GS-9669: A novel non-nucleoside inhibitor of viral polymerase for the treatment of hepatitis C virus infection

Expert Review of Anti-Infective Therapy

Volumn 12, Issue 10, 2014, Pages 1179-1186

  Gentile, Ivan ^a   Buonomo, Antonio Riccardo ^a   Zappulo, Emanuela ^a   Coppola, Nicola ^b   Borgia, Guglielmo ^a  

^a UNIVERSITY OF NAPLES FEDERICO II   (Italy)

^b SECOND UNIVERSITY OF NAPLES   (Italy)

Author keywords

GS 9669; interferon free; ledipasvir; pegylated interferon; resistance; ribavirin; sofosbuvir

Indexed keywords

GS 9669; LEDIPASVIR; NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR; RIBAVIRIN; SOFOSBUVIR; UNCLASSIFIED DRUG; ANTIVIRUS AGENT; DNA DIRECTED RNA POLYMERASE; FURAN DERIVATIVE; GS-9669; THIOPHENE DERIVATIVE; VIRUS PROTEIN;

ANTIVIRAL ACTIVITY; ANTIVIRAL RESISTANCE; CLINICAL TRIAL (TOPIC); COMBINATION CHEMOTHERAPY; DIARRHEA; DRUG BIOAVAILABILITY; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG HALF LIFE; DRUG IDENTIFICATION; DRUG SAFETY; DRUG STRUCTURE; DRUG TOLERABILITY; HEMOLYTIC ANEMIA; HEPATITIS C; HEPATITIS C VIRUS; HUMAN; HYPOPHOSPHATEMIA; MONOTHERAPY; NAUSEA; NONHUMAN; PLASMA CONCENTRATION-TIME CURVE; PROTHROMBIN TIME; REVIEW; SIDE EFFECT; VIRAL CLEARANCE; VIRUS REPLICATION; VOLUME OF DISTRIBUTION; VOMITING; ANTAGONISTS AND INHIBITORS; CHEMISTRY; DRUG EFFECTS; GENETICS; HEPACIVIRUS;

ANTIVIRAL AGENTS; CLINICAL TRIALS AS TOPIC; DNA-DIRECTED RNA POLYMERASES; DRUG RESISTANCE, VIRAL; FURANS; HEPACIVIRUS; HEPATITIS C; HUMANS; THIOPHENES; VIRAL PROTEINS;

EID: 84907050326     PISSN: 14787210     EISSN: 17448336     Source Type: Journal    
DOI: 10.1586/14787210.2014.945432     Document Type: Review

References (82)

1. Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect 2011;17(2):107-15
2. Hepatitis C. WHO. 2014. Available from: www.who.int/mediacentre/factsheets/fs164/en/[Last accessed 2 July 2014]
3. Smith DB, Bukh J, Kuiken C, et al. Expanded classification of hepatitis C Virus into 7 genotypes and 67 subtypes: updated criteria and assignment web resource. Hepatology 2013;1(10):318-27
4. Maasoumy B, Wedemeyer H. Natural history of acute and chronic hepatitis C. Best Pract Res Clin Gastroenterol 2012; 26(4):401-12
5. Sagnelli E, Pisaturo M, Stanzione M, et al. Clinical presentation, outcome, and response to therapy among patients with acute exacerbation of chronic hepatitis C. Clin Gastroenterol Hepatol 2013;11(9): 1174-80
6. Coppola N, Gentile I, Pasquale G, et al. Anti-HBc positivity was associated with histological cirrhosis in patients with chronic hepatitis C. Ann Hepatol 2013;13(1):20-6
7. Gentile I, Coppola N, Pasquale G, et al. A simple noninvasive score based on routine parameters can predict liver cirrhosis in patients with chronic Hepatitis C. Hepat Mon 2013;13(5):e8352
8. Fortunato G, Calcagno G, Bresciamorra V, et al. Multiple sclerosis and hepatitis C virus infection are associated with single nucleotide polymorphisms in interferon pathway genes. J Interferon Cytokine Res 2008;28(3):141-52
9. Fortunato G, Castaldo G, Oriani G, et al. Multivariate discriminant function based on six biochemical markers in blood can predict the cirrhotic evolution of chronic hepatitis. Clin Chem 2001;47(9):1696-700
10. Gentile I, Meola M, Buonomo AR, et al. Human platelet antigen-3 genotype predicts platelet count in patients with HCV infection. In vivo 2013;27(6):773-7
11. Macaluso FS, Maida M, Minissale MG, et al. Metabolic factors and chronic hepatitis C: a complex interplay. Biomed Res Int 2013;564645(10):17
12. Missiha SB, Ostrowski M, Heathcote EJ. Disease progression in chronic hepatitis C: modifiable and nonmodifiable factors. Gastroenterology 2008;134(6):1699-714
13. Borgia G, Reynaud L, Gentile I, Piazza M. HIV and hepatitis C virus: facts and controversies. Infection 2003;31(4):232-40
14. Gentile I, Buonomo AR, Zappulo E, Borgia G. Is it possible to predict HCV-related liver cirrhosis non-invasively through routine laboratory parameters? Infez Med 2014;22(1):11-18
15. Gentile I, Viola C, Graf M, et al. A simple noninvasive score predicts gastroesophageal varices in patients with chronic viral hepatitis. J Clin Gastroenterol 2009;43(1): 81-7
16. Davis GL, Alter MJ, El-Serag H, et al. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology 2010; 138(2):513-21
17. Alazawi W, Cunningham M, Dearden J, Foster GR. Systematic review: outcome of compensated cirrhosis due to chronic hepatitis C infection. Aliment Pharmacol Ther 2010;32(3):344-55
18. Ferrari SM, Fallahi P, Mancusi C, et al. HCV-related autoimmune disorders in HCV chronic infection. Clin Ter 2013; 164(4):e305-12
19. Coppola N, Pisaturo M, Guastafierro S, et al. Increased hepatitis C viral load and reactivation of liver disease in HCV RNA-positive patients with onco-haematological disease undergoing chemotherapy. Dig Liver Dis 2012;44(1): 49-54
20. Zampino R CN, Cirillo G, Boemio A, et al. Abdominal fat interacts with PNPLA3 I148M, but not with the APOC3 variant in the pathogenesis of liver steatosis in chronic hepatitis C. J Viral Hep 2013;20(8):517-23
21. Coppola N, Pascalis SD, Pisaturo M, et al. Sustained virological response to antiviral treatment in chronic hepatitis C patients may be predictable by HCV-RNA clearance in peripheral blood mononuclear cells. J Clin Virol 2013;S1386-653
22. Fusco F, D'Anzeo G, Rossi A, et al. Erectile dysfunction in patients with chronic viral hepatitis: a systematic review of the literature. Expert Opin Pharmacother 2013; 14(18):2533-44
23. Guadagnino V, Stroffolini T, Rapicetta M, et al. Prevalence, risk factors, and genotype distribution of hepatitis C virus infection in the general population: a community-based survey in southern Italy. Hepatology 1997; 26(4):1006-11
24. Sagnelli E, Stroffolini T, Mele A, et al. The importance of HCV on the burden of chronic liver disease in Italy: a multicenter prevalence study of 9997 cases. J Med Virol 2005;75(4):522-7
25. Guadagnino V, Stroffolini T, Caroleo B, et al. Hepatitis C virus infection in an endemic area of Southern Italy 14 years later: evidence for a vanishing infection. Dig Liver Dis 2013;45(5):403-7
26. Petruzziello A, Coppola N, Diodato AM, et al. Age and gender distribution of hepatitis C virus genotypes in the metropolitan area of Naples. Intervirology 2013;56(3):206-12
27. Carney K, Dhalla S, Aytaman A, et al. Association of tattooing and hepatitis C virus infection: a multicenter case-control study. Hepatology 2013;57(6):2117-23
28. Coppola N, Pisapia R, Tonziello G, et al. Improvement in the aetiological diagnosis of acute hepatitis C: a diagnostic protocol based on the anti-HCV-IgM titre and IgG Avidity Index. J Clin Virol 2009;46(3): 222-9
29. Coppola N, Pisapia R, Marrocco C, et al. Anti-HCV IgG avidity index in acute hepatitis C. J Clin Virol 2007;40(2):110-15
30. Gentile I, De Stefano A, Di Flumeri G, et al. Concomitant interferon-alpha and chemotherapy in hepatitis C and colorectal cancer: a case report. In vivo 2013;27(4): 527-9
31. Gentile I, Di Flumeri G, Scarica S, et al. Acute hepatitis C in patients undergoing hemodialysis: experience with high-dose interferon therapy. Minerva Urol Nefrol 2013;65(1):83-4
32. Gentile I, Borgia G. Surrogate endpoints and non-inferiority trials in chronic viral hepatitis. J Hepatol 2010;52(5):778
33. Braks RE, Ganne-Carrie N, Fontaine H, et al. Effect of sustained virological response on long-term clinical outcome in 113 patients with compensated hepatitis C-related cirrhosis treated by interferon alpha and ribavirin. World J Gastroenterol 2007; 13(42):5648-53
34. Tsuda N, Yuki N, Mochizuki K, et al. Long-term clinical and virological outcomes of chronic hepatitis C after successful interferon therapy. J Med Virol 2004;74(3): 406-13
35. Bruno S, Stroffolini T, Colombo M, et al. Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study. Hepatology 2007; 45(3):579-87
36. Di Marco V, Almasio PL, Ferraro D, et al. Peg-interferon alone or combined with ribavirin in HCV cirrhosis with portal hypertension: a randomized controlled trial. J Hepatol 2007;47(4):484-91
37. Hermine O, Lefrere F, Bronowicki JP, et al. Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med 2002;347(2): 89-94
38. Takahashi K, Nishida N, Kawabata H, et al. Regression of Hodgkin lymphoma in response to antiviral therapy for hepatitis C virus infection. Intern Med 2012;51(19): 2745-7
39. Rosina F, Tosti ME, Borghesio E, et al. Pegylated interferon alpha plus ribavirin for the treatment of chronic hepatitis C: a multicentre independent study supported by the Italian Drug Agency. Dig Liver Dis 2014;27(14):00372-7
40. Recommendations for testing, managing, and treating hepatitis C. AASLD, IDSA. 2014. Available from: www.hcvguidelines. org/fullreport [Last accessed 4 July 2014]
41. EASL Recommendations on Treatment of Hepatitis C. EASL. 2014. Available from: http://files.easl.eu/easl-recommendations-on-treatment-of-hepatitis-C.pdf [Last accessed 4 July 2014]
42. European Medicines Agency recommends approval of sofosbuvir for the treatment of chronic hepatitis C. Agency EM. 2013. Available from: http://www.ema.europa.eu/docs/en-GB/document-library/Press-release/2013/11/WC500155469.pdf [Last accessed 1 February 2014]
43. Approval of Sovaldi (sofosbuvir) tablets for the treatment of chronic hepatitis C. FDA. 2014. Available from: www.fda.gov/forconsumers/byaudience/forpatientadvocates/ucm377920.htm [Last accessed 4 July 2014]
44. Morisco F, Granata R, Stroffolini T, et al. Sustained virological response: a milestone in the treatment of chronic hepatitis C. World J Gastroenterol 2013;19(18):2793-8
45. Chen J, Florian J, Carter W, et al. Earlier sustained virologic response end points for regulatory approval and dose selection of hepatitis C therapies. Gastroenterology 2013;144(7):1450-5
46. Lange CM, Bojunga J, Ramos-Lopez E, et al. Vitamin D deficiency and a CYP27B1-1260 promoter polymorphism are associated with chronic hepatitis C and poor response to interferon-alfa based therapy. J Hepatol 2011;54(5):887-93
47. Ismail MH. Prediction of sustained virologic responses to combination therapy of pegylated interferon-alpha and ribavirin in patients with chronic hepatitis C infection. J Family Community Med 2013;20(1):35-40
48. Borgia G, Gentile I, Fortunato G, et al. Homocysteine levels and sustained virological response to pegylated-interferon alpha2b plus ribavirin therapy for chronic hepatitis C: a prospective study. Liver Int 2009;29(2):248-52
49. Distante S, Bjoro K, Hellum KB, et al. Raised serum ferritin predicts non-response to interferon and ribavirin treatment in patients with chronic hepatitis C infection. Liver 2002;22(3):269-75
50. Gentile I, Viola C, Paesano L, et al. Iron depletion before HCV antiviral therapy: a pilot, randomized, controlled trial. J Clin Apher 2009;24(5):190-6
51. Abu-Mouch S, Fireman Z, Jarchovsky J, et al. Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-naive patients. World J Gastroenterol 2011;17(47):5184-90
52. Nimer A, Mouch A. Vitamin D improves viral response in hepatitis C genotype 2-3 naive patients. World J Gastroenterol 2012;18(8):800-5
53. Coppola N, Marrone A, Pisaturo M, et al. Role of interleukin 28-B in the spontaneous and treatment-related clearance of HCV infection in patients with chronic HBV/HCV dual infection. Eur J Clin Microbiol Infect Dis 2013;1:1
54. Ghany MG, Nelson DR, Strader DB, et al. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011;54(4):1433-44
55. Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009;49(4):1335-74
56. Borgia G, Reynaud L, Gentile I, et al. Pernicious anemia during IFN-alpha treatment for chronic hepatitis C. J Interferon Cytokine Res 2003;23(1):11-12
57. Borgia G, Reynaud L, Gentile I, et al. Myasthenia gravis during low-dose IFN-alpha therapy for chronic hepatitis C. J Interferon Cytokine Res 2001;21(7):469-70
58. Gentile I, Viola C, Reynaud L, et al. Hemolytic anemia during pegylated IFN-alpha2b plus ribavirin treatment for chronic hepatitis C: ribavirin is not always the culprit. J Interferon Cytokine Res 2005; 25(5):283-5
59. Tosone G, Borgia G, Gentile I, et al. A case of pegylated interferon alpha-related diabetic ketoacidosis: can this complication be avoided? Acta Diabetol 2007;44(3):167-9
60. Gentile I, Borgia F, Buonomo AR, et al. A novel promising therapeutic option against hepatitis C virus: an oral nucleotide NS5B polymerase inhibitor sofosbuvir. Curr Med Chem 2013;20(30):3733-42
61. Sarrazin C, Hezode C, Zeuzem S, Pawlotsky JM. Antiviral strategies in hepatitis C virus infection. J Hepatol 2012; 56(1):S88-S100
62. Gentile I, Borgia F, Coppola N, et al. Daclatasvir: the First of a New Class of Drugs Targeted Against Hepatitis C Virus NS5A. Curr Med Chem 2014;21(12): 1391-404
63. Gentile I, Buonomo AR, Borgia F, et al. Ledipasvir: a novel synthetic antiviral for the treatment of HCV Infection. Expert Opin Investig Drugs 2014;23(4):561-71
64. Gentile I, Buonomo A, Zappulo E, et al. Asunaprevir, a protease inhibitor for the treatment of hepatitis C infection. Therapeutics and Clinical Risk Management 2014;10:493-504
65. Gentile I, Coppola N, Buonomo AR, et al. Investigational nucleoside and nucleotide polymerase inhibitors and their use in treating hepatitis C virus. Expert Opin Investig Drugs 2014;In press
66. Gentile I, Buonomo AR, Borgia G. Dasabuvir: a non-nucleoside inhibitor of NS5B for the treatment of hepatitis C virus infection. Rev Recent Clin Trials 2014;In press PMID: 24882169
67. Gentile I, Buonomo AR, Zappulo E, Borgia G. Interferon-free therapies for chronic hepatitis C: toward a hepatitis C virus-free world? Expert Rev Anti Infect Ther 2014;12(7):763-73
68. Scheel TK, Rice CM. Understanding the hepatitis C virus life cycle paves the way for highly effective therapies. Nat Med 2013; 19(7):837-49
69. Gentile I, Viola C, Borgia F, et al. Telaprevir: a promising protease inhibitor for the treatment of hepatitis C virus infection. Curr Med Chem 2009;16(9): 1115-21
70. Gentile I, Carleo MA, Borgia F, et al. The efficacy and safety of telaprevir-a new protease inhibitor against hepatitis C virus. Expert Opin Investig Drugs 2010;19(1): 151-9
71. Lange CM, Zeuzem S. Perspectives and challenges of interferon-free therapy for chronic hepatitis C. J Hepatol 2013;58(3): 583-92
72. Beaulieu PL. Non-nucleoside inhibitors of the HCV NS5B polymerase: progress in the discovery and development of novel agents for the treatment of HCV infections. Curr Opin Investig Drugs 2007;8(8):614-34
73. Soriano V, Vispo E, de Mendoza C, et al. Hepatitis C therapy with HCV NS5B polymerase inhibitors. Expert Opin Pharmacother 2013;14(9):1161-70
74. Lazerwith SE, Lew W, Zhang J, et al. Discovery of GS-9669, a thumb site II non-nucleoside inhibitor of NS5B for the treatment of genotype 1 chronic hepatitis C infection. J Med Chem 2014;57(5): 1893-901
75. Fenaux M, Eng S, Leavitt SA, et al. Preclinical characterization of GS-9669, a thumb site II inhibitor of the hepatitis C virus NS5B polymerase. Antimicrob Agents Chemother 2013;57(2):804-10
76. Lawitz E, Hazan L, Gruener D, et al. GS-9669, A novel ns5b non-nucleotide site ii inhibitor, demonstrates potent antiviral activity, favorable safety profile and potential for once-daily dosing. J Hepatol 2012;56:S471-S
77. German P, Mathias A, Pang PS, et al. Lack of a clinically significant pharmacokinetic drug-drug interaction between sofosbuvir (GS-7977) and GS-5885 or GS-9669 in Healthy Volunteers. Hepatology 2012;56: 1072A-3A
78. Kohli A SZ, Marti M, et al. editor. Combination oral, ribavirin free, antiviral therapy to optimize treatment outcomes for hepatitis C GT-1 treatment naive patients: interim results from the NIAID SYNERGY Trial. 64th Annual Meeting of the American Association for the Study of Liver Diseases; Washington, DC; 2013
79. Gane EJ, Stedman CA, Hyland RH, et al. Efficacy of nucleotide polymerase inhibitor sofosbuvir plus the NS5A Inhibitor ledipasvir or the NS5B non-nucleoside inhibitor GS-9669 against HCV genotype 1 infection. Gastroenterology 2014;146(3):736-43
80. Dvory-Sobol H, Svarovskaia ES, Gontcharova V, et al. Resistance analyses using deep and population sequencing after 3 day monotherapy with GS-9669, a novel non-nucleoside NS5B inhibitor in genotype 1 HCV patients. J Hepatol 2013;58:S485-S
81. Gentile I, Zappulo E, Buonomo AR, Borgia G. Prevention of mother-to-child transmission of HBV and HCV. Expert Rev Anti Infect Ther 2014;12(7):775-82
82. Borgia G, Carleo MA, Gaeta GB, Gentile I. Hepatitis B in pregnancy. World J Gastroenterol 2012;18(34):4677-83