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1 PG 1 PG Course 2014 Treatment of Viral Hepatitis 인제대학교의과대학부산백병원내과 Current and Future of HCV Treatment Youn Jae Lee Inje University, Korea 서 론 C형간염의치료는놀라울정도로빠르게발전하고있다. 인터페론알파단독 6개월요법으로지속바이러스반응 (Sustained Virological Response:SVR) 이약 10% 전후이던것이페그인터페론알파의소개로리바비린과병합치료시 SVR은약 54-56% 로비약하였다. 1-4 그러나이치료법의제한적인효과및상당한부작용과불편함을극복하기위해많은노력이이루어져왔다. 특히바이러스생활사의특정부위에작용하는 direct acting antivirals (DAA) 의소개로 SVR률이괄목할정도로증가되었다. 최근에는다양한시도들이진행되고있는데특히인터페론이포함되지않은경구약물간의병합요법 (interferon-free regimen) 들이시도되고있고어떤조합은거의 100% 에가까운 SVR률을보고하고있다. 5 아쉽게도우리나라는아직이런 DAA는인가되지않아현재페그인터페론알파와리바비린병합요법이표준치료이다. 국내에서도다양한조합의 DAA들의임상시험이진행되고있어곧이런약제들이임상에적용될것으로생각된다. 여기서는우리나라, 미국및유럽의치료법의진화과정을살펴보고향후치료에대한예상을해보고자한다. 현재의치료 1. 우리나라 2013년개정된대한간학회 C형간염진료가이드라인 6 은페그인터페론알파와리바비린병합요법을표준치료로하였다. 유전자 1, 4형은치료기간이 48주간이고 2, 3, 6형은 24주간치료한다. 페그인터페론알파는 2a의경우는 180 ug, 2b의경우는 1.5 ug/kg를유전자형에관계없이동일한용량으로주 1회피하주사하고, 리바비린은유전자형 1, 4, 6형은페그인터페론알파2a 투여시에는체중 75 kg 이하이면 1,000 mg/d, 75 kg을초과할때는 1,200 mg/d으로투여하고, 페그인터페론알파 2b 투여시는체중 65 kg 미만은 800 mg/d, kg은 1,000 mg/d, kg은 1,200 mg/d, 105 kg을초과하면 1,400 mg/d으로투여하고, 유전자형 2, 3형은체중에관계없이고정용량 800 mg을투여한다. 그리고유전자형 1, 2, 3, 4형의경우는치료반응에따라치료기간을조절할수있는 20

2 Figure 1. Treatment algorithm for patients with genotype 1 chronic HCV infection. This algorithm applies to genotype 4 at a B2 grade of evidence. The dotted lines indicated weaker strength of recommendation compared with the solid lines. *Negative factors for response include advanced liver fibrosis or cirrhosis, obesity, insulin resistance. Figure 2. Treatment algorithm for patients with genotype 2, 3 chronic HCV infection. The dotted lines indicate weaker strength of recommendation compared with the solid lines. * Negative factors for response may include advanced fibrosis, cirrhosis and others. ** The shortened therapy may result in higher relapse rate. 21

3 Postgraduate Course 2014 치료반응에따른요법 (Response-guided therapy) 을이용할수있다고하였다 (Figure 1, 2). 우리나라의치료성적은 SVR률이유전자형 1형은 %, 7-12 유전자형 2/3형 ( 대부분유전자형 2형 ) 은 % 이었다. 12,13 치료경험이있는경우는유전자형 1, 2, 3, 4형에서이전치료가인터페론알파단독또는리바비린과병합치료또는페그인터페론알파단독으로사용한경우초치료와같은방법으로치료를할수있다. 이때는치료반응에따른요법은사용하지않는다. 아직은우리나라에는인가가되지는않았지만 Boceprevir와 Telaprevir는유전자 1형에서만초치료및재치료에서표준치료와병합요법으로권장한다고하였다. 2. 미국신약이계속개발됨에따라새로운가이드라인이계속계발되고있다. 2009년, 2011년가이드라인이발표되었고, 2014년미국간학회와미국감염병학회공동으로 guidance를발표하였다. 1) 2009년미국간학회가이드라인 14 이것은 2013년대한간학회가이드라인과거의동일한데, 다른점은유전자형 6형이포함되어있지않고, 치료반응에따른요법에서약간의차이를보인다. 유전자형 1, 4형에서지연바이러스반응 (delayed virological response, DVR) 을보일때 72주연장치료는동일하나, 급속바이러스반응 (rapid virological response, RVR) 을보이고치료전 HCV RNA 농도가낮고 (<400,000 iu/ml), 치료실패예측인자 ( 진행된간섬유화또는간경변증, 비만이나인슐린저항성등 ) 가없을때우리나라는치료기간을 24주로단축할수있다고하였으나, 미국가이드라인에서는인정하지않았다. 2) 2011년미국간학회가이드라인 15 몇몇의 DAA소개이후중요한임상결과들이발표되어 이를근거로유전자형 1형에서 DAA제제인 boceprevir 또는 talaprevir와페그인터페론알파및리바비린가포함된 3제요법을표준치료로한내용이다. 치료경험이없는환자, 과거페그인터페론알파와리바비린병합요법후재발했던환자그리고무반응자에서 SVR률은각각 63-75%, 69-88%, 29-33% 로페그인터페론알파와리바비린병합요법보다초치료에서는약 25-30%, 재치료에서는약 25-60% 의추가적인치료성적향상을보였으나boceprevir나 telaprevir가포함된 3제요법은기존의치료보다부작용은더많았다 Boceprevia는이상미각 (dysgeusia), 빈혈, 호중구감소증등이더흔하였고, telaprevir는피부발진, 빈혈, 항문직장증상등이더흔히나타났다. 그리고두약물모두하루 3회의다량의약을복용해야하는불편감, 많은약물상호작용그리고고비용의문제점이있다. (1) 치료경험이없는경우 a. boceprevir 포함 3제요법 - 페그인터페론알파와리바비린을 4주간투여 (lead-in) 후 boceprevir, 페그인터페론알파, 리바비린을 24-44주간투여한다. Boceprevir는 800 mg을하루세번, 식사와함께복용한다. - 간경변증이없는경우치료 8주째와 24주째 HCV RNA가검출되지않으면총 28주치료를고려하며, 간경변증이있는경우 48주간치료한다. - 치료 12주째 HCV RNA 치가 100 IU/mL 이상이거나 24주째 HCVRNA가검출되면치료를중단한다. b. Telaprevir 포함 3제요법 - Telaprevir, 페그인터페론알파, 리바비린을 12주간투여후페그인터페론알파와리바비린을 12-36주간투여한다. telaprevir는 750 mg을하루세번, 식사와함께복용한다. 22

4 - 간경변증이없는경우치료 4주째와 12주째에 HCV RNA가검출되지않으면 24주치료를고려하며, 간경변증이있는경우 48주간치료한다. - 치료 4주혹은 12주에혈청 HCV RNA가 1,000 IU/mL 이상이거나치료 24주에 HCV RNA가검출되면치료를중단한다. (2) 치료경험이있는경우 a. boceprevir 포함 3제요법 - 이전치료에재발또는부분반응을보인경우에는페그인터페론알파와리바비린을 4주간투여 (lead-in) 후 boceprevir, 페그인터페론알파, 리바비린을 32주그리고페그인터페론알파와리바비린을 12주간총 48주간치료한다. 초치료에서와같이치료반응에따른단축치료가가능하다. - 이전에무반응이었던경우는페그인터페론알파와리바비린을 4주간투여 (lead-in) 후 boceprevir, 페그인터페론알파, 리바비린을 44주치료하고치료반응에따른요법은적용되지않는다. - 치료 12주째 HCV RNA 치가 100 IU/mL 이상이면치료를중단한다. b. Telaprevir 포함 3제요법 - 이전치료에재발한경우는치료경험이없는경우와치료는동일하다. - 이전치료에부분반응또는무반응이었던경우는 telaprevir, 페그인터페론알파, 리바비린을 12주간투여후페그인터페론알파와리바비린을 36주간투여한다. - 치료 4주혹은 12주에혈청 HCV RNA가 1,000 IU/mL 이상이면치료를중단한다. 3) 2014년미국간학회-미국감염병학회 guidance 21 최근 C형간염의치료에급격한발달로미국간학회와미국감염병학회공동으로전문가집단에서근거중심으로개발한 C형간염관리 ( 최적의선별검사, 관리, 및치료 ) 에대한권고안을신속하게입안하고전파할수있도록웹에기반으로개발하였고, 정기적으로새로운자료들을반영하여갱신하기로하였다 ( 이 guidance 내용중치료에관한내용을살펴보고자한다. (1) 치료경험이없거나재발한경우 (Table 1) a. 유전자형 1형유전자형 1형 291명을대상으로한 3상연구인 NEUTRINO 연구 22 결과 sofosbuvir (400 mg daily), 페그인터페론알파, 리바비린삼제요법으로치료시 SVR12률이 89% 이고이치료성적은치료전여러요소에관계가없었으나간경변증의유무에따라서는 SVR12 률은각각 80, 92% 로차이가있었다. 치료경험이없거나이전치료에무반응 (null response) 인환자를대상으로 Simeprevir (150 mg) 와 sofosbuvir (400 mg) 이제요법또는리바비린을추가한 3제요법을비교한 2상임상시험인 COSMOS연구에서 Metavir 점수 0-2인경우는12주치료에 SVR12 률이 93-96% 이었고 23 Metavir 점수 3, 4인코호트연구에서는 12주또는 24주치료에리바비린추가와상관없이 SVR12률은 % 이었고, 이는 HCV 아형 (subtype), Q80K 다형성, 간섬유화정도, IL28B 유전자형, 이전치료병력과무관하였다. 24 위두가지를사용할수없는경우대안으로사용할수있는두가지는다음과같다. 첫째, Simeprevir/ 페그인터페론알파 / 리바비린을이용한두 3상시험 (QUEST-1, -2) 25,26 에서삼제요법 12주치료후페그인터페론알파 / 리바비린으로 12주더치료하는것이페그인터페론알파 / 리바비린치료보다각각 80, 81% 그리고 50, 50% 로삼제요법이우수하였다둘째, Sofosbuvir와리바비린을 24주간사용한연구에서 SVR률은리바비린을체중에따라사용한군과저용량 23

5 Postgraduate Course 2014 Table 1. Recommendations for Patients Who are Initiating Therapy for HCV Infection or Who Experienced Relapse after Prior PEG/RBV Therapy Genotype Recommended Alternative 1 IFN eligible: SOF+PEG/RVB 12 weeks (l, A) IFN eligible: SMV 12 * weeks + PEG/RBV 24 weeks (lla, A) IFN ineligible: SOF + SMV ± RBV 12 weeks (l, B) IFN ineligible: SOF + SMV 24 weeks (llb, B) 2 SOF + RVB 12 weeks (l, A) none 3 SOF + RVB 24 weeks (l, B) SOF + PEG/RVB 12 weeks (lla, A) 4 IFN eligible: SOF + PEG/RVB 12 weeks (lla, B) SMV 12 weeks + PEG/RBV weeks (llb, B) IFN ineligible: SOF + RBV 24 weeks (llb, B) 5 or 6 SOF + PEG/RVB 12 weeks (lla, B) PEG/RVB 48 weeks (llb, A) * For genotype 1a, baseline resistance testing for Q80K should be performed and alternative treatments considered if this mutation is present. # IFN, interferon; SOF, sofosbuvir; PEG, peginterferon alpha; RBV, ribavirin; SMV, simeprevir. (600 mg) 으로사용한군에서각각 68%, 48% 이었다. 27 b. 유전자형 2형 Sofosbuvir와리바비린 (1,000-1,200 mg) 을사용한 3개 (FISSION 28, POSITRON 29, VALANCE 30 ) 의임상시험에서 sofosbuvir/ 리바비린 12주치료군과페그인터페론알파 / 리바비린 24주치료군에서의초치료 SVR률은각각 94% (201/214), 78% (FISSION) 이었다. c. 유전자형 3형 VALANCE 연구 30 에서 sofosbuvir/ 리바비린 (1,000-1,200 mg) 으로 24주치료시 SVR률은 84 ( 초치료 : 93, 재치료 : 77)% 이었고, 이는다른연구들에서 12-16주치료시 SVR률이 61-63% 보다높았다. 대안으로사용할수있는것은 2개의 2상연구 (PROTON 31, LONSTAR-2 32 ) 에서 sofosbuvir// 페그인터페론알파 / 리바비린삼제요법으로 SVR률이각각 90, 83% 이었으나많은부작용으로더잦은관찰이필요하여일차치료로추천되지는않는다. d. 유전자형 4, 5, 6형치료를결정하는데도움을줄만한연구는거의없으나빠른치료가요하는경우이용할수있도록권고안이만들어졌다. 유전자형 4형은 NEUTRINO 연구 22 (sofosbuvir/ 리바비린 / 페그인터페론알파 ) 에포함되어있는 28명중 27 (96%) 명에서 SVR12가관찰되었다. 미국에있는이집트인을대상으로 sofosbuvir/ 리바비린을이용한한연구에서는 12주, 24주치료군에서각각 79%, 100% 의 SVR12 를보였다 33 그리고 simeprevir/ 페그인터페론알파 / 리바비린삼제요법으로 3상시험이진행중이다. 유전자형 5, 6형은참조할만한연구결과가거의없고특히인터페론이포함되지않은요법의결과는없다. 24

6 (2) 이전치료에실패한경우 ( 무반응또는부분반응 ) (Table 2) a. 유전자형 1형 COSMOS연구에서이전무반응자에서 Metavir 점수 0-2인경우는12주치료에 SVR12 률이 79-96% 이었고 Metavir 점수 3, 4인코호트연구에서는 12주또는 24주치료에리바비린추가와상관없이 SVR12 률은 93% 이었다. 23,24 NEUTRINO 연구 22 는치료실패자를대상으로한연구는아니지만인터페론을근거로한치료에반응이낮은것으로알려진요인을가지고있는경우의반응률과비슷할것으로추산하였다. 이연구에서유전자 1형, non-cc, 치료전높은바이러스양, Metavir 섬유화점수가 3, 4인경우에서의 SVR률은 71% 이었다. 34 ASPIRE 연구 35 에서 simeprevir / 페그인터페론알파 / 리바비린 48주치료시이전부분반응, 무반응각각 65, 53% 의 SVR률을보였다. b. 유전자형 2형많은자료는없지만 FUSION 연구 29 에서 sofosbuvir/ 리바비린 12주또는 16주, VALANCE 연구 30 에서 sofosbuvir/ 리바비린 12주치료시각각 60, 78, 88% 의 SVR률을보였다., 아직치료기간에대한자료는부족하기때문에 12 또는 16주치료를정하는것은상황에따라결정해야할것이다. 대안으로는 LONSTAR-2연구 36 에서 sofosbuvir/ 리바비린 / 페그인터페론알파 12주치료시 SVR률은 96% 이었다. Table 2. Recommendations for Patients in Whom Previous PEG/RBV Treatment Has Failed Genotype Recommended Alternative Patients in whom previous PEG/RBV has failed * 1 SOF + SMV ± RBV 12 weeks (lla, B) SOF + PEG/RVB 12 weeks (llb, C) SMV 12 weeks + PEG/RBV 24 weeks ** (lla, A) 2 SOF + RVB 12 weeks (l, A) SOF+PEG/RVB 12 weeks (lla, B) 3 SOF + RVB 24 weeks (lla, B) SOF+PEG/RVB 12 weeks (lla, B) 4 SOF + PEG/RVB 12 weeks (lla, C) SMV 12 weeks + PEG/RBV weeks SOF + RBV 24 weeks (lla, B) 5 or 6 SOF + PEG/RVB 12 weeks (lla, C) none Patients in whom previous treatment with PEG/RBV plus either telaprevir or boceprevir *** has failed, 1a SOF 12 weeks + PEG/RBV 24 weeks SOF + RVB 24 weeks 1b SOF 12 weeks + PEG/RBV weeks SOF + RVB 24 weeks Consideration should be given to postponing treatment, pending release of new drugs for patients with limited (F 0-2) hepatic fibrosis. * Non-responder is defined as partial or null response to treatment with PEG/RBV. Relapse to prior therapy should be treated the same as treatment-naïve. ** For genotype 1a, baseline resistance testing for Q80K should be performed and alternative treatments considered if this mutation is present *** Non-responder is defined as partial or null response to treatment with PEG/RBV plus telaprevir or boceprevir. Relapse to prior therapy should be treated the same as treatment naive A recommendation for simeprevir use for patients with previous telaprevir or boceprevir exposure not provided due to potential risk of preexistant resistance to protease inhibitor treatment. Given the lack of prior approval PI therapy for genotypes 2, 3, 4, 5, 6, and the lack of sufficient data, no recommendations are given for these genotype at this time # IFN, interferon; SOF, sofosbuvir; PEG, peginterferon alpha; RBV, ribavirin; SMV, simeprevir. c. 유전자형 3 형 FUSION 연구 29 에서 sofosbuvir/ 리바비린 12, 16 주치료시각각 30, 62% 이었다. 이를근거로시행한 VALANCE 연구 30 25

7 Postgraduate Course 2014 에서 sofosbuvir/ 리바비린을 24주로연장하여치료시는 79% 의 SVR률을보였다. LONSTAR-2연구 36 에서 sofosbuvir/ 리바비린 / 페그인터페론알파 12주치료시 SVR률이 83 (20/24)% 이었다. 대상자가적어어느것이나은지판단하기는어렵다. d. 유전자형 4, 5, 6 NEUTRINO 연구 22 에서 sofosbuvir/ 리바비린 / 페그인터페론알파 12주치료에유전자형 4, 5, 6형의 SVR률은각각 96 (27/28), 100 (1/1), 100 (7/7)% 이었다. Ruane 등 33 의연구에서유전자형 4형을대상으로 sofosbuvir/ 리바비린 12주, 24주치료시 SVR률은각각 59%, 93% 이었다. 3. 유럽유럽도미국과같이가이드라인이급격히변하고있다. 2011년, 2014년초, 그리고 2014년 4월에부분개정판이발표되었다. 1) 2011년가이드라인 36 이것은 2013년대한간학회가이드라인과거의동일한데약간의다른점은유전자형 1, 4형에서는페그인터페론알파 2a, 2b관계없이 RBV을 15 mg/kg로사용하는것과치료반응에따른치료시단축치료를고려할때기준중치료전바이러스양이우리나라는 40만 IU/mL 미만이나유럽은 40-80만 IU/mL 미만인점이다르다. 유전자형 2, 3형에서이라도치료전예측인자에서낮은반응이예상될때는리바비린을유전자형 1형과동일한용량을사용한다는것이다. 우리나라에는없는기준은치료중 EVR에도달하지못하거나치료 24주에바이러스가검출되면치료를중지하고, RVR에도달하지못한경우 48주치료를권하는것이다. 2) 2014년 1월발표된가이드라인 년미국가이드라인과같이유전자형 1형에서 boceprevir와 telaprevir를사용한것으로미국가이드라인과동일하다. 3) 2014년 4월발표된가이드라인 38 기존의인터페론알파와리바비린과최근유럽에서인가된 sofosbuvir, simeprevir, daclatasvir를이용한다양한치료방법들을소개하였다 (Table 3, 4). 4. 향후치료의전망미국및유럽가이드라인변천을보면인터페론이근간이된병합치료에서 DAA가근간이되는병합치료로빠르게진화하고있음을알수있다. Table 5와같이현재진행되거나계획중인연구도대부분 DAA가근간이되면서인터페론을포함하고있지않고, 그리고몇가지특징이있다. 39,40 NA (nucleoside/nucleotide analogues) 를근간으로하는치료는두가지 ( 또는세가지 ) 의약물로병합치료가진행중이고, NA가포함되지않은 1세대약물들의조합일경우는세가지약물의병합이필요하다. 이는 NA의경우내성에강하기때문이다. 그기전은 RNA-dependent RNA polymerase 의작용에중요한위치인 282번위치에 serine이 threonine으로대치되었을때내성이주로발생하는데, 이경우중합효소의활성도가약 11배까지감소하여바이러스증식이상당히감소되기때문에내성바이러스생존이어렵기때문이다

8 Table 3. Treatment of chronic hepatitis C Genotype Recommendations 1 option 1 PEG/RBV/SOFx12 weeks (A1) option 2 SMVx12 weeks+ PEG/RBVx24 weeks for treatment-naïve and prior relapse(b1) SMVx12 weeks+ PEG/RBVx48 weeks for prior partial and null responders(b1) option 3 option 4 option 5 option 6 genotype 1b: PEG/RBV/DCV for 24 weeks(b2) IFN ineligible: SOF+RVBx24 weeks(b2) SOF+SMV x 12 weeks(b1) SOF+SMV+RBVx12 weeks for patients with predictors of poor response to anti-hcv therapy(b1) SOF + DCVx12 weeks for treatment-naïve patients(b1) SOF + DCVx24 weeks for treatment-experienced patients*(b1) SOF+DCV+RBV for patients with predictors of poor response to anti-hcv therapy(b1) 2 option 1 SOF+RVBx12 weeks(a1) SOF+RVBx16 or 20 weeks for cirrhotic, esp treatment-experienced patients(b1) option 2 SOF+PEG/RVBx12 weeks for cirrhotic and/or treatment-experienced patients(b1) 3 option 1 SOF+PEG/RVBx12 weeks(a2) option 2 SOF+RVBx24 weeks(a2) option 3 SOF+DCVx24 weeks(b1) SOF+DCV+RBV for patients with predictors of poor response to anti-hcv therapy(b1) 4 option 1 SOF+PEG/RVBx12 weeks(b1) option 2 SMVx12 weeks+ PEG/RBVx24 weeks for treatment-naïve and prior relapser, including cirrhotics (B1) SMVx12 weeks+ PEG/RBVx48 weeks for prior partial and null responders, including cirrhotics (B1) option 3 DCV+PEG/RVBx12 weeks (B1) DCV+PEG/RVBx24 weeks for patents who do not achieve an HCV RNA <25 IU/mL at week 4 and undetectable at week 10 DCVx12 weeks+peg/rvbx24 weeks for patents who achieve an HCV RNA <25 IU/mL at week 4 and undetectable at week 10(B1) option 4 IFN ineligible: SOF+RBVx24 weeks(c2) option 5 SOF+SMV x 12 weeks(b2) SOF+SMV+RBVx12 weeks for patients with predictors of poor response to anti-hcv therapy(b2) option 6 SOF + DCVx12 weeks for treatment-naïve patients(b2) SOF + DCVx24 weeks for treatment-experienced patients(b2) SOF+DCV+RBV for patients with predictors of poor response to anti-hcv therapy(b2) 5, 6 option 1 SOF+PEG/RVBx12 weeks(b1) option 2 SOF+RVBx24 weeks # IFN, interferon; SOF, sofosbuvir; PEG, peginterferon alpha; RBV, ribavirin; SMV, simeprevir; DCV, daclatasvir. 그러나 NA가포함되지않은조합이라도내성에강한 2세대약물의경우는두가지약물로도가능하다. 그리고 sofosbuvir와 daclatasvir (± ribavirin), sofosbuvir와 ledipasvir (± ribavirin) 로치료할경우 SVR은약 95% 이상이었고특히이전의치료에서는반응률이낮은것으로알려진유전자형 1a, 간경변증, 흑인, 이전치료에실패와치료에대한반응률은무관하였고, 리바비린추가유무에도관계가없음을보였다 즉, 적절한조합으로 27

9 Postgraduate Course 2014 Table 4. Retreatment for patients who failed to achieve an SVR with new treatment regimens including sofosbuvir, simeprevir and/or daclatasvir - SOF+SMV (genotype 1 or 4) or SOF+DCV(all genotype) for previous failure to a regimen containing sofosbuvir as the only DAA(B1) - SOF+DCV for for previous failure to a regimen containing simeprevir, telaprevir, boceprevir as the only DAA - SOF+SMV (genotype 1 or 4) for previous failure to a regimen containing daclatasvir as the only DAA - SOF+DCV for for previous failure to a regimen containing sofosbuvir and simeprevir - SOF+SMV (genotype 1 or 4) for previous failure to a regimen containing sofosbuvir and daclatasvir - Alternatively, patients who failed on any of the new treatment regimens including sofosbuvir, simeprevir and/or daclatasvir can wait until new treatment combinations are available if they do not need urgent therapy # IFN, interferon; SOF, sofosbuvir; PEG, peginterferon alpha; RBV, ribavirin; SMV, simeprevir; DCV, daclatasvir. Table 5. Interferon-free regimens for HCV therapeutic agents in clinical development NA NS3-4A I NS5A I NS5B I non-na RBV NA-based strategy Sofosbuvir Ledipasvir ± Sofosbuvir GS-5816 ± Sofosbuvir Ledipasvir GS Sofosbuvir Vedroprevir Ledipasvir - Sofosbuvir Simeprevir ± Sofosbuvir Daclatasvir ± Vx-135 Simeprevir ± Vx-135 Daclatasvir ± Mericitabine Danoprevir/r ± ± NA-free triple combo strategy ABT-450/r ABT-267 ABT-333 ± (drug with low barrier to resistance) Asunaprevir Daclatasvir BMS ± Simeprevir GSK TMC ± Simeprevir Samatasvir TMC ± ± NA-free double combo strategy MK-5172 MK-8742 ± (drug with high barrier to resistance) ACH-2684 ACH-3102 ± # NA, nucleoside/nucleotide analogues; NS3-4A I, NS3-4A inhibitor; NS5A I, NS5A inhibitor; NS5B I non-na, NS5B inhibitor non-nucleoside; RBV, ribavirin. 치료를한다면이제까지의 difficult-to-treatment 군도해결할수있을것으로기대된다. 그러나현재이런인가된경구약제들은너무가격이높기때문에가장경제적이며효과적이고부작용이가장 적은조합을찾아내는것이향후의과제이다.. 28

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12 47. Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al. Ledipasvir and Sofosbuvir for 8 or 12 Weeks for Chronic HCV without Cirrhosis. N Engl J Med Apr 10. [Epub ahead of print] 31