DOCSLIB.ORG

And Ribavirin Oral Therapy for Treatment-Naive HCV Genotype 1: SOUND-C1 Final Results

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
And Ribavirin Oral Therapy for Treatment-Naive HCV Genotype 1: SOUND-C1 Final Results Antiviral Therapy 2013; 18:1015–1019 (doi: 10.3851/IMP2567) Short communication Faldaprevir (BI 201335), deleobuvir (BI 207127) and ribavirin oral therapy for treatment-naive HCV genotype 1: SOUND-C1 final results Stefan Zeuzem1*, Tarik Asselah2, Peter Angus3, Jean-Pierre Zarski4, Dominique Larrey5, Beat Müllhaupt6, Ed Gane7, Marcus Schuchmann8, Ansgar W Lohse9, Stanislas Pol10, Jean-Pierre Bronowicki11, Stuart Roberts12, Keikawus Arasteh13, Fabien Zoulim14, Markus Heim15, Jerry O Stern16, Gerhard Nehmiz17, George Kukolj18, Wulf O Böcher17, Federico J Mensa16 1JW Goethe University Hospital, Frankfurt am Main, Germany 2Service d’Hépatologie, Hôpital Beaujon, Université Diderot-Paris 7, INSERM U773, CRB3, Clichy, France 3Austin Hospital, Heidelberg, Victoria, Australia 4Hôpital Albert Michallon, Grenoble, France 5Département d’Hépato-Gastroentérologie-CIC-IRB INSERM 1040, Hôpital Saint-Eloi, Montpellier, France 6University Hospital of Zürich, Zürich, Switzerland 7Auckland City Hospital, Auckland, New Zealand 8University Medical Center Mainz, Mainz, Germany 9University Hospital Hamburg-Eppendorf, Hamburg, Germany 10Université Paris Descartes, INSERM U1016 et APHP, Hôpital Cochin, Paris, France 11INSERM U954, Centre Hospitalier Universitaire de Nancy, Université de Lorraine, Vandoeuvre-lès-Nancy, France 12Alfred Hospital, Melbourne, Victoria, Australia 13Epimed GmbH, Berlin, Germany 14Hepatology Department, Hospices Civils de Lyon, Lyon University, Lyon, France 15University Hospital Basel, Basel, Switzerland 16Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA 17Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany 18Boehringer Ingelheim (Canada) Ltd, Laval, QC, Canada *Corresponding author e-mail: [email protected] Background: Faldaprevir (BI 201335) and deleobuvir was reported in one patient and re-increase of HCV (BI 207127) are direct-acting antiviral agents under RNA in one patient. Both patients were successfully development for the treatment of chronic HCV infection. treated with interferon-containing therapy. The rate of This article describes the final results of the Phase Ib sustained virological response 24 weeks after comple- SOUND-C1 study that evaluated the interferon-free oral tion of treatment was 73% (11/15) in the deleobuvir combination of faldaprevir, deleobuvir and ribavirin in 32 400 mg group and 94% (16/17) in the 600 mg group. treatment-naive patients infected with HCV genotype 1. During faldaprevir plus pegylated interferon-a2a/ Methods: Patients were randomized to receive deleobuvir ribavirin treatment, the most common adverse events 400 mg (n=15) or 600 mg (n=17) three times daily plus were pruritus (38% of patients), rash (31%) and asthe- faldaprevir 120 mg once daily and weight-based ribavi- nia (31%); these were severe in approximately 3% of rin for 4 weeks. Interferon-free therapy was followed by patients. response-guided faldaprevir plus pegylated interferon- Conclusions: Potent antiviral activity and favourable a2a/ribavirin to week 24 or 48. safety of the treatment regimen were demonstrated. Results: At week 4, 73% (11/15) and 100% (17/17) of Furthermore, the results suggest that patients with patients in the deleobuvir 400 mg and 600 mg groups breakthrough at week 4 may be rescued with an inter- achieved HCV RNA<25 IU/ml, respectively. During feron-containing regimen. Clinical trials.gov number interferon-free treatment, virological breakthrough NCT01132313. ©2013 International Medical Press 1359-6535 (print) 2040-2058 (online) 1015 S Zeuzem et al. Introduction Figure 1. Virological response rates according to deleobuvir (BI 207127) treatment group Many patients with chronic HCV infection cannot be 400 mg three times daily treated due to intolerance or contraindications to inter- 600 mg three times daily feron (IFN), a component of all approved treatment regimens. Trials with new direct-acting antiviral agents 100 100 94 94 (DAAs) aim to improve IFN-containing regimens and 80 to introduce IFN-free therapy. DAAs under develop- 80 73 73 ment include faldaprevir (BI 201335), a potent, selec- % tive non-covalent linear NS3/4A protease inhibitor [1], 60 and deleobuvir (BI 207127), a non-nucleoside NS5B 40 polymerase thumb pocket 1 inhibitor [2]. We recently Patients, reported interim (week 4) results of the Phase Ib, mul- 20 ticentre, open-label, randomized SOUND-C1 study of 11/15 17/17 12/15a 16/17b 11/15 16/17c a novel IFN-free combination [3]. We now report the 0 Wk 4 VR EOT SVR 24 final SOUND-C1 results, including the sustained viro- logical response (SVR) rate 24 weeks after completion aIncludes one patient who switched to pegylated interferon/ribavirin (PEG-IFN/ of treatment (SVR24) and safety data. RBV). Two patients had viral load data missing at end of treatment (EOT). bOne patient had viral load data missing at EOT. cRemaining patient achieved sustained virological response 12 weeks after completion of treatment (SVR12), Methods but was subsequently unavailable for testing and SVR24 assessment was missing. Wk 4 VR, virological response after 4 weeks of treatment (HCV RNA<25 IU/ml). In SOUND-C1, 32 treatment-naive patients with chronic HCV genotype 1 (GT-1) infection were randomized to receive 4 weeks’ treatment with deleobuvir 400 mg or of patients achieved undetectable HCV RNA in the 600 mg three times daily plus faldaprevir 120 mg once deleobuvir 400 mg and 600 mg groups, respectively daily and weight-based ribavirin (RBV), followed by (Figure 1). The SVR24 rate was 73% (11/15) in the faldaprevir 120 mg once daily plus pegylated interferon- deleobuvir 400 mg group and 94% in the 600 mg a2a (PEG-IFN) and RBV for 20 weeks. Depending on group (16/17; one patient was missing the SVR24 extended rapid virological response (HCV RNA<25 IU/ assessment but achieved SVR12). ml at week 4 and undetectable at weeks 5–18), patients During the 4-week IFN-free phase, one patient expe- stopped treatment at week 24 or continued PEG-IFN/ rienced viral breakthrough (≥1 log10 IU/ml rebound in RBV through week 48 (Additional file 1) [3]. HCV RNA from a quantifiable nadir) and another experienced a re-increase in HCV RNA (0.7 log10 IU/ Results ml; Additional file 2). Both were HCV GT-1a-infected patients and received deleobuvir 400 mg. Their viral As previously reported, most baseline characteristics variants have been described previously [3]. After were well balanced between the deleobuvir 400 mg switching on day 29 to PEG-IFN/RBV, the patient three times daily (n=15) and 600 mg three times daily with breakthrough achieved HCV RNA<25 IU/ml by (n=17) groups [3]. More patients had HCV GT-1a week 28, but died shortly thereafter in a road traf- infection in the 400 mg group (67%, 10/15) than in the fic accident. The patient with re-increase achieved 600 mg group (47%, 8/17). Patients (GT-1a or GT-1b) SVR24 after treatment with faldaprevir plus PEG- showed an initial rapid and steep decline in HCV RNA IFN/RBV during weeks 5–24 followed by PEG-IFN/ levels (median HCV RNA decay 3.4 log10 IU/ml in both RBV through week 48. No cases of viral break- groups at day 2), followed by a slower second-phase through or rebound occurred during faldaprevir plus decline until the end of 4 weeks of IFN-free treatment. PEG-IFN/RBV treatment. Two patients with HCV At week 4, 73% (11/15) and 100% (17/17) of patients GT-1a in the deleobuvir 400 mg group (one with in the deleobuvir 400 mg and 600 mg groups achieved and one without prolonged treatment) relapsed after HCV RNA<25 IU/ml, respectively. scheduled EOT (Additional file 2); both patients had Virological response continued after the switch emergent NS3 R155K variants and no known NS5B from IFN-free treatment to faldaprevir plus PEG-IFN/ resistance-associated variants. RBV on day 29. At week 24, 47% (7/15) of patients in There were no severe or serious adverse events (AEs) the deleobuvir 400 mg group and 71% (12/17) in the and no premature treatment discontinuations due 600 mg group stopped treatment; the remainder con- to AEs during IFN-free treatment; the most common tinued PEG-IFN/RBV through to week 48. At the end AEs during this period were mild-to-moderate nausea of treatment (EOT), 80% (12/15) and 94% (16/17) (47%), vomiting (38%), diarrhoea (22%), asthenia 1016 ©2013 International Medical Press HCV genotype 1 oral therapy: SOUND-C1 results (28%), pruritus (28%), rash (16%) and photosensitiv- viral breakthrough or rebound during faldaprevir plus ity (19%) [3]. One patient in the deleobuvir 400 mg PEG-IFN/RBV suggests an effective barrier to resist- group experienced anaemia on day 22 and the RBV ance. The safety and tolerability of IFN-free treatment dose was reduced on day 25. The patient achieved SVR were favourable and consistent with Phase II studies following 20 weeks’ faldaprevir plus PEG-IFN/RBV of faldaprevir plus PEG-IFN/RBV [4,5] and a Phase Ib plus a further 24 weeks’ PEG-IFN/RBV alone. study of deleobuvir plus PEG-IFN/RBV (in which rash From week 5 to EOT during faldaprevir plus PEG- was also observed) [6]. Faldaprevir plus PEG-IFN/ IFN/RBV treatment, the most common AEs were pru- RBV and PEG-IFN/RBV alone were generally well- ritus (38%), rash (31%) and asthenia (31%); these tolerated when given after the IFN-free regimen; 13% were severe in approximately 3% of patients during of patients (4/32) discontinued because of severe AEs this period. Three patients discontinued all drugs due and the predominant AEs – gastrointestinal symptoms, to severe AEs: pancytopenia (one patient: haemo- asthenia and dermatological events, including rash – globin 8.1 g/dl, platelets 58×109/l and white blood were consistent with the Phase II studies mentioned cells 1.9×109/l); eczema and pruritus (one patient) above [4,5]. Changes in haemoglobin and platelets and maculopapular rash, pruritus and eye swelling were consistent with known effects of PEG-IFN/RBV (one patient).
Load more

Recommended publications
  • Faldaprevir, Pegylated Interferon, and Ribavirin for Treatment-Naïve HCV Genotype-1: Pooled Analysis of Two Phase 3 Trials
    Faldaprevir, pegylated interferon and ribavirin. , 2016; 15 (3): 333-349 333 ORIGINAL ARTICLE May-June, Vol. 15 No. 3, 2016: 333-349 The Official Journal of the Mexican Association of Hepatology, the Latin-American Association for Study of the Liver and the Canadian Association for the Study of the Liver Faldaprevir, pegylated interferon, and ribavirin for treatment-naïve HCV genotype-1: pooled analysis of two phase 3 trials Donald M. Jensen,1 Tarik Asselah,2 Douglas Dieterich,3 Graham R. Foster,4 Mark S. Sulkowski,5 Stefan Zeuzem,6 Parvez Mantry,7 Eric M. Yoshida,8 Christophe Moreno,9 Denis Ouzan,10 Mark Wright,11 Luis E. Morano,12 Robert Buynak,13 Marc Bourlière,14 Tarek Hassanein,15 Shuhei Nishiguchi,16 Jia-Horng Kao,17 Masao Omata,18 Seung W. Paik,19 David K. Wong,20 Edward Tam,21 Kelly Kaita,22 S. Victor Feinman,23 Jerry O. Stern,24 Joseph Scherer,24 Anne-Marie Quinson,24 Florian Voss,25 John-Paul Gallivan,25 Wulf O. Böcher,25 Peter Ferenci26 1 University of Chicago Medicine, Chicago, IL, USA. 2 Hôpital Beaujon, APHP, University Paris-Diderot and INSERM CRB3, Clichy, France. 3 Icahn School of Medicine at Mount Sinai, New York, NY, USA. 4 Queen Mary University of London, London, UK. 5 Johns Hopkins University School of Medicine, Baltimore, MD, USA. 6 J.W.Goethe University Hospital, Frankfurt, Germany. 7 The Liver Institute at Methodist Dallas Medical Center, Dallas, TX, USA. 8 University of British Columbia, Vancouver, BC, Canada. 9 CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium. 10 Institut Arnault Tzanck, St.
    [Show full text]
  • Faldaprevir Combined with Peginterferon Alfa2a and Ribavirin In
    Faldaprevir Combined With Peginterferon Alfa-2a and Ribavirin in Chronic Hepatitis C Virus Genotype-1 Patients With Prior Nonresponse: SILEN-C2 Trial Mark S. Sulkowski,1 Marc Bourlie`re,2 Jean-Pierre Bronowicki,3 Tarik Asselah,4 Jean-Michel Pawlotsky,5 Stephen D. Shafran,6 Stanislas Pol,7 Stefan Mauss,8 Dominique Larrey,9 Yakov Datsenko,10 Jerry O. Stern,11 George Kukolj,12 Joseph Scherer,11 Gerhard Nehmiz,10 Gerhard G. Steinmann,10 and Wulf O. B€ocher13 Faldaprevir (BI 201335) is a potent, hepatitis C virus (HCV) NS3/4A protease inhibitor. In all, 290 noncirrhotic HCV genotype (GT)-1 patients with prior null (<1log10 viral load [VL] drop at any time on treatment) or partial response (1log10 VL drop but never undetectable on treatment) were randomized 2:1:1 to receive 48 weeks of peginterferon alfa-2a and ribavirin (PegIFN/RBV) in combination with faldaprevir 240 mg once daily (QD) with 3 days PegIFN/RBV lead-in (LI), 240 mg QD without LI, or 240 mg twice daily (BID) with LI. Patients in the 240 mg QD/LI group achieving maintained rapid virologic response (mRVR; VL <25 IU/mL [Roche TaqMan] at week 4 and undetectable at weeks 8 to 20) were rerandomized to cease all treatment at week 24 or continue PegIFN/RBV up to week 48. Sustained virologic response (SVR) rates were 32%, 50%, and 42% in prior partial responders, and 21%, 35%, and 29% in prior null responders in the faldaprevir 240 mg QD/LI, 240 mg QD, and 240 mg BID/LI groups, respectively.
    [Show full text]
  • Startverso4 PHASE III TRIAL of FALDAPREVIR PLUS PEGYLATED INTERFERON Α-2A and RIBAVIRIN in PATIENTS with HIV and HCV GENOTYPE-1 CO-INFECTION
    STARTVerso4 PHASE III TRIAL OF FALDAPREVIR PLUS PEGYLATED INTERFERON α-2a AND RIBAVIRIN IN PATIENTS WITH HIV AND HCV GENOTYPE-1 CO-INFECTION JK Rockstroh1, M Nelson2, V Soriano3, K Arastéh4, J Guardiola5, S Bhagani6, J Mallolas7, C Tural8, M Puoti9, P Ingiliz10, M Battegay11, MK Jain12, M Núñez13, K Marks14, J Kort15, JO Stern15, R Vinisko15, M Manero16, D Dieterich17, on behalf of the STARTVerso4 Study Group 1University of Bonn, Bonn, Germany; 2Chelsea and Westminster Hospital, London, UK; 3Hospital Carlos III, Madrid, Spain; 4EPIMED, Vivantes Auguste-Viktoria Hospital, Berlin, Germany; 5Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 6Royal Free Hospital, London, UK; 7Hospital Clínic, Barcelona, Spain; Jürgen K. Rockstroh 1099 8Hospital Universitari Germans Trias i Pujol, Barcelona, Spain; 9AO Ospedale Niguarda Cà Granda, Milan, Italy; 10Medizinisches Infektiologiezentrum Berlin (MIB), Berlin, Germany; 11Division of Infectious Diseases and Hospital Epidemiology, Basel, Switzerland; 12UT Southwestern Medical Center, Dallas, TX, USA; 13Wake Forest University, Winston-Salem, NC, USA; 14Weill Cornell Medical College, New York, NY, USA; 15Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA; 16Boehringer Ingelheim España S.A., Barcelona, Spain; 17Mount Sinai School of Medicine, New York, NY, USA [email protected] BACKGROUND RESULTS EFFICACY FIGURE 4e. SVR4 by ART (total population) TABLE 5. AE summary ●● SVR4 was achieved by 74% of patients overall (Figure 3). FDV 120 mg FDV 240 mg + PR + PR Total ●● Faldaprevir (FDV) is a potent inhibitor of HCV NS3/4A.1 PATIENTS - SVR4 rates were comparable across FDV doses and durations of treatment. 24 weeks Total FDV + PR a ●● 1 n (%) (N=123) (N=185) (N=308) FDV has antiviral activity against HCV genotypes (GT) 1, 4, 5, and 6 in vitro.
    [Show full text]
  • Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors
    Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 197 Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors Targeting Different Genotypes and Drug-Resistant Variants ANNA KARIN BELFRAGE ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6192 ISBN 978-91-554-9166-6 UPPSALA urn:nbn:se:uu:diva-243317 2015 Dissertation presented at Uppsala University to be publicly examined in B41 BMC, Husargatan 3, Uppsala, Friday, 27 March 2015 at 09:15 for the degree of Doctor of Philosophy (Faculty of Pharmacy). The examination will be conducted in Swedish. Faculty examiner: Ulf Ellervik (Lunds tekniska högskola). Abstract Belfrage, A. K. 2015. Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors. Targeting Different Genotypes and Drug-Resistant Variants. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 197. 108 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-554-9166-6. Since the first approved hepatitis C virus (HCV) NS3 protease inhibitors in 2011, numerous direct acting antivirals (DAAs) have reached late stages of clinical trials. Today, several combination therapies, based on different DAAs, with or without the need of pegylated interferon-α injection, are available for chronic HCV infections. The chemical foundation of the approved and late-stage HCV NS3 protease inhibitors is markedly similar. This could partly explain the cross-resistance that have emerged under the pressure of NS3 protease inhibitors. The first-generation NS3 protease inhibitors were developed to efficiently inhibit genotype 1 of the virus and were less potent against other genotypes. The main focus in this thesis was to design and synthesize a new class of 2(1H)-pyrazinone based HCV NS3 protease inhibitors, structurally dissimilar to the inhibitors evaluated in clinical trials or approved, potentially with a unique resistance profile and with a broad genotypic coverage.
    [Show full text]
  • Incidence and Predictors of Hepatocellular Carcinoma In
    Massimo Puoti Dept. of Infectious Diseases AO Ospedale Niguarda Cà Granda Milan, Italy The revolving alphabet soup of hepatitis viral infections Hepatitis C drug therapy – present© by and author future ESCMID Online Lecture Library Hepatitis C drug therapy • The present • The future © by author ESCMID Online Lecture Library Anti HCV agents Interferon and Ribavirin © by author ESCMID Online Lecture Library Viral Load vs. Time 1.E+08 • Lack of sensitivity to IFN 1.E+07 • Insufficient antiviral activity 1st phase 1.E+06 2nd phase • Defective clearance of DNA (cp/ml) DNA - 1.E+05 3rd phase infected cells HBV 1.E+04 4th phase 1.E+03 -7 7 21 35 ©49 by63 author77 91 105 119 133 147 161 175 Time (days) • In theESCMID first 2-3 weeks of therapy, Online the viral load Lecturedecline derives mainly Library from the reduction of viral production direct antiviral effect of the drug • Thereafter the viremia decline derives mainly from the clearance of infected cell Colombatto P et al.. Antiv Ther, 2003 Patterns of Virologic Response 7 Null response [1] 6 5 IU/mL) 10 4 Partial response 3 Relapse 40% chance 2 of SVR with © by author pegIFN/RBV[2] HCV RNA (log HCV RNA 1 Undetectable RVR EVR EOT SVR 0 ESCMID-8 -4 -2 0 4Online 8 12 16 Lecture20 24 32 40 48Library 52 60 72 Wks After Start of Therapy 1. Ghany MG, et al. Hepatology. 2009;49:1335-1374. 2. McHutchison JG, et al. N Engl J Med. 2009;361:580-593. WHAT WE HAVE LEARNED ABOUT TREATMENT (IFN) FAILURE Response to IFN alfa depends on : .
    [Show full text]
  • Interplay Between Hepatitis D Virus and the Interferon Response
    viruses Review Interplay between Hepatitis D Virus and the Interferon Response Zhenfeng Zhang 1 and Stephan Urban 1,2,* 1 Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany; [email protected] 2 German Centre for Infection Research (DZIF), Partner Site Heidelberg, 69120 Heidelberg, Germany * Correspondence: [email protected]; Tel.: +49-6221-564-902 Received: 27 October 2020; Accepted: 18 November 2020; Published: 20 November 2020 Abstract: Chronic hepatitis D (CHD) is the most severe form of viral hepatitis, with rapid progression of liver-related diseases and high rates of development of hepatocellular carcinoma. The causative agent, hepatitis D virus (HDV), contains a small (approximately 1.7 kb) highly self-pairing single-strand circular RNA genome that assembles with the HDV antigen to form a ribonucleoprotein (RNP) complex. HDV depends on hepatitis B virus (HBV) envelope proteins for envelopment and de novo hepatocyte entry; however, its intracellular RNA replication is autonomous. In addition, HDV can amplify HBV independently through cell division. Cellular innate immune responses, mainly interferon (IFN) response, are crucial for controlling invading viruses, while viruses counteract these responses to favor their propagation. In contrast to HBV, HDV activates profound IFN response through the melanoma differentiation antigen 5 (MDA5) pathway. This cellular response efficiently suppresses cell-division-mediated HDV spread and, to some extent, early stages of HDV de novo infection, but only marginally impairs RNA replication in resting hepatocytes. In this review, we summarize the current knowledge on HDV structure, replication, and persistence and subsequently focus on the interplay between HDV and IFN response, including IFN activation, sensing, antiviral effects, and viral countermeasures.
    [Show full text]
  • Estimating the Long-Term Clinical and Economic Outcomes of Daclatasvir
    VALUE IN HEALTH REGIONAL ISSUES ] ( ]]]]) ]]]– ]]] Available online at www.sciencedirect.com journal homepage: www.elsevier.com/locate/vhri Estimating the Long-Term Clinical and Economic Outcomes of Daclatasvir Plus Asunaprevir in Difficult-to-Treat Japanese Patients Chronically Infected with Hepatitis C Genotype 1b Phil McEwan, PhD1,2, Thomas Ward, MSc1,*, Samantha Webster, BSc1, Yong Yuan, PhD3, Anupama Kalsekar, MS3, Kristine Broglio, MS4, Isao Kamae, PhD5, Melanie Quintana, PhD4, Scott M. Berry, PhD4, Masahiro Kobayashi, MD6, Sachie Inoue, PhD7, Ann Tang, PhD8, Hiromitsu Kumada, MD6 1Health Economics and Outcomes Research Ltd., Monmouth, UK; 2Centre for Health Economics, Swansea University, Swansea, UK; 3Global Health Economics and Outcomes Research, Princeton, NJ, USA; 4Berry Consultants, LLC, Austin, TX, USA; 5Graduate School of Public Policy, University of Tokyo, Tokyo, Japan; 6Department of Hepatology, Toranomon Hospital, Tokyo, Japan; 7CRECON Research and Consulting, Inc., Tokyo, Japan; 8Health Economics and Outcomes Research, Bristol-Myers K.K., Tokyo, Japan ABSTRACT Objectives: Japan has one of the highest endemic rates of hepatitis C treated with TVR þ pegIFN-α/RBV. Results: Initiating DCV þ ASV virus (HCV) infection. Treatments in Japan are currently limited to treatment in patients in the chronic hepatitis C disease stage resulted interferon-alfa–based regimens, which are associated with tolerability in quality-adjusted life-year gains of 0.96 and 0.77 over TVR þ pegIFN- and efficacy issues. A novel regimen combining two oral HCV α/RBV for NRs and PRs, respectively, and a gain of 2.61 in interferon- therapies, daclatasvir and asunaprevir (DCV þ ASV), has shown alfa–ineligible/intolerant patients over no treatment.
    [Show full text]
  • HCV Eradication with Direct Acting Antivirals (Daas)?
    HCV eradication with direct acting antivirals (DAAs)? Emilie Estrabaud Service d’Hépatologie et INSERM UMR1149, AP-HP Hôpital Beaujon, Paris, France. [email protected] HCV eradication with direct acting antivirals (DAAs)? HCV replication HCV genome and DAAs targets NS3 inhibitors NS5A inhibitors NS5B inhibitors Take home messages HCV viral cycle Asselah et al. Liver Int. 2015;35 S1:56-64. Direct acting antivirals 5’NTR Structural proteins Nonstructural proteins 3’NTR Metalloprotease Envelope Serine protease Glycoproteins RNA Capsid RNA helicase Cofactors Polymerase C E1 E2 NS1 NS2 NS3 NS4A NS4B NS5A NS5B Protease Inhibitors NS5A Inhibitors Polymerase Inhibitors Telaprevir Daclatasvir Nucs Non-Nucs Boceprevir Ledipasvir Simeprevir ABT-267 Sofosbuvir ABT-333 Faldaprevir GS-5816 VX-135 Deleobuvir Asunaprevir Direct Acting Antivirals: 2015 Asselah et al. Liver Int. 2015;35 S1:56-64. Genetic barrier for HCV direct acting antivirals High Nucleos(t)ide 1 mutation= high cost to Analog Inhibitors fitness, 2-3 additional mutations to increase fitness 2 st generation Protease Inhibitors n Non Nucleos(t)ide Analog Inhibitors : NS5 A Inhibitors 1 st generation Protease Inhibitors 1 mutation= low cost to fitness Low Halfon et al. J Hepatol 2011. Vol 55(1):192-206. HCV protease inhibitors (PI) Inhibit NS3/NS4A serine protease responsible for the processing of the polyprotein 1st generation 1st generation, 2nd wave 2nd generation Resistance low low high barrier Genotype activity 1: 1 a< 1b All except 3 all Drug drug Important Less Less interaction Drugs Boceprevir Simeprevir (Janssen) MK-5172 Telaprevir Faldaprevir (BI) ACH-2684 Paritaprevir (ABT-450)/r (AbbVie) Vedroprevir (Gilead) Vaniprevir (Merck) Sovaprevir (Achillion) Asunaprevir (BMS) NS3/NS4A structure Repositioning of helicase domain Self cleavage Lipid Bilayer Inactive Insertion of the Active carboxy-terminal tail Bartenschlager et al.
    [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]
  • S Sofosbuvir (Sovaldi )
    Sofosbuvir (Sovaldi ™) UTILIZATION MANAGEMENT CRITERIA DRUG CLASS: Nucleotide Analog NS5B Polymerase Inhibitor BRAND (generic) NAME: Sovaldi (sofosbuvir ) 400 mg strength tablet FDA -APPROVED INDICATIONS Sovaldi is a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor indicated for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen. • Sovaldi efficacy has been established in subjects with HCV genotype 1, 2, 3 or 4 infection, including those with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation) and those with HCV/HIV -1 co-infection. COVERAGE AUTHORIZATION CRITE RIA Sofosbuvir (Sovaldi) is cover ed for the following condition and situations: • Diagnosis of chronic hepatitis C (CHC) infection with c onfirmed genotype 1, 2, 3, or 4, OR • CHC infection with hepatocellular carcinoma awaiting liver transplant, AND • Sofosbuvir is prescribed in combination with ribavirin and pegylated interferon alfa for genotypes 1 and 4, OR • Sofosbuvir is prescribed in combination with ribavirin for p atients with genotype 1 who are peginterferon-ineligible* (medical record documentation of ineligibility for peginterferon therapy must be submitted for review), OR • Sofosbuvir is prescribed in combination with simeprevir, with or without ribavirin, for 12 weeks duration of therapy, for patients with genotype 1 that have advanced fi brosis (METAVIR score 2, 3, 4, OR cirrhosis secondary to Hepatitis C ), and are peginterferon - ineligible* (medical record
    [Show full text]
  • Pegasys®) Peginterferon Alfa-2B (Peg-Intron®
    Peginterferon alfa-2a (Pegasys®) Peginterferon alfa-2b (Peg-Intron®) UTILIZATION MANAGEMENT CRITERIA DRUG CLASS: Pegylated Interferons BRAND (generic) NAME: Pegasys (peginterferon alfa-2a) Single-use vial 180 mcg/1.0 mL; Prefilled syringe 180 mcg/0.5 mL Peg-Intron (peginterferon alfa-2b) Single-use vial (with 1.25 mL diluent) and REDIPEN®: 50 mcg, 80 mcg, 120 mcg, 150 mcg per 0.5 mL. FDA-APPROVED INDICATIONS PEG-Intron (peginterferon alfa-2b): Combination therapy with ribavirin: • Chronic Hepatitis C (CHC) in patients 3 years of age and older with compensated liver disease. • Patients with the following characteristics are less likely to benefit from re-treatment after failing a course of therapy: previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, and genotype 1 infection. Monotherapy: CHC in patients (18 years of age and older) with compensated liver disease previously untreated with interferon alpha. Pegasys (Peginterferon alfa-2a): • Treatment of Chronic Hepatitis C (CHC) in adults with compensated liver disease not previously treated with interferon alpha, in patients with histological evidence of cirrhosis and compensated liver disease, and in adults with CHC/HIV coinfection and CD4 count > 100 cells/mm3. o Combination therapy with ribavirin is recommended unless patient has contraindication to or significant intolerance to ribavirin. Pegasys monotherapy is indicated for: • Treatment of adult patients with HBeAg positive and HBeAg negative chronic hepatitis B who have compensated
    [Show full text]
  • Combination of Entecavir Or Tenofovir with Pegylated Interferon
    International Journal of Molecular Sciences Review Combination of Entecavir or Tenofovir with Pegylated Interferon-α for Long-Term Reduction in Hepatitis B Surface Antigen Levels: Simultaneous, Sequential, or Add-on Combination Therapy Kanako Yoshida 1, Masaru Enomoto 1,*, Akihiro Tamori 1 , Shuhei Nishiguchi 2,3 and Norifumi Kawada 1 1 Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan; [email protected] (K.Y.); [email protected] (A.T.); [email protected] (N.K.) 2 Division of Medical Science of Regional Cooperation for Liver Diseases, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan; [email protected] 3 Department of Internal Medicine, Kano General Hospital, Osaka 531-0041, Japan * Correspondence: [email protected]; Tel.: +81-666-453-811 Abstract: Seroclearance of hepatitis B surface antigen (HBsAg) (“functional cure”) is the optimal endpoint of antiviral therapy for chronic hepatitis B virus (HBV) infection. Currently available anti-HBV therapy includes nucleoside/nucleotide analogs (NAs) and peginterferon-α (Peg-IFNα). Combination of NAs and Peg-IFNα, each with different mechanisms of action, is an attractive approach for treating chronic HBV infection. In earlier studies, compared with monotherapy using IFNα, combination therapy showed greater on-treatment HBV DNA suppression but no difference in the sustained response. However, responses to the combination of non-pegylated IFNα with Citation: Yoshida, K.; Enomoto, M.; lamivudine or adefovir were not assessed based on HBsAg quantification but were defined by Tamori, A.; Nishiguchi, S.; Kawada, normal alanine aminotransferase levels, testing negative for hepatitis B e-antigen, and low HBV DNA N.
    [Show full text]