transplantologiyaТрансплантологияTransplantologiya. The Russian Journal of Transplantation2074-05062542-0909IPO Association of Transplantologists10.23873/2074-0506-2017-9-1-13-22transplantologiya-150Research ArticleАКТУАЛЬНЫЕ ВОПРОСЫ ТРАНСПЛАНТОЛОГИИACTUAL ISSUES OF TRANSPLANTATIONПрименение софосбувира для лечения возвратного гепатита C после трансплантации печениThe use of sofosbuvir for the treatment of recurrent hepatitis C after liver transplantationХубутияМ. Ш.KhubutiyaM. Sh.

акад. РАН, профессор, директор 

Москва, Россия 

Acad. of RAS, Professor, Director

Moscow, Russia

sklifos@inbox.ruСюткинВ. Е.SyutkinV. E.

Москва, Россия

Moscow, Russia

ЖуравельС. В.Zhuravel'S. V.

Москва, Россия

Moscow, Russia

НоврузбековМ. С.NovruzbekovM. S.

Москва, Россия

Moscow, Russia

ФединА. Б.FedinA. B.

Москва, Россия

Moscow, Russia

СалиенкоА. А.SalienkoA. A.

Москва, Россия

Moscow, Russia

ГБУЗ «НИИ скорой помощи им. Н.В. Склифосовского ДЗМ»РоссияN.V. Sklifosovsky Research Institute for Emergency MedicineRussian FederationФГБУ ГНЦ ФМБЦ им. А.И. Бурназяна ФМБА РоссииРоссияBurnasyan Federal Medical Biophysical Center of FMBARussian Federation201720032017911322Copyright © Хубутия М.Ш., Сюткин В.Е., Журавель С.В., Новрузбеков М.С., Федин А.Б., Салиенко А.А., 20172017Хубутия М.Ш., Сюткин В.Е., Журавель С.В., Новрузбеков М.С., Федин А.Б., Салиенко А.А.Khubutiya M.S., Syutkin V.E., Zhuravel' S.V., Novruzbekov M.S., Fedin A.B., Salienko A.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.jtransplantologiya.ru/jour/article/view/150

В статье приведен опыт лечения гепатита С лекарственными средствами с прямым противовирусным действием у больных после трансплантации печени. Терминальная стадия заболевания печени вследствие хронического гепатита C является основным показанием для ортотопической трансплантации печени. В 2013 г. в клиническую практику внедрен первый в своем классе препарат с прямым противовирусным действием на HCV – ингибитор полимеразы HCV софосбувир, который возможно применять в безинтерфероновом режиме.

Материал и методы

Материал и методы. В исследование включены 33 реципиента печени с возвратным гепатитом С. Были проведены 35 курсов противовирусной терапии, одним из компонентов которой являлся софосбувир.

Результаты

Результаты. На момент проведения анализа 21 пациент завершил противовирусную терапию. У всех пациентов наблюдался первоначальный ответ на противовирусную терапию, была получена авиремия HCV. У 3 больных, у которых была возможна оценка стойкого вирусологического ответа, отмечено возобновление репликации HCV в первые недели после завершения противовирусной терапии.

Заключение

Заключение. Появление новых лекарственных препаратов прямого действия позволяет проводить эффективную противовирусную терапию всем реципиентам печени, инфицированным HCV.

The article presents the experience of direct-acting antiviral (DAA) drug treatment for hepatitis C in the patients after liver transplantation. The end-stage liver disease caused by hepatitis C is the main indication for orthotopic liver transplantation (OLT). In 2013, the first agent in the class of antiviral drugs directly acting on hepatitis C virus (HCV) was introduced into clinical practice. That was sofosbuvir, a HCV polymerase inhibitor, that could be used without interferon alfa.

Materials and methods

Materials and methods. The study enrolled 33 liver transplant recipients with recurrent hepatitis C. Thirty-five courses of antiviral therapy (AT) were conducted with sofosbuvir being one of AT components.

Results

Results. By the time of analysis, 21 patients had completed the antiviral therapy. All the patients showed an initial response to the antiviral therapy, HCV aviremia was achieved. In 3 patients, with the evaluable sustained virologic response (SVR), a renewed HCV replication was observed in the first weeks after the AT completion.

Conclusion

Conclusion. The new direct-acting antiviral drugs offer an effective antiviral therapy to all liver graft recipients with recurrent HCV.

софосбувирхронический гепатит Странсплантация печениSofocbuvirchronic hepatitis Cliver transplantationReferencesScientific Registry of Transplant Recipients 2012 annual data report. Rockville, MD: Health Resources and Services Administration. 2012; URL: http://srtr.transplant.hrsa.gov/annual_reports/2012/pdf/03_liver_13.pdfScientific Registry of Transplant Recipients 2012 annual data report. Rockville, MD: Health Resources and Services Administration. 2012. Available at: http://srtr.transplant.hrsa.gov/annual_reports/2012/pdf/03_liver_13.pdfWorld Health Organization, Spanish National Transplant Organization. Global observatory on donation and transplantation. 2012; URL: http://issuu.com/o-nt/World Health Organization, Spanish National Transplant Organization. Global observatory on donation and transplantation. 2012. Available at: http://issuu.com/o-n-t/docs/2012addocs/2012adCrespo G., Marino Z., Navasa M., et al. Viral hepatitis in liver transplantation. Gastroenterology. 2012;142(6):1373– 1383,e1371. PMID:22537446 DOI:10.1053/j.gastro.2012.02.011Crespo G., Marino Z., Navasa M. et al. Viral hepatitis in liver transplantation. Gastroenterology. 2012; 142 (6): 1373–1383, e1371. PMID:22537446 DOI:10.1053/j.gastro.2012.02.011Berenguer M., Ferrell L., Watson J., et al. HCV-related fibrosis progression following liver transplantation: increase in recent years. J Hepatol. 2000;32(4):673–684. PMID:10782918Berenguer M., Ferrell L., Watson J. et al. HCV-related fibrosis progression following liver transplantation: increase in recent years. J. Hepatol. 2000; 32 (4): 673–684. PMID:10782918Prieto M., Berenguer M., Rayon J.M., et al. High incidence of allograft cirrhosis in hepatitis C virus genotype 1b infection following transplantation: relationship with rejection episodes. Hepatology. 1999;29(1):250–256. PMID:9862874 DOI:10.1002/hep.510290122Prieto M., Berenguer M., Rayon J.M. et al. High incidence of allograft cirrhosis in hepatitis C virus genotype 1b infection following transplantation: relationship with rejection episodes. Hepatology. 1999; 29 (1): 250–256. PMID:9862874 DOI:10.1002/hep.510290122Carrion J.A., Navasa M., Garcia-Retortillo M., et al. Efficacy of antiviral therapy on hepatitis C recurrence after liver transplantation: a rando mized controlled study. Gastroenterology. 2007;132(5):1746–1756. PMID:17484872 DOI:10.1053/j.gastro.2007.03.041Carrion J.A., Navasa M., Garcia-Retortillo M. et al. Efficacy of antiviral therapy on hepatitis C recurrence after liver transplantation: a randomized controlled study. Gastroenterology. 2007; 132 (5): 1746–1756. PMID:17484872 DOI:10.1053/j.gastro.2007.03.041Belli L.S., Volpes R., Graziadei I., et al. Antiviral therapy and fibrosis progression in patients with mild-moderate hepatitis C recurrence after liver transplantation. A randomized controlled study. Dig Liver Dis. 2012;44(7):603–609. PMID:22424641 DOI:10.1016/j.dld.2012.01.017Belli L.S., Volpes R., Graziadei I. et al. Antiviral therapy and fibrosis progression in patients with mild-modera te hepatitis C recurrence after liver transplantation. A randomized controlled study. Dig. Liver Dis. 2012; 44 (7): 603–609. PMID:22424641 DOI:10.1016/j.dld.2012.01.017Berenguer M. Systematic review of the treatment of established recurrent hepatitis C with pegylated interferon in combination with ribavirin. J Hepatol. 2008;49(2):274–287. PMID:18571272 DOI:10.1016/j.jhep.2008.05.002Berenguer M. Systematic review of the treatment of established recurrent hepatitis C with pegylated interferon in combination with ribavirin. J. Hepatol. 2008; 49 (2): 274–287. PMID:18571272 DOI:10.1016/j.jhep.2008.05.002Burton J.R. Jr., O'Leary J.G., Verna E.C., et al. A US multicenter study of hepatitis C treatment of liver transplant recipients with protease-inhibitor triple therapy. J Hepatol. 2014;61(3):508– 514. PMID:24801415 DOI:10.1016/j.jhep.2014.04.037Burton J.R. Jr., O'Leary J.G., Verna E.C. et al. A US multicenter study of hepatitis C treatment of liver transplant recipients with protease-inhibitor triple therapy. J. Hepatol. 2014; 61 (3): 508–514. PMID:24801415 DOI:10.1016/j.jhep.2014.04.037Nair S.P. Protease inhibitor therapy post-liver transplantation in the treatment of hepatitis C virus infection. Gastroenterol Hepatol (NY). 2013;9(6):388– 390. PMID:23935546Nair S.P. Protease inhibitor therapy post-liver transplantation in the treatment of hepatitis C virus infection. Gastroenterol. Hepatol. (NY). 2013; 9 (6): 388–390. PMID:23935546Faisal N., Yoshida E.M., Bilodeau M., et al. Protease inhibitor-based triple therapy is highly effective for hepatitis C recurrence after liver transplant: a multicenter experience. Ann Hepatol. 2014;13(5):525–532. PMID:25152985Faisal N., Yoshida E.M., Bilodeau M. et al. Protease inhibitor-based triple therapy is highly effective for hepatitis C recurrence after liver transplant: a multicenter experience. Ann. Hepatol. 2014; 13 (5): 525–532. PMID:25152985Koff R.S. Review article: the efficacy and safety of sofosbuvir, a novel, oral nucleotide NS5B polymerase inhibitor, in the treatment of chronic hepatitis C virus infection. Aliment Pharmacol Ther. 2014;39(5):478–487. PMID:24387618 DOI:10.1111/apt.12601Koff R.S. Review article: the efficacy and safety of sofosbuvir, a novel, oral nucleotide NS5B polymerase inhibitor, in the treatment of chronic hepatitis C virus infection. Aliment. Pharmacol. Ther. 2014; 39 (5): 478–487. PMID:24387618 DOI:10.1111/apt.12601Mathias A., Cornpropst M.T., Clemons D., et al. No clinically significant pharmacokinetic drug-drug interactions between sofosbuvir (GS-7977) and the immunosuppressants, cyclosporine A or tacrolimus in healthy volunteers. Hepatology. 2012;56(Suppl S1):1063A–1064A.Mathias A., Cornpropst M.T., Clemons D. et al. No clinically significant pharmacokinetic drug-drug interactions between sofosbuvir (GS-7977) and the immunosuppressants, cyclosporine A or tacrolimus in healthy volunteers. Hepatology. 2012; 56 (Suppl S1): 1063A–1064A.Charlton M., Gane E., Manns M.P., et al. Sofosbuvir and ribavirin for treatment of compensated recurrent hepatitis C virus infection after liver transplantation. Gastroenterology. 2015.148(1):108– 117. PMID:25304641 DOI:10.1053/j.gastro.2014.10.001Charlton M., Gane E., Manns M.P. et al. Sofosbuvir and ribavirin for treatment of compensated recurrent hepatitis C virus infection after liver transplantation. Gastroenterology. 2015. 148 (1): 108–117. PMID:25304641 DOI:10.1053/j.gastro.2014.10.001Forns X., Charlton M., Denning J., et al. Sofosbuvir compassionate use program for patients with severe recurrent hepatitis C after liver transplantation. Hepatology. 2015;61(5):1485–1494. PMID:25557906 DOI:10.1002/hep.27681Forns X., Charlton M., Denning J. et al. Sofosbuvir compassionate use program for patients with severe recurrent hepatitis C after liver transplantation. Hepatology. 2015; 61 (5): 1485–1494. PMID:25557906 DOI:10.1002/hep.27681Nguyen N.H., Yee B.E., Chang C., et al. Tolerability and effectiveness of sofosbuvir and simeprevir in the posttransplant setting: systematic review and meta- analysis. BMJ Open Gastroenterology.2016;3(1):e000066. PMID:26966549 DOI:10.1136/bmjgast-2015-000066Nguyen N.H., Yee B.E., Chang C. et al. Tolerability and effectiveness of sofosbuvir and simeprevir in the posttransplant setting: systematic review and meta-analysis. BMJ Open Gastroenterology. 2016; 3 (1): e000066. PMID:26966549 DOI:10.1136/bmjgast-2015-000066Punzalan C.S., Barry C., Zacharias I., et al. Sofosbuvir plus simeprevir treatment of recurrent genotype 1 hepatitis C after liver transplant. Clin Transplant. 2015;29(12):1105–1111. PMID:26358816 DOI:10.1111/ctr.12634Punzalan C.S., Barry C., Zacharias I. et al. Sofosbuvir plus simeprevir treatment of recurrent genotype 1 hepatitis C after liver transplant. Clin. Transplant. 2015; 29 (12): 1105– 1111. PMID:26358816 DOI:10.1111/ctr.12634Saab S., Greenberg A., Li E., et al. Sofosbuvir and simeprevir is effective for recurrent hepatitis C in liver transplant recipients. Liver Int. 2015;35(11):2442– 2447. PMID:25913321 DOI:10.1111/liv.12856Saab S., Greenberg A., Li E. et al. Sofosbuvir and simeprevir is effective for recurrent hepatitis C in liver transplant recipients. Liver Int. 2015; 35 (11): 2442–2447. PMID:25913321 DOI:10.1111/liv.12856Nair S., Satapathy S.K., Gonzalez H. Sofosbuvir and Simeprevir for Treatment of Recurrent Hepatitis C Infection After Liver Transplant. Exp Clin Transplant. 2016. Epub ahead of print PMID:26926117 DOI:10.6002/ect.2015.0289Nair S., Satapathy S.K., Gonzalez H. Sofosbuvir and Simeprevir for Treatment of Recurrent Hepatitis C Infection After Liver Transplant. Exp. Clin. Transplant. 2016. Epub ahead of print PMID:26926117 DOI:10.6002/ect.2015.0289Issa D., Eghtesad B., Zein N.N., et al. Sofosbuvir and Simeprevir for the Treatment of Recurrent Hepatitis C with Fibrosing Cholestatic Hepatitis after Liver Transplantation. Int J Organ Transplant Med. 2016;7(1):38–45. PMID:26889372Issa D., Eghtesad B., Zein N.N. et al. Sofosbuvir and Simeprevir for the Treatment of Recurrent Hepatitis C with Fibrosing Cholestatic Hepatitis after Liver Transplantation. Int. J. Organ Transplant. Med. 2016; 7 (1): 38–45. PMID:26889372Ouwerkerk-Mahadevan S., Snoeys J., Peeters M., et al. Drug-Drug Interactions with the NS3/4A Protease Inhibitor Simeprevir. Clin Pharmacokinetics. 2016;55(2):197–208. PMID:26353895 DOI:10.1007/s40262-015-0314-yOuwerkerk-Mahadevan S., Snoeys J., Peeters M. et al. Drug-Drug Interactions with the NS3/4A Protease Inhibitor Simeprevir. Clin. Pharmacokinetics. 2016; 55 (2): 197–208. PMID:26353895 DOI:10.1007/s40262-015-0314-yKirby B.J., Symonds W.T., Kearney B.P., et al. Pharmacokinetic, Pharmacodynamic, and Drug-Interaction Profile of the Hepatitis C Virus NS5B Polymerase Inhibitor Sofosbuvir. Clin Pharmacokinetics. 2015;54(7):677–690. PMID:25822283 DOI:10.1007/s40262-015-0261-7Kirby B.J., Symonds W.T., Kearney B.P. et al. Pharmacokinetic, Pharmacodynamic, and Drug-Interaction Profile of the Hepatitis C Virus NS5B Polymerase Inhibitor Sofosbuvir. Clin. Pharmacokinetics. 2015; 54 (7): 677–690. DOI:10.1007/s40262-015-0261-7. PMID:25822283Bifano M., Adamczyk R., Hwang C., et al. An open-label investigation into drugdrug interactions between multiple doses of daclatasvir and single-dose cyclosporine or tacrolimus in healthy subjects. Clin Drug Investig. 2015;35(5):281– 289. PMID:25896946 DOI:10.1007/s40261-015-0279-5.Bifano M., Adamczyk R., Hwang C. et al. An open-label investigation into drug-drug interactions between multiple doses of daclatasvir and single-dose cyclosporine or tacrolimus in healthy subjects. Clin. Drug Investig. 2015; 35 (5): 281–289. DOI:10.1007/s40261-015-0279-5. PMID:25896946Poordad F., Schiff E.R., Vierling J.M., et al. Daclatasvir with sofosbuvir and ribavirin for hepatitis C virus infection with advanced cirrhosis or post-liver transplantation recurrence. Hepatology. 2016;63(5):1493–1505. PMID:26754432 DOI:10.1002/hep.28446Poordad F., Schiff E.R., Vierling J.M. et al. Daclatasvir with sofosbuvir and ribavirin for hepatitis C virus infection with advanced cirrhosis or post-liver transplantation recurrence. Hepatology. 2016; 63 (5): 1493–1505. PMID:26754432 DOI:10.1002/hep.28446Fontana R.J., Brown R.S., Jr., Moreno-Zamora A., et al. Daclatasvir combined with sofosbuvir or simeprevir in liver transplant recipients with severe recurrent hepatitis C infection. Liver Transpl. 2016;22(4):446–458. PMID:26890629 DOI:10.1002/lt.24416Fontana R.J., Brown R.S., Jr., Moreno-Zamora A. et al. Daclatasvir combined with sofosbuvir or simeprevir in liver transplant recipients with severe recurrent hepatitis C infection. Liver Transpl. 2016; 22 (4): 446–458. PMID:26890629 DOI:10.1002/lt.24416Charlton M., Everson G.T., Flamm S.L., et al. Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Di sease. Gastroenterol. 2015;149(3):649–659. PMID:25985734 DOI:10.1053/j.gastro.2015.05.010Charlton M., Everson G.T., Flamm S.L. et al. Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease. Gastroenterol. 2015; 149 (3): 649–659. PMID:25985734 DOI:10.1053/j.gastro.2015.05.010Manns M., Samuel D., Gane E.J. et al. Ledipasvir and sofosbuvir plus ribavirin in patients with genotype 1 or 4 hepatitis C virus infection and advanced liver disease: a multicentre, open-label, randomised, phase 2 trial. Lancet Infect Dis. 2016;16(6):685–697. PMID:26907736 DOI:10.1016/S1473-3099(16)00052-9Manns M., Samuel D., Gane E.J. et al. Ledipasvir and sofosbuvir plus ribavirin in patients with genotype 1 or 4 hepatitis C virus infection and advanced liver disease: a multicentre, open-label, randomised, phase 2 trial. Lancet Infect. Dis. 2016; 16 (6): 685–697. PMID:26907736 DOI:10.1016/S1473-3099(16)00052-9HCV guidance: recommendations for testing, managing, and treating hepatitis C. Available at: http://www.hcvguidelines.org/full-report-view.HCV guidance: recommendations for testing, managing, and treating hepatitis C. URL: http://www.hcvguidelines.org/full-report-view.Lawitz E., Lalezari J.P., Hassanein T., et al. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, doubleblind, phase 2 trial. Lancet Infect Dis. 2013;13(5):401–408. PMID:23499158 DOI:10.1016/S1473-3099(13)70033-1Lawitz E., Lalezari J.P., Hassanein T. et al. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, doubleblind, phase 2 trial. Lancet Infect. Dis. 2013; 13 (5): 401–408. PMID:23499158 DOI:10.1016/S1473-3099(13)70033-1Lawitz E., Mangia A., Wyles D., et al. Sofosbuvir for Previously Untre ated Chronic Hepatitis C Infection. N Engl J Med. 2013;368(20):1878–1887. PMID:23607594 DOI:10.1056/NEJMoa1214853Lawitz E., Mangia A., Wyles D. et al. Sofosbuvir for Previously Untreated Chronic Hepatitis C Infection. N. Engl. J. Med. 2013; 368 (20): 1878–1887. PMID:23607594 DOI:10.1056/NEJMoa1214853Zeuzem S., Dusheiko G.M., Salupere R., et al. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med. 2014;370(21):1993–2001. PMID:24795201 DOI:10.1056/NEJMoa1316145.Zeuzem S., Dusheiko G.M., Salupere R. et al. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N. Engl. J. Med. 2014; 370 (21): 1993–2001. PMID:24795201 DOI:10.1056/NEJMoa1316145Coilly A., Fougerou-Leurent C., De Ledinghen V., et al. Multicentre experience using daclatasvir and sofosbuvir to treat hepatitis C recurrence after liver transplantation – The CO23 ANRS CUPILT study. J Hepatol. 2016;65(4):711–718. PMID:27262758 DOI:10.1016/j.jhep.2016.05.039Coilly A., Fougerou-Leurent C., De Ledinghen V. et al. Multicentre experience using daclatasvir and sofosbuvir to treat hepatitis C recurrence after liver transplantation – The CO23 ANRS CUPILT study. J. Hepatol. 2016; 65 (4): 711–718. PMID:27262758 DOI:10.1016/j.jhep.2016.05.039Coilly A., Fougerou-Leurent C., De Ledinghen V. et al. Multicentre experience using daclatasvir and sofosbuvir to treat hepatitis C recurrence after liver transplantation – The CO23 ANRS CUPILT study. J. Hepatol. 2016; 65 (4): 711–718. PMID:27262758 DOI:10.1016/j.jhep.2016.05.039

The authors declare that there are no conflicts of interest present.