THE SAFETY OF ANTIVIRAL THERAPY FOR CHRONIC HEPATITIS C USING PEG-INTERFERON AND RIBAVIRIN IN HIV PATIENTS RECEIVING HAART

Objective. To study the safety of ribavirin and PEG-interferon at maximum doses over the full course of therapy for chronic viral hepatitis C in HIV patients. Patients and methods. This open non-randomized prospective study included 242 HCV/HIV patients. Group 1 patients (n=115) were not treated with HAART. Group 2 patients (n = 127) received HAART. Administered for 48 weeks were either PEG-interferon α2a at 180 mg per week or PEG-interferon α2b at 1,5 mg/kg per week, both combined with ribavirin at 15 mg/kg daily. Results. SVR rates among all patients were 67% in Group 1 and 63% in Group 2 and, among patients who completed their therapeutic courses, 78,6% in Group 1 and 70,8% in Group 2. PEG-interferon course was not completed in 37 patients (15,2%). Hemoglobin levels and leukocyte, granulocyte, platelet and CD4+T-lymphocyte counts decreased in both groups in the course of therapy. The maximal decreases were observed during the first 4 to 12 weeks. After the 24^th week, all parameters increased, and, in 6 months, they completely normalized. Zidovudine included in HAART did not increase the rate of anemia. The cases where hemoglobin did not decrease below 100 g/L were associated with higher initial hemoglobin levels and with the male gender of patients. The cases where platelet counts did not decrease below 50x10⁹/L were associated with higher initial counts. The cases were granulocyte counts did not decrease below 0,75x10⁹/L were associated with higher initial counts and with no HAART. Conclusion. The use of PEG-interferon and ribavirin dosed per unit body mass all over therapy for HCV in HCV/HIV patients, both treated and untreated with HAART, is safe and makes it possible to reach SVR in most cases. HAART does not significantly influence anemia and thrombocytopenia; however, it promotes decreases in granulocyte counts during therapy for HCV

хронический гепатит С, ВГС/ВИЧ-инфекция, ВААРТ, рибавирин, пегилированный интерферон, chronic viral hepatitis C, HCV/HIV co-infection, HAART, ribavirin, PEG-interferon

1. HIV/AIDS [доступ 20 января 2015].- URL: http://www.who.int/features/qa/71/en/.

2. Rockstroh J.K., Mocroft A., Soriano V., Tural C., Losso M.H., Horban A., Kirk O., Phillips A., Ledergerber B., Lundgren J. Influence of hepatitis C virus infection on HIV-1 disease progression and response to highly active antiretroviral therapy // J Infect Dis.- 2005.- Vol. 192 (6).- R 992-1002.

3. Hernandez M.D., Sherman K.E. HIV/HCV co-infection natural history and disease progression, a review of the most recent literature // Curr. Opin.- HIV AIDS.- 2011.- Vol. 6(6).- R 478-482.

4. Lo Re III V., Kallan M.J., Tate J.P., Localio A.R., Lim J.K., Goetz M.B., Klein M.B., Rimland D., Rodriguez-Barradas M.C., Butt A.A., Gibert C.L., Brown S.T., Park L., Dubrow R., Reddy K.R., Kostman J.R., Strom B.L., Justice A.C. Hepatic decompensation in antiretroviral-treated patients co-Infected with HIV and hepatitis C virus compared with Hepatitis C virus-monoinfected patients: a cohort study // Ann Intern Med.- 2014.- Vol. 160 (6).- R 369-379.

5. Konerman M.A., Mehta S.H., Sutcliffe C.G., Vu T., Higgins Y., Torbenson M.S., Moore R.D., Thomas D.L., Sulkowski M.S. Fibrosis progression in human immunodeficiency virus/hepatitis C virus coinfected adults: prospective analysis of 435 liver biopsy pairs // Hepatology.- 2014.- Vol. 59 (3).- R 767-775.

6. Fuster D., Cheng D.M., Quinn E.K. Nunes D., Saitz R., Jeffrey H., Samet J.H., Tsui J.I. Chronic Hepatitis C Virus infection is associated with all-cause and liver-related mortality in a cohort of HIV-infected patients with alcohol problems // Addiction.- 2014.- Vol. 109 (1).- R 62-70.

7. The Data Collection on Adverse Events of Anti-HIV drugs (D:A:D) Study Group. Factors associated with specific causes of death amongst HIV-positive individuals in the D:A:D Study // AIDS.- 2010.- Vol. 24 (10).- R 1537-1548.

8. Bani-Sadr F., Lapidus N., Bedossa P., De Boever C.M., Perronne C., Halfon P., Pol S., Carrat F., Cacoub P. Rrogression of fibrosis in HIV and hepatitis C virus-coinfected patients treated with interferon plus ribavirin-based therapy: analysis of risk factors // Clin. Infect. Dis.- 2008.- Vol. 46(5).- R 768-774.

9. Casado J.L., Quereda С., Moreno А., Pérez-Elias M.J., Marti-Belda P., Moreno S. Regression of liver fibrosis is progressive after sustained viro-logical response to HCV therapy in patients with hepatitis C and HIV coinfection // J. Virall Hepat.- 2013. Vol. 20 (12).- R 829-837.

10. Labarga P., Fernandez-Montero J.V., Barreiro P., Pinilla J., Vispo E., de Mendoza C., Plaza Z., Soriano V. Changes in liver fibrosis in HIV/HCV-coinfected patients following different outcomes with peginterferon plus ribavirin therapy // J. Viral. Hepat.- 2014.- Vol. 21 (7).- R 475-479.

11. Akhtar E., Manne V., Saab S. Cirrhosis regression in hepatitis C patients with sustained virological response after antiviral therapy. A meta-analysis // Liver International.- 2015. Vol. 35 (1).- R 30-36.

12. Berenguer J., Alvarez-Pellicer J., Martin P.M., López-Aldeguer J., Von-Wichmann M.A., Quereda C., Mallolas J., Sanz J., Tural C., Bellón J.M., González-Garcia J. Sustained virological response to interferon plus ribavirin reduces liver-related complications and mortality in patients co-infected with human immunodeficiency virus and hepatitis C virus // Hepatology.- 2009.- Vol. 50 (2).- R 407-413.

13. Berenguer J., Rodríguez E., Miralles P., Von Wichmann M.A., López-Aldeguer J., Mallolas J., Galindo M.J., Van Den Eynde E., Téllez M.J., Quereda C., Jou A., Sanz J., Barros C., Santos I., Pulido F., Guardiola J.M., Ortega E., Rubio R., Jusdado J.J., Montes M.L., Gaspar G., Esteban H., Bellón J.M., González-Garcia J. GESIDA HIV/HCV Cohort Study Group. Sustained virological response to interferon plus ribavirin reduces non-liver-related mortality in patients coinfected with HIV and hepatitis C virus // Clin. Infect. Dis.- 2012.- Vol. 55 (5).- R 728-736.

14. Van der Meer A.J., Veldt B.J., Feld J.J., Wedemeyer H., Dufour J.F., Lammert F., Duarte-Rojo A., Heathcote E.J., Manns M.P., Kuske L., Zeuzem S., Hofmann W.P., de Knegt R.J., Hansen B.E., Janssen H.L. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis // JAMA.- 2012.- Vol. 308 (24).- P 2584-2593.

15. EASL Clinical Practice Guidelines: Management of hepatitis C virus infection // J. Hepatology.- 2011.- Vol. 55 (2).- P 245-264.

16. Chung R.T., Andersen J., Volberding P., Robbins G.K., Liu T., Sherman K.E., Peters M.G., Koziel M.J., Bhan A.K., Alston B., Colquhoun D., Nevin T., Harb G., van der Horst C. Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons // N. Engl. J. Med.- 2004.- Vol. 351 (5).- P 451-459.

17. Laufer N., Laguno M., Perez I., Cifuentes C., Murillas J., Vidal F., Bonet L., Veloso S., Gatell J.M., Mallolas J. Abacavir does not influence the rate of virological response in HIV-HCV-coinfected patients treated with pegylated interferon and weight-adjusted ribavirin // Antivir. Ther.- 2008.- Vol. 13 (7).- P 953-957.

18. Vispo E., Barreiro P., Pineda J.A., Mira J.A., Maida I., Martin-Carbonero L., Rodríguez-Nóvoa S., Santos I., López-Cortes L.F., Merino D., Rivero A., Soriano V. Low response to pegylated interferon plus ribavirin in HIV-infected patients with chronic hepatitis C treated with abacavir // Antivir. Ther.- 2008.- Vol. 13 (3).- P 429-437.

19. Amorosa V.K., Slim J., Mounzer K., Bruno C., Hoffman-Terry M., Dorey-Stein Z., Ferrara T., Kostman J.R., Lo Re V. 3rd The influence of abacavir and other antiretroviral agents on virologic response to hepatitis C virus therapy among antiretroviral-treated HIV-infected patients // Antivir. Ther.- 2010.- Vol. 15 (1).- P 91-99.

20. Vogel M., Ahlenstiel G., Hintsche B., Fenske S., Trein A., Lutz T., Schürmann D., Stephan C., Khaykin P., Bickel M., Mayr C., Baumgarten A., Buggisch P., Klinker H., John C., Gölz J., Staszewski S., Rockstroh J.K. The influence of HAART on the efficacy and safety of pegylated interferon and ribavirin therapy for the treatment of chronic HCV infection in HIV-positive individuals // Eur. J. Med. Res.- 2010.- Vol. 15 (3).- P 102-111.

21. Vellozzi С., Buchacz K., Baker R., Spradling P.R., Richardson J., Moorman A., Tedaldi E., Durham M., Ward J., Brooks J.T. Treatment of hepatitis C virus (HCV) infection in patients coinfected with HIV in the HIV Outpatient Study (HOPS), 1999-2007 // J. Viral. Hepat.- 2011.- Vol. 18 (5).- P 316-324.

22. James P.D., Wong D.K.H. Optimizing hepatitis C therapy in HIV/hepatitis C virus (HCV) coinfected patients: analysis of HCV viral kinetics on treatment // Can. J. Infect. Dis. Med. Microbiol.- 2012.- Vol. 23 (1).- P 31-35.

23. Davies A., Singh K.P., Shubber Z., Ducros P., Mills E.J., Cooke G., Ford N. Treatment outcomes of treatment-naïve hepatitis C patients co-infected with HIV: a systematic review and meta-analysis of observational cohorts // PLoS. One.- 2013.- Vol. 8 (2).- e55373.

24. Ioannou G.N., Scott J.D., Yang Y., Green P.K., Beste L.A. Beste rates and predictors of response to anti-viral treatment for hepatitis C virus in HIV/HCV co-infection in a nationwide Study of 619 patients // Aliment. Pharmacol. Ther.- 2013.- Vol. 38 (11-12).- P. 1373-1384.

25. Beisel C., Heuer M., Otto B., Jochum J., Schmiedel S., Hertling S., Degen O., Lüth S., van Lunzen J., Schulze Zur Wiesch J. German cohort of HCV mono-infected and HCV/HIV co-infected patients reveals relative under-treatment of co-infected patients // AIDS Research and Therapy.- 2014.- Vol. 11.- P 16-24.

26. Стасишкис Т.А., Дунаева Н.В., Ковеленов А.Ю., Исаева Г.Н. Эффективность противовирусной терапии хронического гепатита С на фоне ВААРТ у ВИЧ-позитивных пациентов // Инфекционные болезни.- 2013.- Том 11 (2).- С. 13-20.

27. Максимов С.Л., Иванова Л.М., Кравченко А.В., Серебровская Л.В., Ольшанский А.Я., Моргунова Н.М., Ющук Н.Д. Особенности терапии хронического гепатита С пегилированным интерфероном альфа 2а и рибавирином у больных ВИЧ-инфекцией // Тер. Архив.- 2007.- Том 97 (11).- С. 40-44.

28. Wada М., Marusawa H., Yamada R., Nasu A., Osaki Y., Kudo M., Nabeshima M., Fukuda Y., Chiba T., Matsuda F. Association of genetic polymorphisms with interferon-induced haematologic adverse effects in chronic hepatitis C patients // J. Viral. Hepat.- 2009.- Vol. 16 (6).- P 388-396.

29. Martin-Carbonero L., Tuma P., Vispo E., Medrano J., Labarga P., Gonzalez-Lahoz J., Barreiro P., Soriano V. Treatment of chronic hepatitis C in HIV-infected patients with compensated liver cirrhosis // J. Viral Hepat.- 2011.- Vol. 18 (8).- P 542-548.

30. Кравченко А.В., Куимова У.А., Ганкина Н.Ю., Канестри В.Г., Чуланов В.П. Предикторы устойчивого вирусологического ответа при терапии хронического гепатита пегилированным интерфероном и рибавирином у больных ВИЧ-инфекцией // Инфекционные болезни.- 2014.- Том 12 (2).- С. 30-34.

31. De Franceschi L., Fattovich G., Turrini F., Ayi K., Brugnara C., Manzato F., Noventa F., Stanzial A.M., Solero P., Corrocher R. Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: role of membrane oxidative damage // Hepatology.- 2000.- Vol. 31 (4).- P 997-1004.

32. Tanaka H., Miyano M., Ueda H., Fukui K., Ichinose M. Changes in serum and red blood cell membrane lipids in patients treated with interferon ribavirin for chronic hepatitis C // Clin. Exp. Med.- 2005.- Vol. 5.- P 190-195.

33. Sakamoto N., Tanaka Y., Nakagawa M., Yatsuhashi H., Nishiguchi S., Enomoto N., Azuma S., Nishimura-Sakurai Y., Kakinuma S., Nishida N., Tokunaga K., Honda M., Ito K., Mizokami M., Watanabe M. ITPA gene variant protects against anemia induced by pegylated interferon-and ribavirin therapy for Japanese pa-tients with chronic hepatitis C // Hepatology Research.- 2010.- Vol. 40 (11).- P 1063-1071.

34. Hitomi Y., Cirulli E.T., Fellay J., McHutchison J.G., Thompson A.J., Gumbs C.E., Shianna K.V., Urban T.J., Goldstein D.B. Inosine tripfosphate protects against ribavirin-induced ATP loss by restoring adenylosuccinate synthase function // Gastroenterology.- 2011.- 140 (4).- P 1314-1321.

35. Domingo P., Guardiola J.M., Salazar J., Torres F., Mateo M.G., Pacho C., Del Mar Gutierrez M., Lamarca K., Fontanet A., Martin J., Muñoz J, Vidal F., Baiget M. Association of ITPA gene polymorphisms and the risk of ribavirin-Induced anemia in HIV/Hepatitis C Virus (HCV)-coinfec-ted patients receiving HCV combination therapy // Antimicrobial Agents and Chemotherapy.- 2012.- Vol. 56 (6).- P 2987-2993.

36. Altintas Z.M., Altintas E., Sezgin O., Edgunlu T.G., Ucbilek E., Nayir E., Barlas I.O., Erdal M.E. The effect of genetic variations of methylene tetrahydropholate reductase gene polymorphisms on ribavirin-induced anemia in hepatitis C patients // J. Liver: Dis. Transplant.- 2013.- Vol. 2 (1).- P 1-8.

37. D'Avolio A., De Nicolö A., Cusato J., Ciancio A., Boglione L., Strona S., Cariti G., Troshina G., Caviglia G.P., Smedile A., Rizzetto M., Di Perri G. Association of ITPA polymorphisms rs6051702/rs1127354 instead of rs7270101/rs1127354 as predictor of ribavirin-associated anemia in chronic hepatitis C treated patients // Antiviral Res.- 2013.- Vol. 100 (1).- P 114-119.

38. Fujino T., Aoyagi Y., Takahashi M., Yada R., Yamamoto N., Ohishi Y., Nishiura A., Kohjima M., Yoshimoto T., Fukuizumi K., Nakashima M., Kato M., Kotoh K., Nakamuta M., Enjoji M. Association of ITPA polymorphism with outcomes of peginterferon- plus ribavirin combination therapy // World J. Gastrointest. Pharmacol. Ther.- 2013.- Vol. 4 (3).- P 54-60.

39. Amanzada A., Goralczyk A.D., Reinhardt L., Moriconi F., Cameron S., Mihm S. Erythropoietin rs1617640 G allele associates with an attenuated rise of serum erythropoietin and a marked decline of hemoglobin in hepatitis C patients undergoing antiviral therapy // BMC Infect. Dis. - 2014.- Vol. 14.- P 503 - 512.

40. Ganser A., Carlo-Stella C., Greher J., Völkers B., Hoelzer D. Effect of recombinant interferons alpha and gamma on human marrow-derived megakaryocytic progenitor cells // Blood.- 1987.- Vol. 70 (4).- P 1173 - 1179.

41. Chang C-S., Yan S-L., Lin H-Y., Yu F-L., Tsai C-Y. Pure red cell aplasia caused by pegylated interferon- -2a plus ribavirin in the treatment of chronic hepatitis C // World J. Gastroenterol.- 2011.- Vol. 17 (16).- P 2155-2158.

42. Стасишкис Т.А., Дунаева Н.В., Ковеленов А.В., Киселёв О.И. Динамика концентрации рибавирина в эритроцитах и плазме больных хроническим гепатитом С (ХГС) и её клиническое значение / Мат. XIX Российского конгресса «Гепатология сегодня» (Москва, 24-26 марта 2014 г) // Рос. журнал гастроэнтерологии, гепатологии, колопроктологии.- 2014.- Т. 24 (1), Приложение 43.- С. 33.

43. Стасишкис Т.А., Дунаева Н.В., Ковеленов А.В., Киселёв О.И. Динамика уровня гемоглобина и концентрации рибавирина в эритроцитах у HCV и HCV/ВИЧ-инфицированных, получающих противовирусную терапию / Мат. VI Ежегодного Всерос. конгресса по инфекционным болезням (Москва, 24-26 марта 2014 г.) // Инфекционные болезни.- 2014.- Т. 12, Прил. 1.- С. 298.

44. Schmid M., Kreil A., Jessner W., Homoncik M., Datz C., Gangl A., Ferenci P., Peck-Radosavljevic M. Suppression of haematopoiesis during therapy of chronic hepatitis C with different interferon alpha mono and combination therapy regimens // Gut.- 2005.- Vol. 54 (7).- P 1014 - 1020.

45. Kobayashi T., Hige S., Terashita K., Nakai M., Horimoto H., Sho T., Nakanishi M., Ogawa K., Chuma M., Sakamoto N., Asaka M. Anemia and thrombocytosis induced by ribavirin monotherapy in patients with chronic hepatitis C // J. Gastroenterol.- 2012.- Vol. 47 (11).- P 1228 - 1237.

46. Sullivan P.S., Hanson D.L., Brooks J.T. Impact on hemoglobin of starting combination antiretroviral therapy with or without zidovudine in anemic HIV-infected patients // J. Acquir Immune Defic. Syndr.- 2008.- Vol. 48 (2).- P 163-168.

47. Butt A.A., Umbleja T., Andersen J.W., Chung R.T., Sherman K.E. The incidence, predictors and management of anaemia and its association with virological response in HCV/HIV coinfected persons treated with long-term pegylated interferon alfa 2a and ribavirin // Aliment. Pharmacol. Ther.- 2011.- Vol. 33(11).- P 1234 - 1244.

48. Breilh D., Djabarouti S., Trimoulet P., Le Bail B., Dupon M., Ragnaud J.M., Fleury H., Saux M.C., Thiébaut R., Chêne G., Neau D. Ribavirin plasma concentration predicts sustained virological response to peginterferon Alfa 2a plus ribavirin in previously treated HCV-HIV-coinfected patients // J. Acquir. Immune Defic. Syndr.- 2009.- Vol. 52 (3).- P 428-430.

49. Morello J., Soriano V., Barreiro P., Medrano J., Madejón A., González-Pardo G., Jiménez-Nácher I., González-Lahoz J., Rodríguez-Novoa S. Plasma ribavirin trough concentrations at week 4 predict hepatitis C virus (HCV) relapse in HIV-HCV-coinfected patients treated for chronic hepatitis C // Antimicrob. Agents Chemother.- 2010.- Vol. 54 (4).- P 1647 - 1649.

50. Wang Q., Miyakawa Y., Fox N., Kaushansky K. Interferon-alpha directly represses megakaryopoiesis by inhibiting thrombopoietin-induced signaling through induction of SOCS-1 // Blood.- 2000.- Vol. 96 (6).- P 2093-2099.

51. Ducoulombier D., Roque-Afonso A-M., Di Liberto G., Penin F., Kara R., Richard Y., Dussaix E., Feray C. Frequent compartmentalization of hepatitis C virus variants in circulating B cells and monocytes // Hepatology.- 2004.- Vol. 39 (3).- P 817-825.

52. de Almeida A.J., Campos-de-Magãlhaes M., de Melo Marçal O.P., Brandão-Mello C.E., Okawa M.Y., de Oliveira R.V., do Espirito-Santo M.P., Yoshida C.F., Lampe E. Hepatitis C virus-associated thrombocytopenia: a controlled prospective, virological study // Ann. Hematol.- 2004.- Vol. 83 (7).- P 434-440.

53. de Almeida A.J., Campos-de-Magalhaes M., Brandão-Mello C.E., de Oliveira R.V., Yoshida C.F., Lampe E. Detection of hepatitis C virus in platelets: evaluating its relationship to viral and host factors // Hepatogastroenterology.- 2007.- Vol. 54 (75).- P 964-968.

54. Padovani J.L., Corvino S.M., Drexler J.F., Silva G.F., Pardini M.I., Grotto R.M. In vitro detection of hepatitis C virus in platelets from uninfected individuals exposed to the virus // Rev. Soc. Bras. Med. Trop.- 2013.- Vol. 46 (2).- P 154-155.

55. Bordin G., Ballaré M., Zigrossi P., Bertoncelli M.C., Paccagnino L., Baroli A., Brambilla M., Monteverde A., Inglese E. A laboratory and thrombokinetic study of HCV-associated thrombocytopenia: a direct role of HCV in bone marrow exhaustion? // Clin. Exp. Rheumatol.- 1995.- Vol. 13 (Suppl. 13).- S 39-43.

56. Webster G.F. Local therapy for muculocutaneous Kaposi’s sarcoma in patients with acquired immunodeficiency syndrome // Dermatol. Surg.- 1995.- Vol. 21 (3).- P. 205-229.