만성 C 형간염의치료 : 주사제를포함한요법 Treatment of Chronic Hepatitis C-Interferon-Based Therapy 인제대학교일산백병원내과 김경아 With the development of direct acting antivirals (DAAs), the outcomes of hepatitis C treatment have been improved. Triple therapy including peginterferon, ribavirin and boceprevir or telaprevir is the current standard of care for genotype 1 infection in United States and Europe. Recently, sofosbuvir, a nucleotide analogue NS5B polymerase inhibitor and simeprevir, a NS3A protease inhibitor were approved by FDA. Overall SVR was 90% with combination therapy of sofosbuvir, peginterferon and ribavirin for 24 weeks. SVR was 80% for genotype 1 infection with the combination therapy of simepervir, peginterferon and ribavirin. Several DAAs with different viral targets are under clinical trials in various combination including interferon-free regimens. Keywords: Hepatitis C; Direct-acting antivirals; Sofosbuvir; Simeprevir 서 론 C형간염바이러스의구조및생활사가밝혀지면서이에관여하는바이러스및숙주요인들을겨냥한 direct-acting antiviral agent (DAA) 개발이폭발적으로증가하고있다. Sofosbuvir와 simeprevir가만성 C형간염의치료제로미국 FDA 의승인을얻었고몇몇 DAA도곧 FDA의승인을얻을것으로예상되어향후만성 C형간염치료의선택의폭이넓어질전망이다. 2세대 DAA는기존의 3제요법에비해더짧은치료기간으로도 SVR률이높고부작용, 복약편의성, 약물상호작용의측면에서단점이많이보완되었다. 이글에서는새롭게개발된약제중인터페론을포함함병합요법에대한임상연구결과를정리하고자한다. 페그인터페론알파 + 리바리빈 + 1 세대단백분해효소억제제병합치료 현재미국과유럽의유전자형 1형만성 C형간염의표준치료는페그인터페론알파, 리바비린및단백분해효소억제제 (protease inhibitor, PI) 인 telaprevir 또는 boceprevir의 3제병합요법이다. 64
김경아 만성 C 형간염의치료 : 주사제를포함한요법 Boceprevir 또는 telaprevir를포함한 3제요법으로치료하였을때, 치료경험이없는환자, 과거페그인터페론알파와리바비린병합요법후재발했던환자및페그인터페론알파와리바비린병합요법에무반응자에서 SVR률은각각 63-75%, 69-88%, 29-33% 로페그인터페론알파와리바비린병합요법보다초치료에서는약 25-30%, 재치료에서는약 25-60% 의추가적인치료성적의향상을보였다.1-5 그러나 boceprevir나 telaprevir를포함한 3제요법으로치료시기존치료보다부작용이흔하다. Boceprevir 치료시에는빈혈, 호중구감소증, 이상미각등의증상이흔하고 telaprevir 치료시에는발진, 빈혈, 항문직장증상등이흔하다. 이약제들은하루 3회다량으로복용해야하는불편감으로순응도가떨어질수있으며이로이한약제내성발현위험성도있다. 두약제모두 cytochrome 경로로대사되어약제간상호작용이흔하여이에대해주의해야한다. 페그인터페론알파 + 리바비린 + 2 세대 DAA 병합치료 1. Sofosbuvir Sofosbuvir는 nucleotide 유사체 NS5B 중합효소억제제로하루한번투여하는경구약제이다. 치료경험이없는유전자형 1형환자에서페그인터페론알파및리바비린과병합하여 12주간투여하였을때 89% 의 SVR을보였다. 간경변환자들을대상으로동일한요법으로치료하였을때 SVR은 80% 로약간낮았으나 SVR이치료전요인에의해영향을받지않았다. 유전자형 4형에서는 96%, 유전자형 5, 6형에서는 100% 에이르는 SVR을보였다.6 유전자형 2, 3형에서인터페론없이리바비린과의병합요법으로페그인터페론알파, 리바비린병합용법에비해열등하지않은 SVR을보였다. 7 유전자형 1, 4형만성 C형간염치료시페그인터페론, 리바비린과병합하여 12주, 유전자형 2형에는리바비린과병합하여 12주유전자형 3형에서는리바비린과병합하여 24주투여하는용법으로미국식품의약안정청 (FDA) 의승인을받았다. Sofosbuvir의가장흔한부작용은피로감이며치료를중단할정도의심각한부작용은 2% 로드물다. 2. Simeprevir Simeprevir는단백분해효소억제제로하루한번경구투여한다. 8 치료경험이없는유전자형 1형만성 C형간염환자와페그인터페론알파와리바비린병합요법후재발한환자에서 12주간페그인터페론알파, 리바비린및 simeprevir 투여후페그인터페론알파와리바비린을 12주추가투여하였을때 SVR률이 80% 로기존페그인터페론알파와리바비린병합요법의 50% 에비해우수하였다. 9,10 페그인터페론알파와리바비린병합요법에부분반응또는무반응을보인환자에서 simeprevir를포함한 12주간의 3제요법후 36주간페그인터페론알파와리바비린병합요법을시행하였을때 SVR률이각각 70%, 45% 로우수하였다. 11 Simeprevir는유전자형 1형만성 C형간염에서페그인터페론알파와리바비린와병합치료 65
2014 년대한간학회춘계 Single Topic Symposium 로써미국 FDA 의승인을받았다. 유전자형 1a형에서는 Q80k의변이가흔하고, Q80K 변이가있는경우 simeprevir를추가하여도페그인터페론알파와리바비린병합요법에비해 SVR의향상이없어유전자형 9 1a 치료전에 Q80k 변이검사를시행하는것이권고된다. 가장흔한부작용은피부발진이었으며빈혈은대조군과큰차이가없었고, 심각한부작용의빈도는 2% 로낮다. 9,10 3. Faldaprevir Faldaprevir는경구단백분해효소억제제로하루한번투여한다. 12 치료경험이없는유전자형 1형만성 C형간염에서페그인터페론알파및리바비린과병합투여하였을때 SVR률이 73% 로페그인터페론알파와리바비린병합치료의 50% 에비해우수하였다. 페그인터페론알파와리바비린병합치료후재발한환자에서는 SVR률이 80%, 부분반응자에서는 58%, 무반응자에서는 33% 였다. 13,14 Simeprevir와달리 Q80k 변이가치료성적에영향을미치지않는것으로알려져있다. 13 위약군에비해부작용의빈도가높지않으며약제를중단할정도의심각한부작용은 5% 이다. 12,13 4. Daclatasvir Daclatasvir는경구 NS5A 억제제로 15 유전자형 1형만성 C형간염환자에서페그인터페론, 리바비린과병합하였을때 SVR 90% 의우수한치료성적을보인다. 16 또한인터페론없이 sofosbuvir와병합치료하였을때 90% 이상의 SVR을보였다. 17 페그인터페론알파와리바비린병합요법무반응자에서페그인터페론알파, 리바비린, daclatasvir 및 2세대단백분해효소억제제인 asunaprevir 4제병합치료하였을때 SVR률이 95% 로높았다. 18 인터페론람다 (interferon-lambda) 와 DAA 병합요법 인터페론람다는 3형인터페론으로인터페론알파와동일한항바이러스효과를나타내지만, 수용체의분포가제한적이어서부작용이적다. 19 페그인터페론람다와리바비린의병합요법시페그인터페론알파와리바비린병합요법에비하여 SVR률은비슷하고부작용의빈도는낮았다. 20 유전자형 1형만성 C형간염환자에서페그인터페론람다, 리바비린및 daclatasivir 또는 asunaprevir의 3제를병합한 2상임상시험에서 SVR률이 75% 로보고되었고심각의부작용은드물었다. 21 페그인터페론람다, 리바비린및 1-2개의 DAA 병합요법에대한 3상연구가진행중이다. 결 론 Sofosbuvir 와 simeprevir 등의 2 세대 DAA 가페그인터페론리바비린병합요법으로미국 FDA 의승인을 66
김경아 만성 C 형간염의치료 : 주사제를포함한요법 받아조만간임상에서사용될수있을것으로기대된다. 최근연구에서인터페론을포함하지않은경구약제의조합만으로기존의인터페론병합요법에비해우수한성적을보이고있어 C형간염의치료에서인터페론의역할이축소될것으로예상된다. 가까운시일내에더효과적이고부작용이적은경구요법이표준치료가될가능성이높으므로, 질환의중증도, 동반질환및경제성등을종합적으로고려하여치료시기와방법을결정해야한다. 참고문헌 1. Poordad F, McCone J, Jr., Bacon BR, Bruno S, Manns MP, Sulkowski MS, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011;364:1195-1206. 2. Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011;364:1207-1217. 3. Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011;364:2405-2416. 4. Sherman KE, Flamm SL, Afdhal NH, Nelson DR, Sulkowski MS, Everson GT, et al. Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med 2011;365:1014-1024. 5. Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011;364:2417-2428. 6. Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013;368:1878-1887. 7. Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, Sulkowski MS, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 2013;368:1867-1877. 8. Zeuzem S, Berg T, Gane E, Ferenci P, Foster GR, Fried MW, et al. Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a phase IIb trial. Gastroenterology 2014;146:430-441 e436. 9. Jacobson I, Dore GJ, Foster GR, Fried MW, Manns M, Marcellin P, et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype 1 infection in treatment-naïve patients: efficacy in difficult-to-treat patient sub-populations in the QUEST-1 and 2 Phase III trials. Hepatology 2013;58:1122A. 10. Forns X, Lawitz E, Zeuzem S, Gane E, Bronowicki J-P, Andreone P, et al. Simeprevir (TMC435) with pegylated interferon-a-2a/ribavirin for treatment of chronic HCV genotype 1 infection in patients who relapsed after previous interferon-based therapy: efficacy and safety in patient sub-populations in the PROMISE Phase III trial Hepatology 2013;58:1092A. 11. Zeuzem S, Berg T, Gane E, Ferenci P, Foster GR, Fried MW, et al. TMC435 with peginterferon and ribavirin in treatment-experienced HCV genotype 1 patients: the ASPIRE study, a randomised Phase IIb trial J Hepatol 2012;56:2A. 12. Sulkowski MS, Bourliere M, Bronowicki JP, Asselah T, Pawlotsky JM, Shafran SD, et al. Faldaprevir combined with peginterferon alfa-2a and ribavirin in chronic hepatitis C virus genotype-1 patients with prior nonresponse: SILEN-C2 trial. Hepatology 2013;57:2155-2163. 13. Jensen DM, Asselah T, Dieterich DT, Foster GR, Sulkowski MS, Zeuzem S, et al. A pooled analysis of two randomized, double-blind, placebo-controlled phase III trials (STARTVerso1 AND 2) of fladaprevir plus pegylated interferon α-2a and ribiavirin in treatment-naïve patients with chronic hepatitis C genotype-1 67
2014 년대한간학회춘계 Single Topic Symposium infection. Hepatology 2013;58:1416A. 14. Jacobson IM, Asselah T, Ferenci P, Foster GR, Jensen DM, Negro F, et al. A randomized, double-bline, placebo-controlled phase III trials of faldaprevir in combination with pegylated interferon α-2a and ribavirin in treatment-experienced patients with chronic HCV genotype-1 infection. Hepatology 2013;58:1100A. 15. Gentile I, Borgia F, Coppola N, Buonomo AR, Castaldo G, Borgia G. Daclatasvir: The First of a New Class of Drugs Targeted Against Hepatitis C Virus NS5A. Curr Med Chem 2013. 16. Suzuki F, Toyota J, Ikeda K, Chayama K, Mochida S, Hayashi N, et al. A randomized trial of daclatasvir with peginterferon alfa-2b and ribavirin for HCV genotype 1 infection. Antivir Ther 2014. doi: 10.3851/IMP2730. [Epub ahead of print] 17. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, Reddy KR, Hassanein T, Jacobson I, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014;370:211-221. 18. Lok AS, Gardiner DF, Hezode C, Lawitz EJ, Bourliere M, Everson GT, et al. Randomized trial of daclatasvir and asunaprevir with or without PegIFN/RBV for hepatitis C virus genotype 1 null responders. J Hepatol 2014;60:490-499. 19. Miller DM, Klucher KM, Freeman JA, Hausman DF, Fontana D, Williams DE. Interferon lambda as a potential new therapeutic for hepatitis C. Ann N Y Acad Sci 2009;1182:80-87. 20. Zeuzem S, Arora S, Bacon B, Box T, Charlton M, Diago M, et al. Peginterferon lambda-1a (lambda) compared to peginterferon alfa-2a (alfa) in treatment-naive patients with HCV genotypes (G) 2 or 3: first SVR24 results from EMERGE phase IIB.. J Hepatol 2012;56:10A. 21. Izumi N, LaTaillade N, Chayama K, Toyota J, Mochida S, Kawada N, et al. First report of peginterferon lambda/ribavirin in combination with either daclatasvir or asunaprevir in HCV genotype 1 Japanese subjects: early sustained virologic response (SVR4) results from the D-LITE Japanese substudy. Hepatology 2012;56: 234A. 68