NS5A replication complex inhibitor daclatasvir in the basis of chronic hepatitis C interferon-free therapy

The aim of review. To analyze antiviral activity of a new NS5A replication complex inhibitor daclatasvir in patients with chronic HCV-infection in relation to different genotypes, including patients with failure of previous antiviral therapy, with liver cirrhosis, within different modes of treatment.
Summary. Daclatasvir is NS5A inhibitor which has proven high antiviral activity in relation to all hepatitis C virus genotypes. Prescription of the drug in combination to pegilated interferon and ribavirin for treatment-naive patients made possible to reduce treatment duration from 48 to 24 weeks and to increase frequency of sustained virologic response (SVR) to 87% in 1b genotype
and to 100% — in 4-th genotype. Daclatasvir is no less effective within treatment modes that include other direct-acting antiviral agents as well. In combination to asunaprevir (second wave
protease inhibitor) it demonstrated high rate of SVR both in untreated patients (91%), and in «difficult to treat» groups patients — with liver cirrhosis and nonresponders to the previous therapy (up to 83%). Quadrotherapy including pegilated interferon, ribavirin and asunaprevir has allowed to increase treatment efficacy in nonresponders with 1b genotype even more (up to 98,9% of SVR). Combination of daclatasvir and sofosbuvir is considered to be effective as well, demonstrating 96% rate of SVR in patients with the 3-rd genotype without liver cirrhosis, irrespective of treatment experience. A safety profile and tolerability of daclatasvir is good, comparable to placebo group. The drug is not registered in Russia yet, its approval in combination to asunaprevir is expected soon.
Conclusion. Clinical trials have demonstrated that combination of daclatasvir with other medications possessing direct antiviral action, in particular with asunaprevir, and with pegilated interferon and ribavirin significantly increases treatment response rate at different categories of patients with chronic HCV-infection; that allows to reduce treatment duration of these patients
groups. The drug possesses favorable safety profile, including at treatment of liver cirrhosis.

1. Ivashkin V.T. Immune system and liver damages at chronic hepatites B and С. Ros zhurn gastroenterol gepatol koloproktol 2009; 19(6):4-10.

2. Fried M.W., Shiffman M.L., Reddy K.R., et al.

3. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347(13):975-82.

4. Manns M.P., McHutchison J.G., Gordon S.C., et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of

5. chronic hepatitis C: a randomized trial. Lancet 2001; 358(9286):958-65.

6. Lisa C. Casey, William M. Lee. Hepatitis C Virus Therapy Update 2013. Curr Opin Gastroenterol 2013; 29(3):243-9.

7. Guidelines on diagnostics and treatment of hepatitis C in adults, Ministry of Health of the Russian Federation. М., 2014.

8. Jacobson I.M., McHutchison J.G., Dusheiko G., et al.

9. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364(25):2405-16.

10. Ivashkin V.T., Mayevskaya M.V., Morozova M.A., Lyusina Ye.O. Modern modes of treatment of chronic hepatitis С. Ros zhurn gastroenterol gepatol koloproktol 2012; 22(1):36-44.

11. Sherman K.E., Flamm S.L., Afdhal N.H., et al. Responseguided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med 2011; 365(11):1014-24.

12. Bacon B.R., Gordon S.C., Lawitz E., et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011; 364(13):1207-17.

13. Poordad F., McCone J.Jr., Bacon B.R., et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364(13):1195-206.

14. Manns M., Marcellin P., Poordad F.P.F., et al.

15. 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. J Hepatol 2013; 58(Suppl. 1):568.

16. Gao M., Nettles R.E., Belema M., Snyder L.B., Nguyen V.N., Fridell R.A., et al. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 2010; 465:96-100.

17. McGivern D.R., Masaki T., Ping L.F., et al. Kinetic analyses of antiviral suppression by NS5A inhibitors reveal early and potent inhibition of viral assembly and release of infectious virus. Hepatology 2013; 58(Suppl. 1):246.

18. http://www.drugs.com/nda/daclatasvir_150312.html

19. Hezode C., Hirschfield G.M., Ghesquiere W., Sievert W., Rodriguez-Torres M., Shafran S.D., et al. Daclatasvir, an NS5A replication complex inhibitor, combined with peginterferon alfa-2a and ribavirin in treatment-naive HCV-genotype 1 or 4 subjects: phase 2b COMMAND-1 SVR12 results. Hepatology 2012; 56(Suppl. 1):553-4.

20. McPhee F., Sheaffer A.K., Friborg J., et al. Preclinical profi le and characterization of the hepatitis C virus NS3 protease inhibitor asunaprevir (BMS-650032). Antimicrob Agents Chemother 2012; 56:5387-96.

21. Manns M., Pol S., Jacobson I.M., Marcellin P., Gordon S.C., Cheng-Yuan Peng, et al. All-oral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study. Lancet 2014; 384:1597-605.

22. Cornberg M., Razavi H.A., Alberti A., et al. A systematic review of hepatitis C virus epidemiology in Europe, Canada and Israel. Liver Int 2011; 31(Suppl. 2):30-60.

23. Kumada H., Suzuki Y., Ikeda K., et al. Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection. Hepatology 2014; 59:2083-91.

24. Lawitz E., Sulkowski M.S., Ghalib R., RodriguezTorres M., Younossi Z.M., Corregidor A., 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; doi:10.1016/S0140-6736(14)61036-9.

25. Sulkowski M.S., Gardiner D.F., Rodriguez-Torres M., Reddy K.R., Hassanein T., Jacobson I., et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014; 370:211-21.

26. Lok A.S., Gardiner D.F., Hézode C., Lawitz E.J., Bourlière M., Everson G.T., et al. Randomized trial of daclatasvir and asunaprevir with or without Peg IFN/RBV for hepatitis C virus genotype 1 null responders. J Hepatol 2014; 60(3):490-9. doi:10.1016/j.jhep.2013.10.019.

27. Jensen D., Sherman K.E., Hezode C., Pol S., Zeuzem S., de Ledinghen V., et al. on behalf of the HALLMARKQUAD Study Team. Daclatasvir and asunaprevir plus peginterferon alfa and ribavirin in HCV genotype 1 or 4 non-responders. J Hepatol (2015), doi: http://dx.doi. org/10.1016/j.jhep.2015.02.018

28. David R. Nelson, James N. Cooper, Jacob P. Lalezari, Eric Lawitz, Paul J. Pockros, Norman Gitlin, et al. On behalf of the ALLY-3 Study Team University. Alloral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase 3 study. doi:10.1002/hep.27726).].

29. L recommendations on treatment of hepatitis C 2015. J Hepatol (2015), http://dx.doi.org/10.1016/j. jhep.2015.03.025

30. Gregory T. Everson, Karen D. Sims, Maribel RodriguezTorres, Christophe Hézode, Eric Lawitz, Marc Bourlière, et al. Efficacy of an interferonand ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 in treatment-naive patients with HCV genotype 1 infection. Gastroenterology 2014; 146:420-9.

31. Jacobson I., Dimitrova D., Hughes E., et al. Safety profile of daclatasvir in combination with peginterferon alfa and ribavirin in 1100 patients with chronic HCV infection treated in phase 2 studies [abstract 1203]. J Hepatol 2013; 58(Suppl. 1):489.