Comparative Efficacy of Etiotropic Therapy of Patients with HBeAg-Positive Chronic Hepatitis B (by the Data of the International Comparative Placebo-Controlled Study)

Comparative placebo-controlled study entrolled 647 patients with verified diagnosis of chronic virus hepatitis B (HBeAg+), not previously subjected to antiviral therapy (with nucleotide analogues or interferons). The drug under the investigation was cycloferon, an earlier interferon inductor. The antiviral combination therapy of the main group patients (323 subjects) included the use of cycloferon + lamivudine for 48 weeks and the therapy of the control group patients (324 subjects) included the use of lamivudine + placebo for 48 weeks. The cycloferon and lamividine combination antiviral therapy was shown preferable vs. the lamivudine + placebo therapy by biochemical remission, virusological response, seroconversion by HBeAg by the 48th week of the treatment and HBsAg clearance. The conbination therapy provided lower frequency of the ralapses within 24 weeks of the observation. The higher efficacy of the antiviral combination therapy was evident of the impact of the antiviral activity of cycloferon itself and its immunomodulating and interferon-inducing activity on elimination of the virus-infected hepatocytes. The use of the 48-week course of the antiviral combination therapy is advisable as the prime treatment in the management of patients with HBeAg-positive chronic hepatitis not previously treated with nucleoside analogues and as a variant of therapy for lamivudine-refractory patients.

HBV, HBeAg+, chronic virus hepatitis B, HBV, HBeAG+, interferon inductor, antivirals, lamivudine, cycloferon

1. Lai C.L., Ratziu V., Yuen M.F., Poynard T. Viral hepatitis B. Lancet 2003; 362: 2089-2094.

2. Lok A.S., Heathcot E.J., Hoofnagle J.H. Management of hepatitis B: 2000 - summary of workshop. Gastroenterology 2001; 120: 1828-1853.

3. Lee W.M. Hepatitis B virus infection. N Ingl J Med 1997; 337: 1733-1745.

4. Ganem D., Prince A.M. Hepatitis B virus infection - natural history and clinical consequences. N Ingl J Med 2004; 350: 1118-1129.

5. EАSL Clinical Practice Guidelines: Management of chronic hepatitis B. Hepatology 2009; 50: 227-242.

6. Keefe E.B., Zeuzem S., Koff R.S. et al. Report of an international workshop: roadmap for management of patients receiving oral therapy for chronic hepatitis B. Clin Gastroenterol Hepatol 2007; 5: in press.

7. Liaw Y.F., Leung N., Kao J.H. et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int 2008; 2: 3: 263-283.

8. Lock A.S., McMahon B.J. Chronic Hepatitis B: update 2009. Hepatology. 2009; 50(3): 1-36.

9. Fattovich G., Rugge M. et al. A randomized controlled trial of lymphoblastoid interferon-alpha in patients with chronic hepatitis B lacking HBeAg. Hepatology 1992; 15: 584-589.

10. Janssen H.L., van Z.M., Senturk H., Zeuzem S., Acarca U.S., Cakaloglu Y. et al. Pegylated interferon alpha-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomized trial. Lancet 2005; 365: 123-129.

11. Law G.K., Piratvisuth T., Luo K.X., Marcellin P., Thongsawat S., Cooksley G. et al. Peginterferon alpha-2a, lamivudine, and the combination for the HBeAg-positive chronic hepatitis B. N Engl J Med 2005; 352: 2682-2695.

12. Marcellin P., Lau G.K., Bonino F. et al. Peginterferon alpha-2a alone, lamivudin alone, and two in combination in patients with HBeAg-negative chronic hepatitis B. N Ingl. J Med 2004, 351, 1206-1217.

13. Foldes I., David K., Horvath G. et al. Thyroid dysfunctions in patients with viral hepatitis treated with interferon-alpha. Orv Heti. 2004; 145: 23: 1211-1216.

14. Kaygusuz I., Ozturk Kaygusuz T., Ozturk A. Effects of interferon-alpha2b on hearing. Int J Audiol 2004; 43: 8: 438-441.

15. Lai C.L., Chien R.N., Leung N.W., Chang T.T., Guan R., Tai D.I. et al. A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. N Engl J Med 1998; 339: 61-68.

16. Marcellin P., Chang T.T., Lim S.G., Tong M.J., Sievert W., Shiffman M.L. et al. Adefovir dipivoxil for the treatment of hepatitis B antigenpositive chronic hepatitis B. N Engl J Med 2003; 348: 808-816.

17. Marcellin P., Heathcote E.J., Buti M., Gane E., de Man R.A., Krastev Z. et al. Tenofovir disoproxil fumarate versus adefovir for chronic hepatitis B. N Engl J Med 2008; 359: 2442-2455.

18. Chang T.T., Gish R.G., de Man R., Gadano A., Sollano J., Chao Y.C. et al. A comparision of entecavir and lamivudine for HbeAg-positive chronic hepatitis B. N Engl J Med 2006; 354: 1001-1010.

19. Lai C.L., Gane E., Liaw Y.E., Hsu C.W., Thongsawat S., Wang Y. et al. Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med 2007; 357: 2576-2588.

20. Сологуб T.B., Романцов М.Г., Баранова И.П. и др. Комбинированная терапия хронического вирусного гепатита В, резистентного к лечению ламивудином. Вест СПбГМА им. И.И. Мечникова 2006; 2: 7-13.

21. Сологуб T.B., Романцов М.Г., Шульдяков А.А. и др. Комбинированная терапия хронического вирусного гепатита В и ее влияние на качество жизни. Вест СПбГМА им. И. И. Мечникова 2006; 1.

22. Ершов Ф.И. Система интерферона в норме и при патологии. М.: 1996; 240.

23. Радченко B.Г., Стельмах B.B., Козлов B.K. Оптимизация этиопатогенетической терапии хронического гепатита С. Руководство для врачей. СПб.: 2004; 168.

24. Романцов М.Г., Ершов Ф.И., Коваленко А.Л., Голубев С.Ю. Иммунодефицитные состояния и коррекция циклофероном: Рук, для врачей, СПб.: 1998; 80.

25. Стельмах B.B. Возможности интерферониндуцирующей терапии при латентной HBV-инфекции Экспериментальная и клиническая фармакология. СПб.: 2011; 74: 5: 35-39.

26. Стельмах B.B. Хронический гепатит В. Вопросы стратегии и тактики профилактики донозологических состояний и заболеваний внутренних органов. Рук, для врачей / Под ред. В.Г. Радченко. СПб.: 2011; 271-283.

27. Горячева Л.Г., Шилова И.B. Диагностика и лечение вирусных гепатитов B и C у детей раннего возраста. Врач 2006; 8: 32-35.

28. Стельмах B.B. Морфофункциональное состояние системы мононуклеарных фагоцитов у больных хроническим вирусным гепатитом В и С при проведении этиопатогенетической терапии / Автореф. дис.....канд. мед. наук. СПб.: 2003.

29. Zarubaev V.V., Slita A.V., Krivitskaya V.Z. et al. Direct antiviral effects of cycloferon (10-carboxymethyl-9-acridanone) against adenovirus type 6. Antiviral Res 2003; 58: 2: 131-137.

30. Ishak K., Baptista A., Bianchi L. et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995; 22: 696-699.

31. Dienstag J.L., Goldin R.D., Heathcote E.J. et al. Histological outcome during long-term lamivudine therapy. Gastroenterology 2003; 124: 105-117.

32. Goodman Z., Dhillon A.P., Wu P.C. et al. Lamivudine treatment reduces progression to cirrhosis in patients with chronic hepatitis B. J Hepatol 1999; 30: Suppl 1: 59-69.

33. Fattovich G., Rugge M., Brollo I. et al. Clinil, virologic and histologic outcome following seroconversion from HBeAg to anti-HBe in chronic hepatitis type B. Hepatology 1986; 6: 167-72.

34. Gish R.G., Lok A.S., Chang T.T. et al. Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B. Gastroenterology. 2007; 133: 5: 1437-1444.

35. Leung N.W., Lai C.L., Chang T.T. et al. Extended lamivudine treatment in patient with chronic hepatitis B enhances hepatite B e antigen seroconversion rates: results after 3 years of therapy. Hepatology 2001; 33: 1527-1532.