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Direct-acting antivirals for the treatment of hepatitis C virus infection

Author
Paul J Pockros, MD
Section Editor
Adrian M Di Bisceglie, MD
Deputy Editor
Allyson Bloom, MD

INTRODUCTION

A greater understanding of the hepatitis C virus (HCV) genome and proteins has enabled efforts to improve efficacy and tolerability of HCV treatment. Notably, this has led to the development of multiple direct-acting antivirals (DAAs), which are medications targeted at specific steps within the HCV life cycle (figure 1). DAAs are molecules that target specific nonstructural proteins of the virus and results in disruption of viral replication and infection. There are four classes of DAAs, which are defined by their mechanism of action and therapeutic target. The four classes are nonstructural proteins 3/4A (NS3/4A) protease inhibitors (PIs), NS5B nucleoside polymerase inhibitors (NPIs), NS5B non-nucleoside polymerase inhibitors (NNPIs), and NS5A inhibitors [1].

This topic reviews the mechanism of action, pharmacology, and spectrum of use of these various agents. Other important issues related to the treatment of chronic HCV infection, including patient evaluation, selection of treatment regimen, and other management issues are discussed in detail elsewhere. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection" and "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults" and "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults" and "Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and 6 infection in adults" and "Overview of the management of chronic hepatitis C virus infection".)

Many direct-acting antivirals are in various stages of development and are not yet available. These are discussed in detail elsewhere.

VIRAL LIFE CYCLE AND REPLICATION

The main targets of the direct-acting antiviral agents are the HCV-encoded proteins that are vital to the replication of the virus (figure 1). The infectious viral structure is comprised of envelope glycoproteins in a lipid bilayer that contain the viral core protein and RNA [2]. After cell entry, the viral RNA is translated through host machinery into a polyprotein, which is cleaved during and after translation by both host and viral-encoded proteases into 10 mature viral proteins, including a number of nonstructural (NS) proteins. One of the viral proteases involved in this post-translational processing is a heterodimeric complex of the NS3 and NS4A proteins (NS3/NS4A). NS3 possesses the proteolytic activity and NS4 is a membrane protein that acts as a cofactor. Synthesis of new viral RNA occurs in a highly structured replication complex that consists of NS3, NS4A, NS4B, NS5A, and NS5B. NS5B is an RNA-dependent RNA polymerase that is essential for viral replication. NS5A has a presumptive role in the organization of the replication complex and in regulating replication. It is also involved in assembly of the viral particle that is released from the host cell.

Direct-acting antivirals are inhibitors of the NS3/4A protease, the NS5A protein, and the NS5B polymerase.

                     

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Literature review current through: Nov 2016. | This topic last updated: Fri Jul 29 00:00:00 GMT+00:00 2016.
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References
Top
  1. Poordad, F, Dieterich, D. Treating hepatitis C: current standard of care and emerging direct-acting antiviral agents. J. Viral Hepat 2012; 19:449.
  2. Scheel TK, Rice CM. Understanding the hepatitis C virus life cycle paves the way for highly effective therapies. Nat Med 2013; 19:837.
  3. Pockros, PJ. New direct-acting antivirals in the development for hepatitis C virus infection. Therap. Adv. Gastroenterol 2010; 3:191.
  4. US Food and Drug Administration. Approval of Victrelis (boceprevir) a direct acting antiviral drug (DAA) to treat hepatitis C virus (HCV). http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/ucm255413. (Accessed on August 1, 2013).
  5. US Food and Drug Administration. Approval of Incivek (telaprevir) a direct
  6. Hunt, D, Pockros, PJ. What are the promising new therapies in the field of chronic hepatitis C after the first-generation direct-acting antivirals? Curr. Gastroenterol 2013; 15:303.
  7. Prescribing Information for OLYSIOTM (simeprevir): Janssen Therapeutics, Division of Janssen Products, LP, Titusville NJ 08560. Issued November 2013.
  8. Olysio (simeprevir). US FDA approved product information. National Library of Medicine. Available online at http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=1816fd68-0ed7-4a37-84bb-e298c5ab6e28 (Accessed on November 17, 2014).
  9. FDA. Olysio U.S. prescribing information http://www.accessdata.fda.gov/drugsatfda (Accessed on October 15, 2014).
  10. Jacobson IM, Dore, GJ, Foster GR, et al. Simeprevir (TMC435) with peginterferon/ribavirin for chronic hCV genotype 1 infection in treatment-naïve patients: results from QUEST-1, a phase III trial. Presented at the 48th annual meeting of the European Association for the Study of the Liver, Amsterdam, The Netherlands, April 24-28, 2013. Abstract 1425.
  11. Manns M, Marcellin P, Poordad F, et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype 1 infection in treatment-naive patients: results from QUEST-2, a phase III trial. Presented at the 48th annual meeting of the European Association for the Study of the Liver, Amsterdam, The Netherlands, April 24-28, 2013. Abstract 1413.
  12. Williams JA, Ring BJ, Cantrell VE, et al. Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7. Drug Metab Dispos 2002; 30:883.
  13. Ali A, Aydin C, Gildemeister R, et al. Evaluating the role of macrocycles in the susceptibility of hepatitis C virus NS3/4A protease inhibitors to drug resistance. ACS Chem. Biol 2013; 8:1469.
  14. Lenz O, Fevery B, Verbinnen T, et al. Resistance analyses of HCV isolates from patients treated with simeprevir in phase 2b/3 studies. Presented at the 64th annual meeting of the American Association for the Study of Liver Diseases, Washington, DC, November 1-5, 2013. Abstract #1101.
  15. Lawitz E, Sulkowski MS, Ghalib R, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet 2014; 384:1756.
  16. Evans MJ, Rice, CM, Goff SP. Phosphorylation of hepatitis C virus nonstructural protein 5A modulates its protein interactions and viral RNA replication. Proc. Natl. Acad. Sci. 2004; 101:13038.
  17. Tellinghuisen TL, Foss KL, Treadaway J. Regulation of hepatitis C virion production via phosphorylation of the NS5A protein. PLoS Pathog. 4, e1000032 (2008).
  18. Gao M, Nettles RE, Belema M, et al. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 2010; 465:96.
  19. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014; 370:1879.
  20. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014; 370:211.
  21. Nelson DR, Cooper JN, Lalezari JP, et al. All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology 2015; 61:1127.
  22. Sovaldi (sofosbuvir). US FDA approved product information; Foster City, CA: Gilead Sciences; December 2013.
  23. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368:1878.
  24. Lawitz E, Lalezari JP, Hassanein T, et al. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial. Lancet Infect Dis 2013; 13:401.
  25. Kowdley KV, Lawitz E, Crespo I, et al. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet 2013; 381:2100.
  26. Fontaine H, Lazarus A, Pol S, et al. Bradyarrhythmias Associated with Sofosbuvir Treatment. N Engl J Med 2015; 373:1886.
  27. Brainard DM, McHutchison JG. Bradyarrhythmias Associated with Sofosbuvir Treatment. N Engl J Med 2015; 373:1888.
  28. FDA Hepatitis Update - Important safety information: Harvoni and Sovaldi. March 21, 2015. http://content.govdelivery.com/accounts/USFDA/bulletins/f97c71 (Accessed on March 30, 2015).
  29. Renet S, Chaumais MC, Antonini T, et al. Extreme bradycardia after first doses of sofosbuvir and daclatasvir in patients receiving amiodarone: 2 cases including a rechallenge. Gastroenterology 2015; 149:1378.
  30. Rajyaguru S, Xu S, Hebner C, et al. Sofosbuvir selects the NS5B S282T mutation in vitro in genotype 1-6 replicons and is not cross-resistant to resistance associated variants selected by other classes of antiviral inhibitors. Presented at the 64th annual meeting of the American Association for the Study of Liver Diseases, Washington, DC, November 1-5, 2013. Abstract #1094.
  31. Harvoni (ledipasvir-sofosbuvir). US FDA approved product information. National Library of Medicine.
  32. Svarovskaia ES, Dvory-Sobol H, Parkin N, et al. Infrequent development of resistance in genotype 1-6 hepatitis C virus-infected subjects treated with sofosbuvir in phase 2 and 3 clinical trials. Clin Infect Dis 2014; 59:1666.
  33. Au J, Pockros PJ. Novel Therapeutic Approaches for Hepatitis C. Clin Pharmacol Ther. 2013 Oct 14. doi: 10.1038/clpt.2013.206. [Epub ahead of print]
  34. Zepatier (elbasvir and grazoprevir). US FDA approved product information; Whitehouse Station, NJ: Merck and Co, Inc; January 2016.
  35. Zeuzem S, Ghalib R, Reddy KR, et al. Grazoprevir-Elbasvir Combination Therapy for Treatment-Naive Cirrhotic and Noncirrhotic Patients With Chronic Hepatitis C Virus Genotype 1, 4, or 6 Infection: A Randomized Trial. Ann Intern Med 2015; 163:1.
  36. Lawitz E, Gane E, Pearlman B, et al. Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without cirrhosis (C-WORTHY): a randomised, open-label phase 2 trial. Lancet 2015; 385:1075.
  37. Thompson A, Zeuzem S, Rockstroh J, Kwo P, et al. The combination of elbasvir and grazoprevir ± RBV is highly effective for the treatment of GT1a-infected patients. Presented at the American Association for the Study of Liver Diseases Liver Meeting, San Francisco CA, November 13-17, 2015.
  38. VIEKIRA PAK (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets). US FDA approved product information. National Library of Medicine. www.dailymed.nlm.nih.gov (Accessed on January 01, 2015).
  39. Feld JJ, Kowdley KV, Coakley E, et al. Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med 2014; 370:1594.
  40. Zeuzem S, Jacobson IM, Baykal T, et al. Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med 2014; 370:1604.
  41. Ferenci P, Bernstein D, Lalezari J, et al. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med 2014; 370:1983.
  42. Andreone P, Colombo MG, Enejosa JV, et al. ABT-450, ritonavir, ombitasvir, and dasabuvir achieves 97% and 100% sustained virologic response with or without ribavirin in treatment-experienced patients with HCV genotype 1b infection. Gastroenterology 2014; 147:359.
  43. FDA Drug Safety Communication: FDA warns of serious liver injury risk with hepatitis C treatments Viekira Pak and Technivie. October 22, 2015. http://www.fda.gov/Drugs/DrugSafety/ucm468634.htm (Accessed on October 22, 2015).
  44. Jacobson IM, Brau N, Bourgeois S, et al. The tolerability of sofosbuvir/velpatasvir for 12 Weeks in >1000 patients treated in the ASTRAL-1, ASTRAL-2, and ASTRAL-3 studies: An integrated safety analysis. Presented at the 51st Annual Meeting of the European Association for the Study of the Liver (EASL), Barcelona, Spain, April 13-17, 2016.
  45. 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.
  46. 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.