 weeks of sofosbuvir/velpatasvir/voxilaprevir. The main exception is persons with genotype 3 and cirrhosis, in whom addition of ribavirin to sofosbuvir/velpatasvir/voxilaprevir for 12 weeks is recommended. Sixteen weeks of glecaprevir/pibrentasvir is an alternative regimen. Elbasvir/grazoprevir treatment failure patients should also be retreated with 12 weeks of sofosbuvir/velpatasvir/voxilaprevir. However, glecaprevir/pibrentasvir for 16 weeks is not recommended as an alternative for this group of patients. Recommended and alternative regimens listed by evidence level and alphabetically for: Sofosbuvir-Based Treatment Failures, With or Without Compensated Cirrhosisa RECOMMENDED DURATION RATING Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 12 weeks I, A mg)/voxilaprevir (100 mg)b ALTERNATIVE DURATION RATING Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) 16 weeks I, A except for NS3/4 protease inhibitor inclusive combination DAA regimen failuresc Not recommended for genotype 3 infection with sofosbuvir/NS5A inhibitor experience. a For decompensated cirrhosis, please refer to the appropriate section. b Genotype 3: Add weight-based ribavirin if cirrhosis is present and there are no contraindications. c This regimen is not recommended for patients with prior exposure to an NS5A inhibitor plus NS3/4 PI regimens (eg. Elbasvir/grazoprevir). Recommended Regimen Sofosbuvir/Velpatasvir/Voxilaprevir The placebo-controlled, phase 3 POLARIS-1 trial evaluated a 12-week course of the daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100mg) in 263 persons with a prior NS5A inhibitor-containing DAA regimen failure.
    [Show full text]
  • Hepatitis C Treatment
    Hepatitis C Treatment The goal of treatment for hepatitis C virus (HCV) is to cure the virus, which can be done with a combination of drugs. The specific meds used and the duration of treatment depend on a number of factors, including HCV genotype (genetic structure of the virus), viral load, past treatment experience, degree of liver damage, ability to tolerate the prescribed treatment, and whether the person is waiting for a liver transplant or is a transplant recipient. In some cases, HCV treatment may be limited by your health insurance plan or drug formulary. Here’s information about each type, or class, of approved HCV treatment along with drugs in the late stages of development: Multi-Class Combination Drugs Brand Name Generic Name Status Pharmaceutical Company Epclusa* sofosbuvir + velpatasvir Approved Gilead Sciences Harvoni* ledipasvir + sofosbuvir Approved Gilead Sciences Mavyret glecaprevir + pibrentasvir Approved AbbVie Vosevi sofosbuvir/velpatasvir/ Approved Gilead Sciences voxilaprevir Zepatier elbasvir + grazoprevir Approved Merck n/a daclatasvir + asunaprevir + Phase III Bristol-Myers Squibb beclabuvir *generic available What are they? Multi-class combination drugs are a combination of drugs formulated into a single pill or package of pills. For instance, the drug Harvoni combines two drugs, ledipasvir and sofosbuvir. Ledipasvir is an NS5A inhibitor and is only sold as part of Harvoni; sofosbuvir may be prescribed separately under the brand name of Sovaldi. Pegylated Interferon Alfa Brand Name Generic Name Status Pharmaceutical Company Pegasys peginterferon alfa-2a Approved Genentech What are they? Interferon is a protein made by the immune system, named because it interferes with viral reproduction. In addition, interferon signals the immune system to recognize and respond to microorganisms, including viral and bacterial infections.
    [Show full text]
  • Treatment of HCV in Persons with Renal Impairment
    © Hepatitis C Online PDF created September 29, 2021, 2:18 pm Treatment of HCV in Persons with Renal Impairment This is a PDF version of the following document: Module 6: Treatment of Key Populations and Unique Situations Lesson 3: Treatment of HCV in Persons with Renal Impairment You can always find the most up to date version of this document at https://www.hepatitisC.uw.edu/go/key-populations-situations/treament-renal-impairment/core-concept/all. Background Epidemiology of Hepatitis C Infection and Renal Disease Persons infected with hepatitis C virus (HCV) can develop kidney disease as a result of extrahepatic manifestation of HCV or as a disease process independent of the HCV infection. In addition, hemodialysis has been a risk factor for acquiring HCV infection, as shown by numerous outbreaks and HCV cross-infections that have occurred in hemodialysis units.[1,2,3,4] Earlier studies conducted in western countries have shown an HCV prevalence in hemodialysis patients that ranged from 2.6 to 23%, with higher prevalence correlating with longer duration of hemodialysis.[5,6,7] The risk of HCV transmission in hemodialysis units has declined due to improved testing and infection control practices.[8,9] Interaction of Hepatitis C Infection and Renal Disease Several studies have shown that patients on chronic hemodialysis have an increased overall mortality risk if they have chronic hepatitis C infection (when compared with those on dialysis who do not have hepatitis C infection).[10,11] There are also some data showing that chronic hepatitis C may be a risk factor for developing renal cell carcinoma.[12] Chronic hepatitis C infection has also been associated with an accelerated course of renal disease, including in persons with HIV coinfection.[13,14] Extrahepatic manifestations related to HCV, including immune complex-related renal disease, can require urgent HCV treatment to resolve or prevent further organ damage.
    [Show full text]
  • Evaluation and Management of Chronic Hepatitis C Virus Infection
    EVALUATION AND MANAGEMENT OF CHRONIC HEPATITIS C VIRUS (HCV) INFECTION Federal Bureau of Prisons Clinical Guidance MAY 2017 Federal Bureau of Prisons (BOP) Clinical Guidance is made available to the public for informational purposes only. The BOP does not warrant this guidance for any other purpose, and assumes no responsibility for any injury or damage resulting from the reliance thereof. Proper medical practice necessitates that all cases are evaluated on an individual basis and that treatment decisions are patient- specific. Consult the BOP Health Management Resources Web page to determine the date of the most recent update to this document: http://www.bop.gov/resources/health_care_mngmt.jsp. Federal Bureau of Prisons Evaluation and Management of Chronic HCV Infection Clinical Guidance May 2017 WHAT’S NEW IN BOP GUIDANCE REGARDING HCV INFECTION? The major changes included in this May 2017 update to the BOP guidance on chronic HCV infection are based primarily on the April 2017 changes to the American Association for the Study of Liver Diseases (AASLD) guidelines, as follows: • The term resistance-associated substitutions (RASs) is now being used instead of resistance- associated variants (RAVs). • Anti-HBs and anti-HBc, in addition to HBsAg, are recommended for baseline testing of hepatitis B status (see LABORATORY TESTS under BASELINE EVALUATION). • Ledipasvir/sofosbuvir once daily for eight weeks is now an AASLD-recommended regimen for treatment in a subgroup of HCV-infected persons who have genotype 1a or 1b, have an HCV viral load <6 million IU/ml, and are treatment-naïve—but who are not black, are not HIV-coinfected, and do not have cirrhosis.
    [Show full text]
  • Caracterización Molecular Del Perfil De Resistencias Del Virus De La
    ADVERTIMENT. Lʼaccés als continguts dʼaquesta tesi queda condicionat a lʼacceptació de les condicions dʼús establertes per la següent llicència Creative Commons: http://cat.creativecommons.org/?page_id=184 ADVERTENCIA. El acceso a los contenidos de esta tesis queda condicionado a la aceptación de las condiciones de uso establecidas por la siguiente licencia Creative Commons: http://es.creativecommons.org/blog/licencias/ WARNING. The access to the contents of this doctoral thesis it is limited to the acceptance of the use conditions set by the following Creative Commons license: https://creativecommons.org/licenses/?lang=en Programa de doctorado en Medicina Departamento de Medicina Facultad de Medicina Universidad Autónoma de Barcelona TESIS DOCTORAL Caracterización molecular del perfil de resistencias del virus de la hepatitis C después del fallo terapéutico a antivirales de acción directa mediante secuenciación masiva Tesis para optar al grado de doctor de Qian Chen Directores de la Tesis Dr. Josep Quer Sivila Dra. Celia Perales Viejo Dr. Josep Gregori i Font Laboratorio de Enfermedades Hepáticas - Hepatitis Víricas Vall d’Hebron Institut de Recerca (VHIR) Barcelona, 2018 ABREVIACIONES Abreviaciones ADN: Ácido desoxirribonucleico AK: Adenosina quinasa ALT: Alanina aminotransferasa ARN: Ácido ribonucleico ASV: Asunaprevir BOC: Boceprevir CCD: Charge Coupled Device CLDN1: Claudina-1 CHC: Carcinoma hepatocelular DAA: Antiviral de acción directa DC-SIGN: Dendritic cell-specific ICAM-3 grabbing non-integrin DCV: Daclatasvir DSV: Dasabuvir
    [Show full text]
  • NDA 208341 Supplement 14 Clinical Review, Cross Discipline Team Leader and Division Director Summary Memorandum
    NDA 208341 Supplement 14 Clinical Review, Cross Discipline Team Leader and Division Director Summary Memorandum Table of Contents 1. Executive Summary..........................................................................................5 1.1. Summary of Regulatory Action ...................................................................5 1.2. Benefit-Risk Assessment ............................................................................6 1.3. Patient Experience Data .............................................................................9 2. Background ....................................................................................................10 2.1. Product Information...................................................................................11 2.2. Summary of Regulatory Activity Related to Submission ...........................12 2.3. Summary of Study Protocol ......................................................................12 2.3.1. Protocol Amendments ........................................................................14 2.4. Product Quality..........................................................................................16 3. Nonclinical Pharmacology/Toxicology ............................................................16 4. Clinical Pharmacology ....................................................................................16 5. Clinical Microbiology.......................................................................................16 6. Clinical/Statistical: Efficacy .............................................................................16
    [Show full text]
  • Legemiddelforbruket I Norge 2014–2018 Drug Consumption in Norway 2014–2018
    LEGEMIDDELSTATISTIKK 2019:1 Legemiddelforbruket i Norge 2014–2018 Drug Consumption in Norway 2014–2018 Legemiddelforbruket i Norge 2014–2018 Drug Consumption in Norway 2014–2018 Solveig Sakshaug Kristine Olsen Christian Berg Hege Salvesen Blix Live Storehagen Dansie Irene Litleskare Tove Granum Utgitt av Folkehelseinstituttet/Published by Norwegian Institute of Public Health Område for Helsedata og digitalisering Avdeling for Legemiddelstatistikk Mai 2019 Tittel/Title: Legemiddelstatistikk 2019:1 Legemiddelforbruket i Norge 2014–2018/Drug Consumption in Norway 2014–2018 Forfattere/Authors: Solveig Sakshaug (redaktør) Kristine Olsen Christian Berg Hege Salvesen Blix Live Storehagen Dansie Irene Litleskare Tove Granum Bestilling: Rapporten kan lastes ned som pdf på Folkehelseinstituttets nettsider: www.fhi.no The report is only available as pdf from www.fhi.no Grafisk design omslag: Fete Typer Kontaktinformasjon/Contact information: Folkehelseinstituttet/Norwegian Institute of Public Health P.O.Box 222 Skøyen N-0213 Oslo Tel: +47 21 07 70 00 ISSN:1890-9647 ISBN elektronisk utgave: 978-82-8406-011-8 Sitering/Citation: Sakshaug, S (red), Legemiddelforbruket i Norge 2014–2018 [Drug Consumption in Norway 2014–2018], Legemiddelstatistikk 2019:1, Oslo: Folkehelseinstituttet, 2019. Tidligere utgaver/Previous editions: 1977: Legemiddelforbruket i Norge 1974–1976 1978: Legemiddelforbruket i Norge 1975–1977 1980: Legemiddelforbruket i Norge 1975–1979 1981: Legemiddelforbruket i Norge 1980 1982: Legemiddelforbruket i Norge 1977–1981 1984: Legemiddelforbruket
    [Show full text]
  • Helsana Arzneimittelreport 2019
    Ausgabe 2019 Helsana- Arzneimittel- Report Ausgabe 2019 Helsana-Arzneimittelreport The rise of antimicro- bial resistance is a global crisis, that must be managed with the utmost urgency Dr. Margaret Chan, Former Director-General of the World Health Organization (2006 – 2017) Der Helsana-Arzneimittelreport wird im Auftrag von Helsana vom Universitätsspital Basel (USB) und dem Institut für Pharmazeutische Medizin (ECPM) der Universität Basel erstellt. Unser Dank gilt den Mitarbeiterinnen und Mitarbeitern des USB und des ECPM für alle vorgenommenen Auswertungen und für die Erstellung des Reports. Helsana-Arzneimittelreport 2019 3 November 2019 Helsana-Arzneimittelreport für die Schweiz 2019 Auswertungsergebnisse der Helsana Arzneimitteldaten aus den Jahren 2015 bis 2018 Rahel Schneider 1,2 Nadine Schur 3 Daphne Reinau 1,2 Matthias Schwenkglenks 3 Christoph R. Meier 1,2,4 1 Basel Pharmacoepidemiology Unit Abteilung Klinische Pharmazie und Epidemiologie Departement Pharmazeutische Wissenschaften Universität Basel & 2 Spital-Pharmazie Universitätsspital Basel & 3 Institut für Pharmazeutische Medizin (ECPM) Universität Basel & 4 Boston Collaborative Drug Surveillance Program (BCSDP) Lexington, MA, USA Helsana-Arzneimittelreport 2019 4 Helsana-Arzneimittelreport 2019 5 Inhaltsverzeichnis Vorwort .................................................................................................................................................................................... 7 Préface ...................................................................................................................................................................................
    [Show full text]
  • SARS-Cov-2: an Update on Potential Antivirals in Light of SARS-Cov Antiviral Drug Discoveries
    Review SARS-CoV-2: An Update on Potential Antivirals in Light of SARS-CoV Antiviral Drug Discoveries Hatem A. Elshabrawy Department of Molecular and Cellular Biology, College of Osteopathic Medicine, Sam Houston State University, Conroe, TX 77304, USA; [email protected] Received: 18 May 2020; Accepted: 17 June 2020; Published: 23 June 2020 Abstract: Coronaviruses (CoVs) are a group of RNA viruses that are associated with different diseases in animals, birds, and humans. Human CoVs (HCoVs) have long been known to be the causative agents of mild respiratory illnesses. However, two HCoVs associated with severe respiratory diseases are Severe Acute Respiratory Syndrome-CoV (SARS-CoV) and Middle East Respiratory Syndrome-CoV (MERS-CoV). Both viruses resulted in hundreds of deaths after spreading to several countries. Most recently, SARS-CoV-2 has emerged as the third HCoV causing severe respiratory distress syndrome and viral pneumonia (known as COVID-19) in patients from Wuhan, China, in December 2019. Soon after its discovery, SARS-CoV-2 spread to all countries, resulting in millions of cases and thousands of deaths. Since the emergence of SARS-CoV, many research groups have dedicated their resources to discovering effective antivirals that can treat such life-threatening infections. The rapid spread and high fatality rate of SARS-CoV-2 necessitate the quick discovery of effective antivirals to control this outbreak. Since SARS-CoV-2 shares 79% sequence identity with SARS-CoV, several anti-SARS-CoV drugs have shown promise in limiting SARS-CoV-2 replication in vitro and in vivo. In this review, we discuss antivirals described for SARS-CoV and provide an update on therapeutic strategies and antivirals against SARS-CoV-2.
    [Show full text]
  • RESOLVE Protocol Safety, Tolerability and Efficacy of Sofosbuvir
    Version 6.0 September 11, 2017 RESOLVE Protocol Safety, Tolerability and Efficacy of Sofosbuvir, Velpatasvir, and Voxilaprevir in Subjects with previous DAA experience Sponsored by Institute of Human Virology, University of Maryland School of Medicine Baltimore, MD And Gilead Sciences, Inc. Foster City, California IND Number 128754 IND sponsored by Institute of Human Virology, University of Maryland School of Medicine Baltimore, MD Medical Monitor Theo Heller, MD Principal Investigator: Eleanor Wilson, MD, MHS Assistant Professor of Medicine Institute of Human Virology University of Maryland School of Medicine 725 W Lombard Street, Room S218 Baltimore MD 21201 Phone: (410) 706-1710 IRB Initial Approval: February 22, 2016 RESOLVE PROTOCOL PROTOCOL DATE: SEPTEMBER 11, 2017 STUDY ROSTER AND CONTACT INFORMATION Principal Investigator: Protocol Statistician: Eleanor Wilson, MD, MHS Søren Bentzen, Ph.D., Assistant Professor of Medicine Biostatistics Research Branch Institute of Human Virology University of Maryland University of Maryland School of Medicine 725 W Lombard Street, Room S218 Baltimore MD 21201 Collaborating Investigators: Phone: (410) 706-1710 Gebeyehu Teferi, MD, Unity Health Care [email protected] Collaborating Institutions: Research contact/Study Coordinator: Jennifer Hoffmann, MSN, MPH Unity Health Care, Inc./Walker Jones Site AI: Gebeyehu Teferi, MD Associate Investigators: FWA: 00009653, expiration date 6/19/2018 Elizabeth Akoth, RN 40 Patterson Street, NE Benjamin Emmanuel, MPH Washington, DC 20002 Emily Comstock,
    [Show full text]
  • Efficacy of NS5A Inhibitors Against Hepatitis C Virus Genotypes 1-7
    Gastroenterology 2018;154:1435–1448 Efficacy of NS5A Inhibitors Against Hepatitis C Virus Genotypes 1–7 and Escape Variants Judith M. Gottwein, Long V. Pham, Lotte S. Mikkelsen, Lubna Ghanem, Santseharay Ramirez, Troels K. H. Scheel, Thomas H. R. Carlsen, and Jens Bukh Copenhagen Hepatitis C Program, Department of Infectious Diseases and Clinical Research Centre, Hvidovre Hospital and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark Hepatitis C virus NS5A inhibitors pibrentasvir and velpatasvir show pangenotypic efficacy HCV genotype Size~EC50 1 5 2 6 3 7 4 Pibrentasvir showed highest efficacy against hepatitis C virus genotype 1-7 escape variants Daclatasvir Ledipasvir Induction of escape Sequencing of genotype 1-7 Reverse genetics Fold Ombitasvir NS5A domain I Resistance testing Resistance (log10) Elbasvir Ruzasvir 6 Velpatasvir 4 2 Pre-existing Y93H results in escape variants with increased fitness and resistance Pibrentasvir 28 30 31 Δ32 93 Pre-existing Y93H Original .5 .0 .5 .0 .5 0 1 2 3 4 5 6 -1 -1 -0 0 0 Fitness + Fold Resistance (log10) (titer difference, log10) BACKGROUND & AIMS: Inhibitors of the hepatitis C virus For the remaining NS5A inhibitors tested, RAS at amino (HCV) NS5A protein are a key component of effective treatment acids 28 and 93 led to high levels of resistance. Among regimens, but the genetic heterogeneity of HCV has limited the these inhibitors, velpatasvir was more effective against variants efficacy of these agents and mutations lead to resistance. We with RAS at amino acid 30 and some variants with RAS at BASIC AND fi directly compared the ef cacy of all clinically relevant NS5A amino acid 31 than the other agents.
    [Show full text]
  • 02-10-7769 KBH NKF HCV Clin Bulletin V2.Indd
    Managing Hepatitis C and CKD: A Clinical Update > Introduction > Associations Between HCV and CKD > Overview of HCV Evaluation > New Options in HCV Management > Summary Introduction Overview of HCV Evaluation Hepatitis C virus (HCV) is the most common Diagnostic tests consist of two broad categories: chronic blood-borne infection in the United States (1) serologic assays that detect antibodies to HCV, (U.S.) and is more prevalent among patients with and (2) molecular assays that detect or quantify chronic kidney disease (CKD) than in the general HCV RNA.12 The Centers for Disease Control and population.1,2,3 HCV is usually asymptomatic, and Prevention (CDC) recommends a testing sequence detection requires screening patients with risk for identifying current HCV infection, consisting factors and testing for serum HCV antibodies or HCV of initial HCV antibody testing (either rapid or RNA (viral load). The field of HCV has dramatically laboratory-conducted assay) followed by an HCV changed in recent years with the advent of direct- RNA assay for all positive antibody tests.4,13 acting antivirals (DAAs) and multi-class drug Several organizations have provided guidelines for combinations. These newer therapies have been which individuals should be tested. All guidelines the focus of clinical research in recent years for their generally recommend screening patients at improved efficacy (90-100% sustained viral response increased risk for HCV (Table 1).4,13,14 Testing of (SVR) in most cases), with improved side effect patients with CKD should be considered in all profiles and better tolerability. Recently approved patients on dialysis and in CKD patients with DAA regimens can safely and effectively treat unexplained proteinuria, microscopic hematuria, patients with CKD and patients on dialysis.
    [Show full text]