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Investigational therapies for hepatitis C virus infection

Authors
Andrew W Tai, MD, PhD
Raymond T Chung, MD
Section Editor
Adrian M Di Bisceglie, MD
Deputy Editor
Allyson Bloom, MD

INTRODUCTION

Major research efforts are underway to identify new therapies for chronic hepatitis C virus (HCV) infection that achieve very high sustained virologic response (SVR) rates, lower the incidence of side effects, have few drug-drug interactions, and/or shorten the duration of treatment. The main targets of most new therapies are the HCV-encoded proteins that are vital to the replication and life cycle of the virus. These targets include the HCV-encoded NS2/3 autoprotease, the NS3/4A serine protease, the NS3 RNA helicase, the NS5A protein, and the NS5B RNA dependent RNA polymerase (RdRp). Another line of investigation has focused on host-encoded proteins that are essential for viral replication, such as cyclophilins.

This topic review will summarize the current state of knowledge of some of the investigational therapies for chronic HCV infection, including those whose efficacy appears to have been disproven. These can be divided conceptually into:

Treatments targeting HCV-encoded proteins

Treatments targeting host-encoded proteins

Therapeutic and preventive vaccines

                      

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Literature review current through: Nov 2016. | This topic last updated: Mon Aug 29 00:00:00 GMT+00:00 2016.
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References
Top
  1. Lohmann V, Körner F, Koch J, et al. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 1999; 285:110.
  2. Wakita T, Pietschmann T, Kato T, et al. Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med 2005; 11:791.
  3. Thompson AJ, Muir AJ, Sulkowski MS, et al. Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus. Gastroenterology 2010; 139:120.
  4. Jacobson IM, Catlett I, Marcellin P, et al. Telaprevir substantially improves SVR rates across all IL28B genotypes in the ADVANCE trial. Presented at the 46th Annual Meeting of the European Association for the Study of the Liver. Berlin, Germany; March 30-April 3, 2011.
  5. Poordad F, Bronowicki JP, Gordon SC, et al. IL28B polymorphism predicts virological response in patients with chronic hepatitis C genotype 1 treated with boceprevir (BOC) combination therapy. Presented at the 46th Annual Meeting of the European Association for the Study of the Liver. Berlin, Germany; March 30-April 3, 2011.
  6. Tellinghuisen TL, Foss KL, Treadaway J. Regulation of hepatitis C virion production via phosphorylation of the NS5A protein. PLoS Pathog 2008; 4:e1000032.
  7. McCown MF, Rajyaguru S, Le Pogam S, et al. The hepatitis C virus replicon presents a higher barrier to resistance to nucleoside analogs than to nonnucleoside polymerase or protease inhibitors. Antimicrob Agents Chemother 2008; 52:1604.
  8. Feld JJ, Jacobson IM, Hézode C, et al. Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection. N Engl J Med 2015; 373:2599.
  9. Foster GR, Afdhal N, Roberts SK, et al. Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection. N Engl J Med 2015; 373:2608.
  10. Pianko S, Flamm SL, Shiffman ML, et al. Sofosbuvir Plus Velpatasvir Combination Therapy for Treatment-Experienced Patients With Genotype 1 or 3 Hepatitis C Virus Infection: A Randomized Trial. Ann Intern Med 2015; 163:809.
  11. Curry MP, O'Leary JG, Bzowej N, et al. Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis. N Engl J Med 2015; 373:2618.
  12. Everson GT, Towner WJ, Davis MN, et al. Sofosbuvir With Velpatasvir in Treatment-Naive Noncirrhotic Patients With Genotype 1 to 6 Hepatitis C Virus Infection: A Randomized Trial. Ann Intern Med 2015; 163:818.
  13. Gane EJ, Hyland RH, Yang Y, et al. Sofosbuvir/GS-5816+GS-9857 for 6 or 8 weeks in genotype 1 or 3 HCV-infected patients. Presented at the American Association for the Study of Liver Diseases Liver Meeting, San Francisco CA, November 13-17, 2015. Abstract #38.
  14. 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; 146:736.
  15. Kohli A, Osinusi A, Sims Z, et al. Virological response after 6 week triple-drug regimens for hepatitis C: a proof-of-concept phase 2A cohort study. Lancet 2015; 385:1107.
  16. Lawitz E, Poordad F, Hyland RH, et al. High rates of SVR in treatment-experienced patients with genotype 1 HCV infection and cirrhosis after treatment with ledipasvir/sofosbuvir and vedroprevir with or without ribavirin for 8 weeks. Presented at the American Association for the Study of Liver Diseases Liver Meeting, San Francisco CA, November 13-17, 2015. Abstract #247.
  17. Kohli A, Kattakuzhy S, Sidharthan S, et al. Four-Week Direct-Acting Antiviral Regimens in Noncirrhotic Patients With Hepatitis C Virus Genotype 1 Infection: An Open-Label, Nonrandomized Trial. Ann Intern Med 2015; 163:899.
  18. Wyles DL, Rodriguez-Torres M, Lawitz E, et al. All-oral combination of ledipasvir, vedroprevir, tegobuvir, and ribavirin in treatment-naïve patients with genotype 1 HCV infection. Hepatology 2014; 60:56.
  19. Poordad F, Felizarta F, Asatryan A, et al. 98-100% SVR4 in HCV genotype 1 non-cirrhotic treatment-naive or pegylated interferon/ribavirin null responders with the combination of the next generation NS3/4A protease inhibitor ABT-493 and NS5A inhibitor ABT-530 (SURVEYOR-I). Presented at the American Association for the Study of Liver Diseases Liver Meeting, San Francisco CA, November 13-17, 2015. Abstract #41.
  20. Poordad F, Felizarta F, Asatryan A, et al. 100% SVR4 in HCV genotype 1 non-cirrhotic treatment-naive or experienced patients with the combination of ABT-493 and ABT-530 for 8 weeks (SURVEYOR-I). Presented at the American Association for the Study of Liver Diseases Liver Meeting, San Francisco CA, November 13-17, 2015. Abstract #LB-14.
  21. Kwo PY, Bennett M, Wang S, et al. High SVR4 rates with the next generation NS3/4A protease inhibitor ABT-493 and NS5A inhibitor ABT-530 in non-cirrhotic treatment-naive and treatment-experiences patients with HCV genotype 3 infection (SURVEYOR-2). Presented at the American Association for the Study of Liver Diseases Liver Meeting, San Francisco CA, November 13-17, 2015. Abstract #248.
  22. Wyles D, Sulkowski M, Wang S, et al. High SVR4 rates achieved with the next generation NS3/4A protease inhibitor ABT-493 and NS5A inhibitor ABT-530 in non-cirrhotic treatment-naive and treatment-experiences patients with HCV genotype 2 infection (SURVEYOR-2). Presented at the American Association for the Study of Liver Diseases Liver Meeting, San Francisco CA, November 13-17, 2015. Abstract #250.
  23. Gane EJ, Pockros PJ, Zeuzem S, et al. Mericitabine and ritonavir-boosted danoprevir with or without ribavirin in treatment-naive HCV genotype 1 patients: INFORM-SVR study. Liver Int 2015; 35:79.
  24. Feld JJ, Jacobson IM, Jensen DM, et al. Randomized study of danoprevir/ritonavir-based therapy for HCV genotype 1 patients with prior partial or null responses to peginterferon/ribavirin. J Hepatol 2015; 62:294.
  25. Kumada H, Suzuki Y, Ikeda K, et al. Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection. Hepatology 2014; 59:2083.
  26. Manns M, Pol S, Jacobson IM, et al. All-oral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study. Lancet 2014; 384:1597.
  27. Everson GT, Sims KD, Rodriguez-Torres M, et al. Efficacy of an interferon- and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 in treatment-naive patients with HCV genotype 1 infection. Gastroenterology 2014; 146:420.
  28. Poordad F, Sievert W, Mollison L, et al. Fixed-dose combination therapy with daclatasvir, asunaprevir, and beclabuvir for noncirrhotic patients with HCV genotype 1 infection. JAMA 2015; 313:1728.
  29. Muir AJ, Poordad F, Lalezari J, et al. Daclatasvir in combination with asunaprevir and beclabuvir for hepatitis C virus genotype 1 infection with compensated cirrhosis. JAMA 2015; 313:1736.
  30. Jopling CL, Yi M, Lancaster AM, et al. Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA. Science 2005; 309:1577.
  31. Lanford RE, Hildebrandt-Eriksen ES, Petri A, et al. Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 2010; 327:198.
  32. Janssen HL, Reesink HW, Lawitz EJ, et al. Treatment of HCV infection by targeting microRNA. N Engl J Med 2013; 368:1685.
  33. Van der Ree MH, de Vree JML, Stelma F, et al. A single subcutaneous dose of 2 mg/kg or 4 mg/kg of RF-101, a GalNAc-conjugated oligonucleotide with antagonist activity against miR-122, results in significant viral load reductions in chronic hepatitis C patients. Presented at the 50th Annual Meeting of the European Association for the Study of the Liver, Vienna, Austria; April 22-26, 2015.
  34. Watashi K, Hijikata M, Hosaka M, et al. Cyclosporin A suppresses replication of hepatitis C virus genome in cultured hepatocytes. Hepatology 2003; 38:1282.
  35. Yang F, Robotham JM, Nelson HB, et al. Cyclophilin A is an essential cofactor for hepatitis C virus infection and the principal mediator of cyclosporine resistance in vitro. J Virol 2008; 82:5269.
  36. Paeshuyse J, Kaul A, De Clercq E, et al. The non-immunosuppressive cyclosporin DEBIO-025 is a potent inhibitor of hepatitis C virus replication in vitro. Hepatology 2006; 43:761.
  37. http://www.medpagetoday.com/InfectiousDisease/Hepatitis/32252 (Accessed on April 20, 2012).
  38. Pawlotsky JM, Flisiak R, Sarin SK, et al. Alisporivir plus ribavirin, interferon free or in combination with pegylated interferon, for hepatitis C virus genotype 2 or 3 infection. Hepatology 2015; 62:1013.
  39. Zeuzem S, Flisiak R, Vierling JM, et al. Randomised clinical trial: alisporivir combined with peginterferon and ribavirin in treatment-naïve patients with chronic HCV genotype 1 infection (ESSENTIAL II). Aliment Pharmacol Ther 2015; 42:829.
  40. Buti M, Flisiak R, Kao JH, et al. Alisporivir with peginterferon/ribavirin in patients with chronic hepatitis C genotype 1 infection who failed to respond to or relapsed after prior interferon-based therapy: FUNDAMENTAL, a Phase II trial. J Viral Hepat 2015; 22:596.
  41. Gordon FD, Chung RT, Curry MP, et al. Monoclonal antibody MBL-HCV1 suppresses return of HCV following liver transplantation. Hepatology 2011; 54:1434A.
  42. Sallberg M, Frelin L, Diepolder H, et al. A first clinical trial of therapeutic vaccination using naked DNA delivered by in vivo electroporation shows antiviral effects in patients with chronic hepatitis C. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver, Copenhagen, Denmark; April 22-26, 2009; abstract #43.
  43. Pockros P, Jacobson I, Boyer TD, et al. GI-5005 therapeutic vaccine plus PEG-IFN/ribavirin improves sustained virologic response versus PEG-IFN/ribavirin in piror non-responders with genotype 1 chronic HCV infection. Hepatology 2010; 52:404A.
  44. Shiffman ML, Muir AJ, Vierling JM, et al. GI-5005 therapeutic vaccine enhances virologic clearance by Peg-IFN/ribavirin in naïve HCV genotype 1 patients with IL28B genotype T/T. Presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases, Boston, MA; November 9-13, 2012.
  45. Di Bisceglie AM, Janczweska-Kazek E, Habersetzer F, et al. Efficacy of immunotherapy with TG4040, peg-interferon, and ribavirin in a Phase 2 study of patients with chronic HCV infection. Gastroenterology 2014; 147:119.
  46. Folgori A, Capone S, Ruggeri L, et al. A T-cell HCV vaccine eliciting effective immunity against heterologous virus challenge in chimpanzees. Nat Med 2006; 12:190.
  47. Elmowalid GA, Qiao M, Jeong SH, et al. Immunization with hepatitis C virus-like particles results in control of hepatitis C virus infection in chimpanzees. Proc Natl Acad Sci U S A 2007; 104:8427.
  48. Swadling L, Capone S, Antrobus RD, et al. A human vaccine strategy based on chimpanzee adenoviral and MVA vectors that primes, boosts, and sustains functional HCV-specific T cell memory. Sci Transl Med 2014; 6:261ra153.
  49. Seeff LB, Curto TM, Szabo G, et al. Herbal product use by persons enrolled in the hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial. Hepatology 2008; 47:605.
  50. Liu J, Manheimer E, Tsutani K, Gluud C. Medicinal herbs for hepatitis C virus infection: a Cochrane hepatobiliary systematic review of randomized trials. Am J Gastroenterol 2003; 98:538.
  51. Polyak SJ, Morishima C, Shuhart MC, et al. Inhibition of T-cell inflammatory cytokines, hepatocyte NF-kappaB signaling, and HCV infection by standardized Silymarin. Gastroenterology 2007; 132:1925.
  52. Ferenci P, Scherzer TM, Kerschner H, et al. Silibinin is a potent antiviral agent in patients with chronic hepatitis C not responding to pegylated interferon/ribavirin therapy. Gastroenterology 2008; 135:1561.
  53. Wagoner J, Negash A, Kane OJ, et al. Multiple effects of silymarin on the hepatitis C virus lifecycle. Hepatology 2010; 51:1912.
  54. Fried MW, Navarro VJ, Afdhal N, et al. Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy: a randomized controlled trial. JAMA 2012; 308:274.
  55. Jakkula M, Boucher TA, Beyendorff U, et al. A randomized trial of Chinese herbal medicines for the treatment of symptomatic hepatitis C. Arch Intern Med 2004; 164:1341.