EFFICACY AND SAFETY OF THE COMBINATION OF RIBAVIRIN AND PEGYLATED INTERFERON ALFA-2A IN PATIENTS WITH CHRONIC HEPATITIS C: THE RESULTS OF TWO MULTICENTER, PROSPECTIVE, OPEN, NON-COMPARATIVE CLINICAL TRIALS

Aim. Study of efficacy and safety of ribavirin in combination to pegylated interferon α-2a (PegIFN- α-2a) within combined mode of treatment of patients with chronic hepatitis C (CHC) including patients with compensated cirrhosis and and HIV coinfection were conducted. Material and methods. Two open prospective multicenter, non-comparative clinical trials ML16709 NCT00922779 and ML27851 «Standart» (NCT01609049) were conducted. 6661 and 1496 patients with CHC were included accordingly. All were administrated combined therapy: ribavirin and PegIFN- α-2a. Patients with HCV genotype 1 received prescribing treatment for at least 12 but not more than 48 weeks, patients with HCV genotypes 2 and 3 – for at least 12 but not more than 24 weeks. The efficacy analysis included determining the frequency of achieving a rapid virologic response (BVO), an early virologic response (RVO), a virologic response at the end of therapy, and a sustained virologic response (SVR). The safety endpoints were assessed on data of all adverse events (AEs), serious adverse events (SNP), and clinical laboratory findings. Results. At 24 weeks SVR frequency was 43.4% in the subgroup of patients with HCV genotype 1 in the ML16709 study and 72,0% in the ML27851 study; 58,9% and 89,3% in the subgroup of patients with HCV genotypes 2 and 3 accordingly. In the ML27851 study proportion of patients with BVO was 46,8% in patients with HCV genotype 1 and 86,0% in patients with a different HCV genotype. RVO frequency was 37,4% in the subgroup of patients with HCV genotype 1 in the ML16709 study and 90,1% in the ML27851 study; 79,7% and 97,4% in a subgroup of patients with HCV genotypes 2 and 3 accordingly. The proportion of patients with virologic response at the end of therapy was 44,6% in the ML16709 study and 86.7% in the ML27851 study; in a subgroup of patients with genotypes 2 and 3, 73.8% and 97.6%, accordingly. In the ML16709 study 5887 AEs were registered, including 5812 (99%) of non-serious AEs and 75 serious AEs. In the ML27851 study 2557 non-serious AEs occurred in 822 (54.95%) patients. 49 serious AEs were registered in 39 patients (2.6%). Conclusion. The results of studies ML16709 and ML27851 confirm the efficacy and safety of treatment with ribavirin plus peginterferon alfa-2a in patients with chronic hepatitis C. The registered AEs profile is representative of pegylated interferons and ribavirin combination.

chronic hepatitis C, HIV infection, cirrhosis, pegylated interferon alfa-2a, ribavirin

1. Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence // Hepatology. – 2013. – Vol. 57(4) – P. 1333-1342.

2. EASL Recommendations on Treatment of Hepatitis C 2015 // Journal of Hepatology. – 2015. – Vol. 63. – P. 199236.

3. Bogoslovskaya E.V., Shipulin G.A., Rodionova E.N., Lapshin A.V., Maevskaya M.V. Otsenka effektivnosti protivovirusnoy terapii hronicheskogo gepatita С v maksimalno rannie sroki // RZhGGK. – 2007. – №2. – S. 35-39.

4. Ofitsialnaya statistika VICh, SPIDa v Rossii (svezhie dannyie). – Statistika. – 2016 – (https://spid-vich-zppp.ru/ statistika/ofitsialnaya-statistika-vich-spid-rf-2016.html).

5. Stela Bivol, Anya Sarang. Gepatit S v Rossii: epidemiya bezdeystviya. – Izdanie v ramkah proekta «Dostupnost lecheniya gepatita S v Rossii: otsenka situatsii i vyirabotka rekomendatsiy dlya dalneyshih deystviy», finansiruemogo Fondami «Otkryitoe obschestvo» – 2013.

6. Muryivanova N.N. Sotsialnyie problemyi VICh-infektsii regionalnogo urovnya // Fundamentalnyie i prikladnyie issledovaniya v sovremennom mire. Materialyi IV Mezhdunarodnoy nauchno-prakticheskoy konferentsii. – 2013. – S. 184-191.

7. Belozerov E.S. VICh-infektsiya: Rukovodstvo dlya vrachey. – SPb.: InformMed., 2012. – 171 s.

8. Yuschuk N.D., Maksimov, L.M. Ivanova S.L., Klimova E.A., Znoyko O.O., Kravchenko A.V. Kombinirovannaya terapiya hronicheskogo gepatita С pegilirovannyim interferonom.

9. Ascione, M. de Luca, M. T. Tartaglione, F. Lampasi, G. G. di Costanzo, A. G. Lanza, F. P. Picciotto, G. Marino-Marsilia, L. Fontanella, G. Leandro. Kombinatsiya peginterferona alfa2a i ribavirina bolee effektivna dlya lecheniya hronicheskogo virusnogo gepatita C, chem kombinatsiya peginterferona alfa2b i ribavirina // Gastroenterologiya. – 2014. – №1(51). – S. 69-77.

10. Sarkisyants N.K., Grigoryan E.G. Opyit prognozirovaniya pobochnyih effektov lecheniya hronicheskogo virusnogo gepatita С peginterferonom α-2а s ribavirinom // Klinicheskaya meditsina. – 2013. – №5. – S. 46-49.

11. Sherman M, Yoshida EM, Deschenes M, Krajden M, Bain VG, Peltekian K, Anderson F, Kaita K, Simonyi S, Balshaw R, Lee SS. Peginterferon alfa-2a (40KD) plus ribavirin in chronic hepatitis C patients who failed previous interferon therapy // Gut. – 2006. – Vol. 55. – P. 1631-1638.

12. Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C: an update // Hepatology. – 2009. – Vol. 49/ – P. 1335-1374.

13. Manns MP, McHutchison JG, Gordon SC et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial // Lancet. – 2001. – Vol.358. – P. 958-965. 14. Mc Hutchison JG, Gordon SC, Schiff ER et al. Interferon alpha-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group // N. Engl. J. Med. – 1998. – Vol. 339. – P. 1485-1492.

14. Sporea I., Danila M., Sirli R. et al. Comparative study concerning the efficacy of Peg-IFN alpha-2a versus Peg-IFN alpha-2b on the early virological response (EVR) in patients with chronic viral C hepatitis // J. Gastrointest. Liver Dis. – 2006. – Vol.15. – P. 125-130.

15. Yenice N., Mehtap O., Gumrah M. et al. The efficacy of pegylated interferon alpha 2a or 2b plus ribavirin in chronic hepatitis C patients // Turk. J. Gastroenterol. – 2006. – Vol. 17. – P. 94-98.

16. Pockros PJ. An urgency to identify and treat chronic hepatitis C // Minerva Gastroenterol Dietol. – 2005. Vol. 51. – P. 235-246.

17. Yuschuk N. D., Klimova E. A., Znoyko O. O., Karetkina G. N. i dr. Protokol diagnostiki i lecheniya bolnyih virusnyimi gepatitami В i С // Rossiyskiy zhurnal gastoenterologii, gepatologii, koloproktologii. – 2010. – №20 (6). – S. 4-60.

18. Weksler B. B. Review article: the pathophysiology of thrombocytopenia in hepatitis C virus infection and chronic liver disease // Aliment. Pharmacol. Ther. – 2007. – Vol. 26 (1). – P. 13-19.

19. Huang Y., Li M.-H., Hou M., Xie Y. Peginterferon alfa-2a for the treatment of chronic hepatitis C in the era of direct-acting antivirals // Hepatobiliary Pancreat Dis Int. – 2017. – Vol. 16 (5). – P. 470-479.