C型肝炎治療的新選擇―― Sovaldi® …

1 13C Sovaldi Tablets sofosbuvir Harvoni Tablets Ledipasvir plus sofosbuvir Gilead Sciences C C HCV DAA Direct-acting antiviral agents 2 C [1-2] Sovaldi Tablets [3] 400 mg sofosbuvir Harvoni Tablets[4] 90 mg Ledipasvir 400 mg sofosbuvir 2 HCV HIV Sovaldi Tablets sofosbuvir sofosbuvir sofosbuvir GS-461203 HCV [1] HCV 132015/10/23 07:12:2914 92 <C Interferon free treatment strategy> PegInterferon Ribavirin RBV HCV HIV sofosbuvir RBV 12 24 sofosbuvir RBV 12 [5-8] [9-13] [14-15] sofosbuvir RBV sofosbuvir 400 mg Ribavirin RBV 12 24 [5-8] Study Name ( ) ( )SVR rate( %) HCV RNA <25 IU/mL ( %)2 4 12 Lawitz et al.

2 [6](FISSION)TN; HCV GT 2 or 3 SOF+RBV (253)1267a92 +RBV (243)246732 67 89TN; HCV GT 2 SOF+RBV (59)1298 Jacobson et al. [7](POSITRON)Interferon intolerant, ineligible or unwillingHCV GT 2 or 3 SOF+RBV (207)127891 99 100 (71) 1200 0 0 HCV GT 2 SOF+RBV (92)1292 Jacobson et al. [7](FUSION)TN; HCV GT 2 or 3 SOF+RBV (100)125081 97 100 SOF+RBV (95)167387 98 100 Zeuzem et al. [8](VALENCE)TN or TE; HCV GT 2 SOF+RBV (73)129378 100TN or TE; HCV GT 3 SOF+RBV (250)248586 99 Osinusi et al. [5]TN; HCV GT 1; early to moderate liver fibrosisSOF+RBV (10)2490TN; HCV GT 1; all stages of liver fibrosisSOF+RBV (25)246896 96 SOF+RBV 600mg/day (25)244896 88 : GT: genotype , PEGIFN: peginterferon-a-2a , SOF: sofosbuvir , SVR: sustained virological response , TE: RBV treat-ment experienced , TN: treatment na ve , Interferon intolerant, ineligible or unwilling: , 142015/10/23 07:12:29 15 C 12 SVR.

3 Sustained virological response FISSION study [5] 98% 58/59 C SVR POSITRON Study [7] 92% 85/92 HCV GT2 SVR VALENCE Study sofosbuvir RBV 12 97% 29/30 SVR FISSION [5], POSITRON [7], VALENCE [8] C sofosbuvir RBV 12 SVR C HCV sofosbuvir RBV 12 SVR 90% RBV sofosbuvir RBV sofosbuvir RBV 9 FUSION study [7]: 60% 6/10 , VALENCE study [7]: 88% 7/8 HCV sofosbuvir RBV C sofosbuvir SVR sofosbuvir RBV HCV genotype1 and genotype 3 [9-13] SVR rate 90% RBV HCV genotype 1 [16] sofosbuvir 400 mg PegInterferon 152015/10/23 07:12.

4 2916 92 <C Interferon free treatment strategy>RBV 12 sofosbuvir 400 mg RBV 12 HCV HIV [14] C [15] HCV sofosbuvir 400 mg RBV 24 SVR rate 76% HCV 12 SVR rate 75% HCV RBV sofosbuvir RBV 24 93% SVR[14] RBV C HCV HIV C sofosbuvir SVR 162015/10/23 07:12:29 17 sofosbuvir 400mg PegInterferon a Ribavirin 12 Study Name ( ) SVR rate ( %)SVR 12 SVR 24 Lawitz et al. [9] (NEUTRINO)TN; HCV GT 1, 4, 5 or 6 SOF+PegINF+RBV (12)3279191 Kowdley et al.

5 [10] (ATOMIC)TE; HCV GT 1, 4, 5 or 6 SOF+PegINF+RBV (12)529089 SOF+PegINF+RBV (24)1099389 SOF+PegINF+RBV (12) SOF or SOF+RBV (12)1559187 Lawitz et al. [11] (PROTON)TN; HCV GT 1 SOF 200mg+PegINF+RBV (12)489085TN; HCV GT 1 SOF+PegINF+RBV (12)479189TN; HCV GT 1 +PegINF+RBV (12)265858TN; HCV GT 2 or 3 SOF+PegINF+RBV (12)259292 Lawitz et al. [12] (LONESTAR-2)TE; HCV GT 2 or 3 SOF+PegINF+RBV (12)4789 Gane et al. (ELECTRON)TN; HCV GT 2 or 3 SOF +RBV (12) +PegINF (4)9100100 SOF +RBV (12) +PegINF (8)10100100 SOF +RBV (12) +PegINF (12)11100100 SOF +RBV (12)10100100 SOF (12)106060 SOF +RBV +PegINF (8)10100100TN; HCV GT 1 SOF +RBV (12)258484TE; HCV GT 1 SOF +RBV (12)101010 : HCV: C hepatitis C virus , GT: genotype , PEGIFN: peginterferon-a-2a , RBV: ribavirin , SOF: sofosbuvir , SVR: sustained virological response , TE: treatment experienced , TN: treatment na ve , Interferon intolerant, ineligible or unwilling: , DAA [17] sofosbuvir sofosbuvir RBV DAA [17] Harvoni Tablets Ledipasvir plus sofosbuvir Harvoni HCV DAA: NS5A Ledipasvir NS5B 172015/10/23 07:12.

6 3018 92 <C Interferon free treatment strategy> sofosbuvir Fixed dose combination 2014 10 10 [18] 2015 [19] Ledipasvir HCV 1a 1b , 4a, 4d, 5a 6a HCV 2a, 2b, 3a 6e HCV [19] NS5A resistance-associated variants, RAVs HCV 1a Q30H/R, L31I/M/V, P32L Y93T HCV 1b P58D Y93S Ledipasvir Ledipasvir/ sofosbuvir C Ledipasvir NS5A Ledipasvir sofosbuvir DAA HCV NS5A [19] sofosbuvir 400mg Ribavirin 12 HCV HIV Study Name ( ) ( )SVR rate( %)Sulkowski et al. [14] (PHOTON-1)TN; HCV GT 1 and HIV-1 SOF + RBV (114)2476TN; HCV GT 2 or 3 and HIV-1 SOF + RBV (68)1275TE; HCV GT 2 or 3 and HIV-1 SOF + RBV (41)2493 Curry et al.

7 [15]CHC and HCC; awaiting liver transplantationSOF + RBV (42)Up to 4869 : HCV: C hepatitis C virus , CHC: C chronic hepatitis C GT: genotype , PEGIFN: peginterferon-a-2a , RBV: ribavirin , SOF: sofosbuvir , SVR: sustained virological response , TE: treatment experienced , TN: treatment na ve , HCC: hepatocellular carcinoma , awaiting liver transplantation: 182015/10/23 07:12:30 19 Ledipasvir/ sofosbuvir C Study Name ( , ) (ITT patients No.)S V R r a t e ( %)SVR 4 SVR 12 ION-1 [20]LDV/SOF (12)2149999 LDV/SOF + RBV (12)2179897 LDV/SOF (24)2179998 LDV/SOF + RBV (24)2179999 ION-2 [21]LDV/SOF (12)1099494 LDV/SOF + RBV (12)1119696 LDV/SOF (24)10910099 LDV/SOF + RBV (24)1119999 ION-3 [22] (overall population)LDV/SOF (8)2159694 LDV/SOF + RBV (8)2169593 LDV/SOF (12)2169695 ION-3 [23] baseline HCV RNA level < 6 log10 IU/mLLDV/SOF (8)12397 LDV/SOF + RBV (8)13896 LDV/SOF (12)13196 ION-3 [23] baseline HCV RNA level 6 log10 IU/mLLDV/SOF (8)9290 LDV/SOF + RBV (8)7887 LDV/SOF (12)8596 : HCV: C hepatitis C virus , ITT: intent-to treat , RBV: ribavirin , LDV: Ledipasvir, SOF: sofosbuvir , SVR 4/12.

8 4 /12 sustained virological response 4 or 12 week s post-treatment Ledipasvir 90 mg sofosbuvir 400 mg fibrosis score F0~F3 Class A Child-Pugh score RBV 600 mg-1,200 mg Class B or C RBV 600 mg-1,200 mg [19] HCV 3 Ledipasvir / sofosbuvir 18 C ION-1 [20] ION-3 [22] C ION-2 RBV NS3/4A 192015/10/23 07:12:3020 92 <C Interferon free treatment strategy>protease inhibitor [21] ION-1 [20] ION-2 [21] 20% compensated cirrhosis HCV RNA 104 IU/mL, ALT AST 10 50,000 /mm3 [20, 21] 90,000 /mm3 [22] Haemoglobin > 11 g/dL > 12 g/dL [20-22] 3 Ledipasvir / sofosbuvir 6 IU/mL 8 12 12 RBV RBV ALT RBV SVR 95% [20-22] HIV HCV Ledipasvir / sofosbuvir ION-4 [24]

9 335 treatment-na ve 45% RBV treatment-experienced 55% HCV 20% Treatment-naive 12 SVR SVR 12 96% treatment-experienced 12 94% SVR 12 HIV HAART HIV HCV [24] < >1. European Medicines Agency. Sovaldi (sofosbovir): EU summary of product characteristics. 2014. Accessed 31 Mar European Medicines Agency. Harvoni 202015/10/23 07:12:30 21(ledipasvir/ sofosbuvir ) film-coated tablets: EU summary of product characteristics. 2014. Accessed 2 Mar Gilead Sciences Inc. Sovaldi ( sofosbuvir ) tablets, for oral use: US prescribing information. 2013. Accessed 31 Mar Gilead Sciences Inc.

10 Harvoni (ledipasvir and sofosbuvir ) tablets for oral use: US prescribing information. 2015. Accessed 30 Mar 20155. Osinusi A, Meissner EG, Lee Y-J, et al. sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial. JAMA 2013;310(8) Lawitz E, Mangia A, Wyles D, et al. sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013;368(20) Jacobson IM, Gordon SC, Kowdley KV, et al. sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 2013;368(20) Zeuzem S, Dusheiko GM, Salupere R, et al. sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med 2014;370(21) Lawitz E, Mangia A, Wyles D, et al. sofosbuvir for previously untreated chronic hepatitis C infection.