gastro-jРоссийский журнал гастроэнтерологии, гепатологии, колопроктологииRussian Journal of Gastroenterology, Hepatology, Coloproctology1382-43762658-6673«Gastro» LLCgastro-j-1310Research ArticleГЕПАТОЛОГИЯHEPATOLOGYТелапревир в лечении больных хроническим гепатитом С: вопросы безопасностиTelaprevir in treatment of chronic hepatitis C: safety issuesИгнатоваТ. М.IgnatovaT. M.ФГБУ «Научно-исследовательский институт ревматологии» Российской академии медицинских наукRussian Federation2012290720122244757Copyright © Игнатова Т.М., 20122012Игнатова Т.М.Ignatova T.M.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.gastro-j.ru/jour/article/view/1310

Цель обзора. Проанализировать результаты контролируемых клинических исследований эффективности и безопасности телапревира в составе тройной противовирусной терапии хронического гепатита С (ХГС) с оценкой частоты и спектра возникающих нежелательных явлений (НЯ).Основные положения. Проведенные к настоящему времени исследования показали, что добавление телапревира к стандартной терапии пегилированным интерфероном α и рибавирином почти в 2 раза повышает процент достижения устойчивого вирусологического ответа у больных ХГС с 1-м генотипом вируса.Переносимость терапии с включением телапревира в целом удовлетворительная, однако отмечено более частое, чем при стандартной двойной терапии (группа плацебо), появление кожных высыпаний и зуда (более 50%), анемии (около 40%) и аноректальных симптомов (26%). Наблюдалась несколько более высокая частота серьезных НЯ (7% случаев) и отмены из-за их развития всех препаратов (8%). Особое значение имеет повышение частоты и степени тяжести кожных реакций, которые были основной причиной отмены лечения. Спектр НЯ при применении телапревира отличается от спектра НЯ при тройной терапии с включением другого нового ингибитора протеазы – боцепревира (преобладание анемии, дисгезии).Разработанная тактика мониторирования НЯ позволила снизить частоту отмены терапии из-за кожных реакций в исследованиях III фазы по сравнению с результатами исследований II фазы. Особое внимание уделяется профилактике взаимодействий телапревира, являющегося субстратом и ингибитором P450 (СYP) 3A4, а также транспортера P-гликопротеина, с другими лекарственными средствами.Заключение. Применение телапревира в составе тройной терапии ХГС приводит к изменению спектра НЯ. Основное значение имеет повышение частоты и тяжести кожных реакций. Тактика ранней диагностики НЯ, мониторирования и активной терапии, профилактика лекарственных взаимодействий ведут к повышению безопасности и эффективности лечения.

The aim of review

The aim of review. To analyze results of controlled clinical studies of efficacy and safety of telaprevir within triple antiviral therapy of chronic hepatitis C (CHC) with evaluation of frequency and spectrum of adverse effects (AE), and also approaches of their management.

Original positions

Original positions. Investigations carried out to the present time demonstrated, that addition of telaprevir to standard therapy by pegilated interferon-alpha and ribavirin increases frequency of achievement sustained virologic response in CHC patients with the 1 genotype of virus almost 2-fold. Tolerability of treatment with addition of telaprevir was satisfactory as a whole; however frequency of skin rashes and pruritus (over 50%), anemia (about 40%) and anorectal symptoms (26%) was higher, than at standard double therapy (placebo group). A little higher frequency of serious AE (7%), cancellation of all drugs due to AE (8%) was observed. Increase of frequency and severity of skin reactions, that was a principal cause of treatment cancellation, is of special importance. AE spectrum at telaprevir application differs from AE spectrum at triple therapy with addition of another new protease inhibitor – boceprevir (predominance of anemia, dysgeusia). Original approach of monitoring and effective management of AE allowed to decrease frequency of cancellation of treatment due to dermal reactions in III phase investigations in comparison to results of II phase studies. Special attention is given to prophylaxis of interactions with other pharmaceuticals, as telaprevir is P450 (СYP) 3A4 substrate and inhibitor and P-glycoprotein transporter.

Conclusion

Conclusion. Application of telaprevir within triple therapy of CHC results in change of AE spectrum. The major importance has elevation of frequency and severity of skin reactions. Tactics of early diagnostics, monitoring and active treatment of AE, and drug interactions prophylaxes increase safety and efficacy of treatment.

телапревирпротивовирусная терапиягепатит Сбезопасностьнежелательные явлениякожные реакциианемияtelaprevirantiviral therapyhepatitis Csafetyadverse effectsdermal reactionsanemiaReferencesIgnatova T.M. Quality of life of patients on antiviral therapy. Hepatological forum 2006, 2 : 4-8Ignatova T.M. Quality of life of patients on antiviral therapy. Hepatological forum 2006, 2 : 4-8Ignatova T.M. Treatment of extrahepatic manifestations of chronic HCV-infection. Clinical hepatology 2005, 1:3-11.Ignatova T.M. Treatment of extrahepatic manifestations of chronic HCV-infection. Clinical hepatology 2005, 1:3-11.Afdhal NH, Dieterich DT, Pocros PJ, et al. Epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind, randomized controlled study. Gastroenterology 2004; 126: 1302–11.Afdhal NH, Dieterich DT, Pocros PJ, et al. Epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind, randomized controlled study. Gastroenterology 2004; 126: 1302–11.Alvian SM, Tabatabaei B, Behnava B. Impact of erythropoietin on sustained virological response to peginterferon and ribavirin therapy for HCV infection: a systematic review and meta-analysis. J Viral Hepat 2012; 19:88–93.Alvian SM, Tabatabaei B, Behnava B. Impact of erythropoietin on sustained virological response to peginterferon and ribavirin therapy for HCV infection: a systematic review and meta-analysis. J Viral Hepat 2012; 19:88–93.Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011; 364, 1207–17.Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011; 364, 1207–17.Cacoub P, Bourliere M, Lubbe J, et al. Dermatological side effects of hepatitis C and its treatment: patient management in the era of direct-acting antivirals. J Hepatol 2012; 56:455–63.Cacoub P, Bourliere M, Lubbe J, et al. Dermatological side effects of hepatitis C and its treatment: patient management in the era of direct-acting antivirals. J Hepatol 2012; 56:455–63.European Association for the Study of the Liver. Clinical practice Guidelines: management of hepatitis C virus infection. J Hepatol 2011; 55: 245–64.European Association for the Study of the Liver. Clinical practice Guidelines: management of hepatitis C virus infection. J Hepatol 2011; 55: 245–64.Foster GR, Hezode C, Bronowicki JP, et al. Telaprevir alone or with peginterferon and ribavirin reduces HCVRNA in patients with chronic genotype 2 but not genotype 3 infections. Gastroenterology 2011; 141: 881–9.Foster GR, Hezode C, Bronowicki JP, et al. Telaprevir alone or with peginterferon and ribavirin reduces HCVRNA in patients with chronic genotype 2 but not genotype 3 infections. Gastroenterology 2011; 141: 881–9.Fried MW, Shiffman ML, Reddy R, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: 975–82.Fried MW, Shiffman ML, Reddy R, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: 975–82.Garg V, van Heeswijk R, Lee JE, et al. Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus. Hepatology 2011; 54, 20–7.Garg V, van Heeswijk R, Lee JE, et al. Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus. Hepatology 2011; 54, 20–7.Hayashi N, Okanoue T, Tsubouchi H, et al. Efficacy and safety of telaprevir, a new protease inhibitor, for difficultto-treat patients with genotype 1 chronic hepatitis C. J Viral Hepat 2012; 19: 134–42.Hayashi N, Okanoue T, Tsubouchi H, et al. Efficacy and safety of telaprevir, a new protease inhibitor, for difficultto-treat patients with genotype 1 chronic hepatitis C. J Viral Hepat 2012; 19: 134–42.Hezode C. Boceprevir and telaprevir for the treatment of chronic hepatitis C: safety management in clinical practice. Liver Intern 2012; 32 (S1), 32–8.Hezode C. Boceprevir and telaprevir for the treatment of chronic hepatitis C: safety management in clinical practice. Liver Intern 2012; 32 (S1), 32–8.Hezode C, Forestier N, Dusheiko G, et al. for the PROVE2 study team. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009; 360: 1839–50.Hezode C, Forestier N, Dusheiko G, et al. for the PROVE2 study team. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009; 360: 1839–50.Jacobson IM. Treatment options for patients with chronic hepatitis C not responding to antiviral therapy. Clin Gastroenterol Hepatol 2009; 7: 921–30.Jacobson IM. Treatment options for patients with chronic hepatitis C not responding to antiviral therapy. Clin Gastroenterol Hepatol 2009; 7: 921–30.Jacobson IM, McHutchison JG, Dusheiko GM, et al. ADVANCE study team. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364: 2405–16.Jacobson IM, McHutchison JG, Dusheiko GM, et al. ADVANCE study team. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364: 2405–16.Kim JJ, Culley CM, Mohammad RA. Telaprevir: an oral protease inhibitor for hepatitis C virus infection. Am J Health Syst Pharm 2012; 69: 19–33.Kim JJ, Culley CM, Mohammad RA. Telaprevir: an oral protease inhibitor for hepatitis C virus infection. Am J Health Syst Pharm 2012; 69: 19–33.Kumada H, Toyota J, Okanoue T, et al. Telaprevir with peginterferon and ribavirin for treatment-naïve patients chronically infected with HCV of genotype 1 in Japan. J Hepatol 2012; 56: 78–84.Kumada H, Toyota J, Okanoue T, et al. Telaprevir with peginterferon and ribavirin for treatment-naïve patients chronically infected with HCV of genotype 1 in Japan. J Hepatol 2012; 56: 78–84.Lawitz EJ. Diagnosis and management of telaprevirassociated rash. Gastroenterol Hepatol 2011; 7: 469–71.Lawitz EJ. Diagnosis and management of telaprevirassociated rash. Gastroenterol Hepatol 2011; 7: 469–71.Lubbe J. Dermatological side effects. Hot Topics Viral Hep 2008; 9: 29–35.Lubbe J. Dermatological side effects. Hot Topics Viral Hep 2008; 9: 29–35.Marcellin P, Forns X, Goeser T, et al. Telaprevir is effective given every 8 or 12 hours with ribavirin and peginterferon alfa-2a or 2b to patients with chronic hepatitis C. Gastroenterology 2011; 140: 459–68.Marcellin P, Forns X, Goeser T, et al. Telaprevir is effective given every 8 or 12 hours with ribavirin and peginterferon alfa-2a or 2b to patients with chronic hepatitis C. Gastroenterology 2011; 140: 459–68.McHutchison JG, Everson GT, Gordon SC, et al. for the PROVE1 study team. Telaprevir with peginterferon and ribavirin for chronic HCV Genotype 1. N Engl J Med 2009; 360: 1827–38.McHutchison JG, Everson GT, Gordon SC, et al. for the PROVE1 study team. Telaprevir with peginterferon and ribavirin for chronic HCV Genotype 1. N Engl J Med 2009; 360: 1827–38.McHutchison JG, Manns MR, Andrew JM, et al. for the PROVE3 study team. Telaprevir for previously treated chronic HCV infection. N Engl J Med 2009; 362: 1292–303.McHutchison JG, Manns MR, Andrew JM, et al. for the PROVE3 study team. Telaprevir for previously treated chronic HCV infection. N Engl J Med 2009; 362: 1292–303.McHutchison JG, Manns MR, Patel K, et al. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology 2002; 123: 1061–69.McHutchison JG, Manns MR, Patel K, et al. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology 2002; 123: 1061–69.Miistry N, Shapero J, Crawford RI. A review of adverse cutaneous reactions resulting from the use of interferon and ribavirin. Can J Gastroenterol 2009; 23: 677–83.Miistry N, Shapero J, Crawford RI. A review of adverse cutaneous reactions resulting from the use of interferon and ribavirin. Can J Gastroenterol 2009; 23: 677–83.Montaudie H, Passeron T, Cardot-Leccia N, et al. Drug rash with eosinophilia and systemic symptoms due to telaprevir. Dermatology 2010; 221: 303–5.Montaudie H, Passeron T, Cardot-Leccia N, et al. Drug rash with eosinophilia and systemic symptoms due to telaprevir. Dermatology 2010; 221: 303–5.Muir AJ, Poordad FF, McHutchison JG, et al. Retreatment with telaprevir combination therapy in hepatitis C patients with well-characterized prior treatment response. Hepatology 2011; 54: 1538–46.Muir AJ, Poordad FF, McHutchison JG, et al. Retreatment with telaprevir combination therapy in hepatitis C patients with well-characterized prior treatment response. Hepatology 2011; 54: 1538–46.Nishimura T, Osaki R, Shioya M, et al. Polymorphism of inosine triphospate pyrophosphatase gene predicts ribavirin-induced anemia in chronic hepatitis C patients. Mol Med Report 2012; 5: 517–20.Nishimura T, Osaki R, Shioya M, et al. Polymorphism of inosine triphospate pyrophosphatase gene predicts ribavirin-induced anemia in chronic hepatitis C patients. Mol Med Report 2012; 5: 517–20.Pawlotsky JM, Chevaliez S, McHutchison JG. The hepatitis C viral life cycle as a target for new antiviral therapies. Gastroenterology 2007; 132: 1979–98.Pawlotsky JM, Chevaliez S, McHutchison JG. The hepatitis C viral life cycle as a target for new antiviral therapies. Gastroenterology 2007; 132: 1979–98.Poordad F, McCone JJr, Bacon BR. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364, 1195–206.Poordad F, McCone JJr, Bacon BR. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364, 1195–206.Readdy KR, Nelson DR, Zeuzem S. Ribavirin: current role in the optimal clinical management of chronic hepatitis C. J Hepatol 2009; 50: 402–11.Readdy KR, Nelson DR, Zeuzem S. Ribavirin: current role in the optimal clinical management of chronic hepatitis C. J Hepatol 2009; 50: 402–11.Readdy KR, Shiffman ML, Morgan TR, et al. Impact of ribavirin dose reductions in hepatitis C virus genotype 1 patients completing alfa-2a/ribavirin treatment. Clin Gastroenterol Hepatol 2007; 5: 124–9.Readdy KR, Shiffman ML, Morgan TR, et al. Impact of ribavirin dose reductions in hepatitis C virus genotype 1 patients completing alfa-2a/ribavirin treatment. Clin Gastroenterol Hepatol 2007; 5: 124–9.Reesink HW, Zeuzem S, Weegink CJ, et al. Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase 1b, placebo-controlled, randomized study. Gastroenterology 2006; 131: 997–1002.Reesink HW, Zeuzem S, Weegink CJ, et al. Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase 1b, placebo-controlled, randomized study. Gastroenterology 2006; 131: 997–1002.Sherman KE, Flamm SL, Afdhal NH, et al. ILLUMINATE study team. Response-Guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med 2011; 365: 1014–24.Sherman KE, Flamm SL, Afdhal NH, et al. ILLUMINATE study team. Response-Guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med 2011; 365: 1014–24.Stickel F, Helbing B, Heim M. Critical review of the use of erythropoietin in the treatment of anaemia during therapy for chronic hepatitis C. J Viral Hepat 2012; 19: 77–87.Stickel F, Helbing B, Heim M. Critical review of the use of erythropoietin in the treatment of anaemia during therapy for chronic hepatitis C. J Viral Hepat 2012; 19: 77–87.Sulkowski MS, Cooper C, Hunyady B, et al. Management of adverse effects of Peg-IFN and ribavirin therapy for hepatitis C. Nat Rev Gastroenterol Hepatol 2011; 8: 212–23.Sulkowski MS, Cooper C, Hunyady B, et al. Management of adverse effects of Peg-IFN and ribavirin therapy for hepatitis C. Nat Rev Gastroenterol Hepatol 2011; 8: 212–23.Sulkowski MS, Poordad F, Manns MP, et al. Anemia during treatment with peginterferon alfa-2b/ribavirin with or without boceprevir is associated with higher SVR rates: analysis of previously untreated and previoustreatment-failure patients. J Hepatol 2011; 54 (S1):194.Sulkowski MS, Poordad F, Manns MP, et al. Anemia during treatment with peginterferon alfa-2b/ribavirin with or without boceprevir is associated with higher SVR rates: analysis of previously untreated and previoustreatment-failure patients. J Hepatol 2011; 54 (S1):194.Sulkowski MS, Reddi R, Afdhal NH, et al. Anemia had no effect on efficacy outcomes in treatment-naïve patients who received telaprevir-based regimen in the advance and illuminate phase 3 studies. J Hepatol 2011; 54 (S1):195.Sulkowski MS, Reddi R, Afdhal NH, et al. Anemia had no effect on efficacy outcomes in treatment-naïve patients who received telaprevir-based regimen in the advance and illuminate phase 3 studies. J Hepatol 2011; 54 (S1):195.Sulkovski MS, Shiffman ML, Afdhal NH, et al. Hepatitis C virus treatment-related anemia is associated with higher sustained virologic response rate. Gastroenterology 2010; 139: 1602–11.Sulkovski MS, Shiffman ML, Afdhal NH, et al. Hepatitis C virus treatment-related anemia is associated with higher sustained virologic response rate. Gastroenterology 2010; 139: 1602–11.Veluru C, Atluri D, Chadavalada R, et al. Skin rash during chronic hepatitis C therapy. Gastroentrol Hepatol (NY) 2010; 6: 323–5.Veluru C, Atluri D, Chadavalada R, et al. Skin rash during chronic hepatitis C therapy. Gastroentrol Hepatol (NY) 2010; 6: 323–5.Wilby KJ, Grenya ED, Ford JE, et al. A review of drug interactions with boceprevir and telaprevir: implications for HIV and transplant patients. Ann Hepatol 2012; 11:179–85.Wilby KJ, Grenya ED, Ford JE, et al. A review of drug interactions with boceprevir and telaprevir: implications for HIV and transplant patients. Ann Hepatol 2012; 11:179–85.Yamada I, Suzuki F, Kamiya N, et al. Safety, pharmacokinetics and resistant variants of telaprevir alone for 12 weeks in hepatitis C virus genotype 1b infection. J Viral Hepat 2012; 19: 112–9.Yamada I, Suzuki F, Kamiya N, et al. Safety, pharmacokinetics and resistant variants of telaprevir alone for 12 weeks in hepatitis C virus genotype 1b infection. J Viral Hepat 2012; 19: 112–9.Zeuzem S, Andreone P, Pol S, et al. REALIZE study team. Telaprevir for retreatment of HCV-infection. N Engl J Med 2011; 364: 2417–28.Zeuzem S, Andreone P, Pol S, et al. REALIZE study team. Telaprevir for retreatment of HCV-infection. N Engl J Med 2011; 364: 2417–28.

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