Results of the ORION open comparative randomized trial: evaluation of efficacy of the Russian drugs Altevir and Phosphogliv in combined treatment of chronic hepatitis C

Aim of investigation. To estimate efficacy and safety of application of «Phosphogliv»® (glycyrrhizinic acid) within combined therapy of patients with chronic hepatitis C (CHC) who received no previous antiviral therapy (AVT).

Material and methods. Overall 80 out-patients over 18 years of age with the diagnosis of CHC confirmed by laboratory and instrumental methods have been included in original study. Patients in group A (n=40) prior to onset of AVT received phosphogliv intravenously (iv) 2,5 g 5 infusions per week for 4 wks, in the subsequent 4 wks it was applied iv on a background of AVT by Altevir® and ribavirin. Altevir was injected subcutaneously in a dose of 3 million IU 3 times per week in combination to ribavirin dosed according to body weight. After the termination of phosphogliv infusions oral intake of phosphogliv forte of 1 capsule tid along with ongoing AVT was prescribed to patients. Total duration of treatment by studied drug for the 1-st HCV genotype patients was 52 wks, with 2nd and 3rd genotypes – 28 wks. The patient of the group B received no phosphogliv treatment, they received only standard AVT according to revealed virus genotype.

Results. Intravenous injection of phosphogliv, prior to beginning of standard AVT, resulted in essential decrease of serum transaminase activity in group A, that was statistically significantly different from initial level. In group B patients with same HCV genotype no dynamics of serum transaminases level prior to AVT was found. Significant decrease of histological activity index in patients with 2/3 genotype of CHC in both groups and change of this score in the group, that received standard AVT in combination to phosphogliv was revealed as well, was much more significant in comparison to the group receiving standard treatment alone. Statistically significant differences in dynamics of viral load and frequency of achievement of sustained virologic response in patients with identical HCV genotype between groups A and B was revealed. No difference in adverse events rate of between groups was observed.

Conclusions. Efficacy of domestic standard IFN-α altevir in combination to ribavirin in CHC treatment at 2nd and 3rd HCV genotypes, and at 1-st genotype HCV in patients with low viral load as well can be considered as high. Addition of phosphogliv to treatment leads to more rapid improvement of biochemical and histological scores.

1. Богомолов П.О., Буеверов А.О. Эффективность и безопасность комбинированной терапии отечественными противовирусными препаратами (интераль и рибапег) хронического гепатита С // Фарматека. – 2006. – № 5. – С. 28–32.

2. Богомолов П.О., Буеверов А.О., Дубинина Н.В. и др. Эффективность лечения больных хроническим гепатитом С с 1-м генотипом вируса стандартным интерфероном альфа // Клин. перспективы гастроэнтерол. гепатол. – 2011. – № 6. – С. 17–22.

3. Богомолов П.О., Буеверов А.О., Кузьмина О.С., Мациевич М.В. Влияние метформина на эффективность противовирусной терапии у больных хроническим гепатитом С с 3-м генотипом вируса (предварительные результаты) // Клин. перспективы гастроэнтерол. гепатол. – 2010. – № 4. – С. 32–39.

4. Болезни печени и желчевыводящих путей / Под ред. В.Т. Ивашкина. – М.: Изд. Дом М-Вести, 2002. – С. 85–90.

5. Ивашкин В.Т., Маевская М.В., Лапшин А.В., Павлов Ч.С. Стандартный интерферон-α в лечении больных хроническим гепатитом С // Рос. журн. гастроэнтерол. гепатол. колопроктол. – 2007. – Т. 18, № 1. – С. 14.

6. Ивашкин В.Т., Морозова М.А., Маевская М.В. и др. Препараты растительного происхождения в лечении гепатита С // Рос. журн. гастроэнтерол. гепатол. колопроктол. – 2009. – Т. 19, № 3. – С. 70–75.

7. Корочкина О.В., Гейвандова Н.И., Ратникова Л.И. и др. Эффективность и безопасность препарата Альтевир при лечении больных хроническим гепатитом С // Клин. перспективы гастроэнтерол. гепатол. – 2009. – № 4.

8. Маевская М.В. Предварительные результаты открытого сравнительного рандомизированного исследования PHG-M3/P01-09 «ОРИОН» по применению препарата «Фосфоглив» в комбинированной терапии больных хроническим гепатитом С // Рос. журн. гастроэнтерол. гепатол. колопроктол. – 2011. – Т. 21, № 4. – С. 52–59.

9. Сведения об инфекционных и паразитарных заболеваниях за 2005 год. Федеральная служба по надзору в сфере защиты прав потребителей и благополучия человека. Федеральный центр гигиены и эпидемиологии. – М., 2006.

10. Сторожаков Г.И., Байкова И.Е., Никитин И.Г. и др. Теоретические и практические аспекты применения глицирризина // Клин. перспективы гастроэнтерол. гепатол. 2003. – № 1. – С. 35–39.

11. Хазанов А.И., Плюснин С.В., Язенок Н.С. Использование российских противовирусных препаратов в лечении хронического гепатита С // Рос. журн. гастроэнтерол. гепатол. колопроктол. – 2005. – Т. 15, № 1. – С. 32.

12. Ющук Н.Д., Климова Е.А., Знойко О.О. и др. Протокол диагностики и лечения больных вирусными гепатитами В и С // Рос. журн. гастроэнтерол. гепатол. колопроктол. – 2010. – Т. 20, № 6. – С. 4–60.

13. Afdhal NH, Levine R, Brown R, et al. Colchicine versus PEG-interferon alfa 2b long term therapy: Results of the 4 year copilot trial. J Hepatol. 2008; 48:4–4.

14. Arase Y, Ikeda K, Murashima N, et al. The long term efficacy of glycyrrhizin in chronic hepatitis C patients. Cancer. 1997; 79:1494–500.

15. Di Bisceglie AM, Shiffman ML, Everson GT, et al. Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon. N Engl J Med. 2008; 359:2429–41.

16. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002; 347:975–82.

17. Hsiang CY, Lai IL, Chao DC, Ho TY. Differential regulation of activator protein 1 activity by glycyrrhizin. Life Sci. 2002; 70:1643–56.

18. Ikeda K, Arase Y, Kobayashi M, et al. A long-term glycyrrhizin injection therapy reduces hepatocellular carcinogenesis rate in patients with interferon-resistant active chronic hepatitis C: a cohort study of 1249 patients. Dig Dis Sci. 2006; 51:603–9.

19. Kumada H. Long-term treatment of chronic hepatitis C with glycyrrhizin [stronger neo-minophagen C (SNMC)] for preventing liver cirrhosis and hepatocellular carcinoma. Oncology. 2002; 62 (suppl 1):94–100.

20. Lindsay KL, Trepo C, Heintges T, et al. A randomized, double-blind trial comparing pegylated interferon alfa2b to interferon alfa-2b as initial treatment for chronic hepatitis C. Hepatology. 2001; 34:395–403.

21. Manns MP, Wedemeyer H, Singer A, et al. The European SNMC Study Group Glycyrrhizin in patients who failed previous interferon alpha-based therapies: biochemical and histological effects after 52 weeks. J Viral Hepatol. 2012; 19 (8):537–46. doi: 10.1111/j.1365-2893.2011.01579.x. Epub 2012 Feb 24.

22. Matsui S, Matsumoto H, Sonoda Y, et al. Glycyrrhizin and related compounds down-regulate production of inflammatory chemokines IL-8 and eotaxin 1 in a human lung fibroblast cell line. Int Immunopharmacol. 2004; 4:1633–44.

23. Miyake K, Tango T, Ota Y, et al. Efficacy of stronger neo-minophagen C compared between two doses administered three times a week on patients with chronic viral hepatitis. J Gastroenterol Hepatol. 2002; 17 (11):1198–204.

24. Moriyama M, Matsumura H, Aoki H, et al. Decreased risk of hepatocellular carcinoma in patients with chronic hepatitis C whose serum alanine aminotransferase levels became less than twice the upper limit of normal following interferon the rapy. Liver Int. 2005; 25:85–90.

25. Moroetal T. Glycyrrhizin and its metabolite inhibit Smad3-mediated type I collagen gene transcription and suppress experimental murine liver fibrosis. Life Sci. 2008; 83:531–9.

26. Ohtsuki K, Abe Y, Shimoyama Y, et al. Separation of phospholipase A2 in Habu snake venom by glycyrrhizin (GL)-affinity column chromatography and identification of a GL-sensitive enzyme. Biol Pharm Bull. 1998; 21:574–8.

27. Orlent H, Hansen BE, Willems M, et al. Biochemical and histological effects of 26 weeks of glycyrrhizin treatment in chronic hepatitis C: a randomized phase II trial. J Hepatol. 2006; 45:539–46.

28. Rino Y, Tarao K, Morinaga S, et al. Reduction therapy of alanine aminotransferase levels prevent HCC development in patients with HCV associated cirrhosis. Anticancer Res. 2006; 26:2221–6.

29. Rosen HR. Chronic hepatitis C infection. Clinical practice. N Engl J Med. 2011; 364:2429–38.

30. Shimoyama Y, Ohtaka H, Nagata N, et al. Physiological correlation between glycyrrhizin, glycyrrhizin-binding lipoxygenase and casein kinase II. FEBS Lett. 1996; 391:238–42.

31. Suzuki H, Ohta T, Takino T, et al. Effects of glycyrrhizin on biochemical tests in patients with chronic hepatitis. Asian Med J. 1983; 26:423–38.

32. Tarao K, Rino Y, Ohkawa S, et al. Association between high serum alanine aminotransferase levels and more rapid development and higher rate of incidence of hepatocellular carcinoma in patients with hepatitis C virus-associated cirrhosis. Cancer. 1999; 86:589–95.

33. Tekla GJ, van Rossum MD, Vulto AG, Wim CJ. Hop glycyrrhizin-induced reduction of ALT in European patients with chronic hepatitis C. Am J Gastroenterol. 2001; 96(8):2291–2.

34. Tsubota A, Fujise K, Namiki Y, Tada N. Peginterferon and ribavirin treatment for hepatitis C virus infection. World J Gastroenterol. 2011; 17:419–32.

35. Van Rossum TG, Vulto AG, Hop WC, et al. Intravenous glycyrrhizin for the treatment of chronic hepatitis C: a double-blind, randomized, placebocontrolled phase I/II trial. J Gastroenterol Hepatol. 1999; 14:1093–1099.

36. Veldt BJ, Hansen BE, Ikeda K, et al. Long-term clinical outcome and effect of glycyrrhizin in 1093 chronic hepatitis C patients with non-response or relapse to interferon. Scand J Gastroenterol. 2006; 41:1087–94.

37. Zaman A, Fennerty MB, Keeffe EB. Systematic review: peginterferon vs. standard interferon in the treatment of chronic hepatitis C. Aliment Pharmacol Ther. 2003; 18:661–70.