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Sheng-Shun Yang, M.D., Ph.D. Division of Gastroenterology & Hepatology ,

Direct Acting Antivirals for Chronic Hepatitis C. Sheng-Shun Yang, M.D., Ph.D. Division of Gastroenterology & Hepatology , Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan 2013-11-28. C 型肝炎病毒感染之併發症.

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Sheng-Shun Yang, M.D., Ph.D. Division of Gastroenterology & Hepatology ,

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  1. Direct Acting Antivirals for Chronic Hepatitis C Sheng-Shun Yang, M.D., Ph.D. Division of Gastroenterology & Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan 2013-11-28

  2. C型肝炎病毒感染之併發症 1. Lavanchy D. ClinMicrobiolInfect2011;17:107-115. 2. Montalto G, et al. Ann NY Acad Sci 2002;963: 13-20. 3. Milliman, Inc. Consequences of HCV: costs of a baby boomer epidemic, 2009. 4. Jacobson IM, et al. Clin Gastroenterol Hepatol2010;8:1017-1029. • 慢性C型肝炎是導致肝病重要的原因[1] • 1/4 of the ~500,000 new HCC cases identified globally each year are attributable to HCV[2] • 預估未來幾年，C型肝炎相關的併發症增加兩倍[3] • C型肝炎感染經常合併許多肝外疾病或症候[4] • Mixed cryoglobulinemiavasculitis, lymphoproliferative disorders, diabetes (2-3 ↑ odds), renal disease, rheumatoid arthritis–like polyarthritis, sicca syndrome, depression, neurocognitive impairment

  3. 治療C型肝炎的目標 • 首要目標乃是根除此病毒 • 次要目標 • Slow disease progression • Minimize risk of liver cancer • Improve liver damage • Enhance quality of life • Prevent transmission of virus • Reduce extra-hepatic manifestations

  4. Outline • 國內當前標準療法 (standard of care) • DAAs新藥介紹 - 已上市 (Boceprevir & Telaprevir) - 即將上市 (Sofosbuvir & Simeprevir) -研發中藥物

  5. 慢性C型肝炎治療里程碑 SVR rates remain suboptimal in HCV genotype 1 Direct acting antivirals (DAAs): ~2011 IL28B genotypes: ~2009 68-75% Response-guided therapy (RGT): ~2004 54-63% Sustained Virologic Response (%) 45-47% 38-43% 31-35% 13-19% 6% 2011 2001-2010 1992

  6. 治療C型肝炎之病毒動力學

  7. SVRIs Durable & Beneficial “These patients should be considered as cured” • 99.1% HCV RNA undetectable independent of population - Elevated ALT, persistently normal ALT, immunocompromised • Independent of treatment by - IFN monotherapy, IFN/RBV, IFN/RBV/DAAs • 34-61% reverse cirrhosis • ~90% improve fibrosis • Improved neurocognitive function, fatigue; reduces insulin resistance • Reduces risk of HCC and improves liver & all-cause mortality Camma et al. Hepatology 2004;39(2):333-42; D’ Ambrosio et al. Hepatology 2012;56:532-43 Kraus MR, et al. Hepatology 2013;58:497-504; Brandman et al. Diabetes Care 2012;35(5):1090-4 Van der Maar, et al. JAMA 2012;308:2584-93.

  8. ISDRin NS5A • IL28B SNPs

  9. 宿主IL28B基因多型性 Genetic polymorphism near IL28B, which encodes for IFN lambda-3 CC genotype對當前標準療法有較佳的治療反應 (基因第一型病毒) Ge D, et al. Nature. 2009;461:399-401.

  10. 當前C型肝炎標準療法及療效 IFNMonotherapy PegIFN PegIFN SVR,% PegIFN +RBV +RBV (Taiwan) (West) 24wks 48wks 78wks Allgenotypes 6-19 11-19 10-22 18-39 -- -- GT1(48wks) -- -- -- -- 75-80 42-46 GT2/3(24wks) -- -- -- -- 85-90 76-82 Modified from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

  11. 目前治療成效不錯我們還需要 DAAs嗎? Multiple AEs from SOC Null/partial responders, relapsers Unwilling, intolerant, ineligible ‘Difficulty-to-treat’ (cirrhotics, HIV coinfected, post LT recurrent, renal transplant candidates & HCV infected post kidney transplantation)

  12. 部分地區或國家上市DAAs Boceprevir (BOC) Telaprevir (TVR)

  13. 限定基因第一型：標準療法 (P/R)+ C肝病毒蛋白酶抑制劑 (PI)使用於過去未曾治療過 (naïve) 的病患

  14. Telaprevir + pegIFN/RBV 用於基因第一型未曾治療過的病患 Dosage and Administration • 750 mg (two 375-mg tablets) TID (every 7-9 hrs) with food (not low fat; standard fat meal is 21 g, eg, 1/2 cup nuts or 2 oz cheddar cheese) • Must be administered with both pegIFN and RBV; telaprevir dose must not be reduced or interrupted Response-Guided Therapy • Treatment-naïve patients with compensated cirrhosis and eRVR may benefit from additional 36 wks of pegIFN + RBV (ie, to wk 48) eRVR; stop at Wk 24, f/u 24 wks TVR + PegIFN + RBV PegIFN + RBV F/u 24 wks No eRVR; PegIFN + RBV 0 4 12 24 48 Wks *Assay should have a lower limit of HCV RNA quantification ≤ 25 IU/mL. Telaprevir [package insert]. May 2011. Vertex/Johnson & Johnson's Incivo.

  15. Telaprevir + PR: 基因第一型未曾治療過的病患之持續病毒反應率 ADVANCE: TVR + PegIFN/RBV in Treatment-Naïve Genotype 1 P < .001 100 T12PR PR 75 80 60 SVR (%) 44 40 20 n/N = 271/363 158/361 0 SVR Jacobson IM, et al. NEJM2011;364:2405-2416.

  16. Higher rates of rash, anemia, and anorectal signs/symptoms in TVR arms vs control Anorectal symptom management Fiber, loperamide, hydrocortisone, and pramoxine topical cream Telaprevir + PR: 副作用 *Results from patients with 8 wks and 12 wks of TVR exposure pooled. Anemia rates from T12 groups estimated to be ~ 40%. †Anemia was managed with RBV dose modification; epoetin alfa was not permitted in clinical trials. Telaprevir package insert. May 2011.

  17. Boceprevir + PR 使用於基因第一型未曾治療過者 Dosage and Administration • 800 mg (four 200-mg capsules) TID (every 7-9 hrs) with food (meal or light snack) • Must be administered with both pegIFN and RBV • Boceprevir dose must not be reduced or interrupted Response-Guided Therapy* • If undetectable at wks 8 and 24, continue 3-drug regimen to wk 28 • If detectable at wk 8, but undetectable at wk 24, continue 3-drug regimen to wk 36, then administer pegIFN/RBV to wk 48 • All cirrhotic patients should receive lead-in followed by pegIFN/RBV + boceprevir for 44 wks • Futility: stop all 3 drugs if wk 12 HCV RNA ≥ 100 IU/mL or wk 24 HCV RNA detectable • Wk 4 < 1 log HCV RNA reduction associated with greater risk of developing resistance and lower SVR rates: consider pegIFN/RBV + boceprevir for 44 wks after lead-in, no RGT PegIFN + RBV Boceprevir + PegIFN + RBV F/u 24 wks F/u 24 wks PegIFN + RBV Boceprevir + PegIFN + RBV 36 0 4 12 28 48 8 24 Wks *Assay should have a lower limit of HCV RNA quantification ≤ 25 IU/mL. Boceprevir [package insert]. May 2011. Merck & Co’s Victrelis.

  18. Boceprevir + PR: 持續病毒反應率 SPRINT-2: BOC + PegIFN/RBV in Genotype 1 Treatment-Naïve Patients P < .001 P < .001 P = .004 100 100 80 80 68 P = .04 67 53 60 60 40 42 SVR (%) SVR (%) 40 40 23 20 20 125/ 311 211/ 316 213/ 311 12/ 52 22/ 52 29/ 55 n/N = n/N = 0 0 PR48 PR48 BOC/PR48 BOC/PR48 BOC RGT BOC RGT Nonblack Patients Black Patients Poordad F, et al. NEJM2011;364:1195-1206.

  19. Significantly higher rates of anemia, neutropenia, and dysgeusia in boceprevir arms vs control Boceprevir + PR: 副作用 *Anemia was managed with RBV reduction and/or epoetin alfa (43% of boceprevir + PR and 24% PR). Boceprevir [package insert]. May 2011.

  20. Triple Therapy使用於基因第一型過去治療失敗者

  21. Telaprevir + PR:基因第一型過去治療失敗者 Dosage and Administration • 750 mg (two 375-mg tablets) TID (every 7-9 hrs) with food (not low fat; standard fat meal is 21 g, eg, 1/2 cup nuts or 2 oz cheddar cheese) • Must be administered with both pegIFN and RBV • Telaprevir dose must not be reduced or interrupted Treatment duration • All previous partial responders or null responders receive 12 wks of triple therapy followed by 36 wks of pegIFN/RBV • Previous relapsers follow the same response-guided approach as treatment-naive patients TVR + PegIFN + RBV PegIFN + RBV F/u 24 wks 12 24 48 0 4 Wks Telaprevir [package insert]. May 2011.

  22. Telaprevir使用於過去治療失敗者的療效 REALIZE: TVR + PegIFN/RBV in Genotype 1 Previous Relapsers and Nonresponders • Lead-in examined, but found to have no impact on response and not used in TVR label T12/PR48 LI T12/PR48 Pbo/PR48 Previous Relapsers Previous Partial Responders Previous Null Responders 100 88* 83* 80 59* 60 54* SVR (%) 40 33* 29* 24 15 20 5 n/N = 121/145 124/141 16/68 29/49 26/48 4/27 21/72 25/75 2/37 0 *P < .001 vs placebo/PR48. Zeuzem S, et al. NEJM2011;364:2417-2428.

  23. Boceprevir + PR用於基因第一型過去治療失敗之無肝硬化患者 Dosage and Administration • 800 mg (four 200-mg capsules) TID (every 7-9 hrs) with food (meal or light snack) • Must be administered with both pegIFN and RBV • Boceprevir dose must not be reduced or interrupted Partial Responders, Relapsers: Duration Based on Wks 8 and 24 HCV RNA* • If undetectable at both time points, continue 3-drug regimen to Wk 36 • If detectable at Wk 8 but undetectable at Wk 24, continue 3-drug regimen to Wk 36, then administer pegIFN/RBV to Wk 48 • All cirrhotic patients should receive lead-in then boceprevir + PR for 44 wks • Futility: stop all 3 drugs if Wk 12 HCV RNA ≥ 100 IU/mL or Wk 24 HCV RNA detectable • Wk 4 < 1 log HCV RNA reduction associated with greater risk of developing resistance associated variants and lower SVR rates: consider boceprevir + PR for 44 wks after lead-in, no RGT • If considered for treatment, previous null responders should receive lead-in then boceprevir + PR for 44 wks Boceprevir + PegIFN + RBV PegIFN + RBV F/u 24 wks Boceprevir + PegIFN + RBV PegIFN + RBV 36 0 4 12 24 28 48 8 Wks *Assay should have a lower limit of HCV RNA quantification ≤ 25 IU/mL. Boceprevir [package insert]. May 2011.

  24. BOC + PR: SVR by Historical Response (Partial Responders and Relapsers*) RESPOND-2: BOC + PegIFN/RBV in GT 1 Treatment-Experienced Patients PR48 (n = 80) BOC RGT (n = 162) BOC/PR48 (n = 161) 100 75 80 69 60 52 SVR (%) 40 40 29 20 7 n/N = 23/57 30/58 23/57 30/58 2/29 2/29 0 Partial Responder Relapser *Partial responders had a decrease in plasma HCV RNA of at least 2 log10 by Wk 12 of previous therapy but with detectable HCV RNA throughout the course of therapy. Relapsers had undetectable HCV RNA at end of previous therapy without subsequent attainment of SVR. Bacon BR, et al. NEJM2011;364:1207-1217.

  25. CUPIC: Telaprevir or Boceprevir + P/R in GT 1 Treatment-Experienced Cirrhotics • French compassionate use program for early access to TVR and BOC before approval 100 Telaprevir + P/RBoceprevir + P/R 80 60 53 51 SVR12 (%) 41 40 40 40 32 29 20 11 79/190 61/116 43/85 43/135 32/80 8/28 118/295 n/N = 1/9 0 Overall Relapsers Partial Response Null Response Previous Response to P/R Fontaine H, et al. EASL 2013. Abstract 60.

  26. 與蛋白酶抑制劑交互反應的藥物 • HCV PIs are CYP3A4 inhibitors • Approximately one half of drugs are metabolized by CYP3A4 • List of drugs affected by CYP3A4 inhibitors is long • Consult package insert and review med lists frequently • Until the drug is specifically studied, magnitude of the impact of PI on its level is not known • Exercise caution with ALL coadministered medications

  27. Telaprevir: Take Home • Administered with full-fat foods • For treatment-naïve and relapser patients • 12 wks of TVR + pegIFN/RBV followed by RGT with pegIFN/RBV • Additional 12 wks if HCV RNA undetectable at Wks 4 and 12; otherwise, additional 36 wks • Recommended that all cirrhotics receive T12PR48 • For partial and null responders • T12PR48 • Futility rules for all patients: stop all therapy if HCV RNA > 1000 IU/mL at wk 4 or 12 or detectable at wk 24 • TVR-associated adverse events: rash, anemia, anorectal symptoms

  28. Boceprevir: Take Home • Administer with meal or light snack • PegIFN/RBV x 4 wks, then add BOC for up to 44 wks of triple therapy • Key HCV RNA assessments at wks 4, 8, 12, 24 • RGT based on wk 8 HCV RNA • Treatment-naïve patients may be eligible for 24 wks of triple therapy following lead-in • Treatment-experienced patients may be eligible for 32 wks of triple therapy following lead-in • Late or slow responders (ie, detectable at wk 8 but undetectable by wk 24) should receive 32 wks of triple therapy then 12 wks of pegIFN/RBV alone • Stop all therapy if HCV RNA ≥ 100 IU/mL at wk 12 or detectable at wk 24 • All compensated cirrhotic patients should receive lead-in then BOC + PR for 44 wks • Same regimen should be used for null responders, if considered for treatment • BOC-associated adverse events: anemia, dysgeusia

  29. 即將上市DAAs US FDA Advisory Committee, Oct 24-25, 2013 Unanimous recommendations to approve Simeprevir (SMV) Sofosbuvir (SOF)

  30. DAAs Currently in Development (not all-inclusive)

  31. QUEST-1: Simeprevir + P/R RGT in Treatment-Naïve GT 1 HCV • Randomized, double-blind, placebo-controlled phase III trial • 12% to 13% had cirrhosis, 56% to 57% had GT 1a HCV Stratified by GT 1 subtype, IL28B genotype Wk 12 Wk 24 Wk 48 Simeprevir 150 mg QD + P/R* (n = 264) P/R Treatment-naive pts with GT 1 HCV (N = 394) P/R Placebo + P/R(n = 130) P/R *Response-guided therapy: Patients with HCV RNA < 25 IU/mL at Wk 4 and HCV RNA undetectable at Wk12 received a total of 24 wks of therapy. Those not achieving this on-treatment response received 48 wks of therapy. P/R, peginterferon alfa-2a 180 µg/wk + ribavirin 1000-1200 mg/day. Jacobson IM, et al. EASL2013 Abstract 1425; AASLD 2013 Abstract 1122.

  32. QUEST-1: Virologic Response to Simeprevir + P/R Treatment Virologic Outcomes SVR12 by RGT Group SMV + P/R P/R 85% of pts in SMV arm met RGT criteria 100 100 91 80 80 80 80 60 60 50 SVR12 (%) HCV RNA Undetectable (%) 40 40 21 20 20 12 n/N = 202/254 210/264 65/130 n/N = 203/224 6/28 0 0 Wk 4 SVR12 24 Wks 48 Wks SMV Arm: Total Duration of RGT Jacobson I, et al. EASL2013 Abstract 1425; AASLD2013 Abstract 1122.

  33. QUEST-1: SVR12 by Fibrosis Level, Subtype, and Baseline Resistance 100 100 SMV + P/RP/R 90 82 80 80 71 58 60 60 53 52 49 SVR12 (%) SVR12 (%) 40 40 29 20 20 n/N = 188/229 60/113 18/31 5/17 105/147 36/74 105/117 29/56 0 0 GT 1a GT 1b No Cirrhosis Cirrhosis Differences in SVR12 by Subgroup (95% CIs) SMV (n) Pbo (n) GT 1a/other HCV • With baseline Q80K vs Pbo • Without baseline Q80K vs Pbo GT 1b HCV 28.2 (13.4-42.9) 4.7 (-14.6 to 24.1) 40.3 (25.8-54.8) 42.1 (26.5-57.6) 147 60 86 117 74 74 74 56 -100 -50 0 50 100 Favors SMV Favors Placebo Jacobson I, et al. EASL2013 Abstract 1425; AASLD2013 Abstract 1122.

  34. QUEST-2: Simeprevir + P/R RGT in Treatment-Naïve GT 1 HCV • Phase III, randomized, double-blind, placebo-controlled trial • 7% to 11% had cirrhosis, 58% had GT 1b HCV Randomized 2:1*; stratified by GT 1 subtype, IL28B genotype Wk 12 Wk 24 Wk 48 P/R Simeprevir 150 mg QD + P/R† (n = 257) P/R Treatment-naive pts with GT 1 HCV (N = 391) Placebo + P/R (n = 134) P/R *63% of patients in each arm were randomly assigned to receive pegIFN alfa-2a or pegIFN alfa-2b; the remainder were assigned pegIFN alfa-2a. †RGT: Patients with HCV RNA < 25 IU/mL at Wk 4 and HCV RNA undetectable at Wk 12 received a total of 24 wks of therapy. Those not achieving this on-treatment response received 48 wks of therapy. Manns M, et al. EASL2013 Abstract 1413.

  35. QUEST-2: Virologic Response to Simeprevir + P/R Treatment SMV + P/RP/R 100 86 81 80 91% of pts in SMV arm met RGT criteria 60 50 SVR12 (%) 40 32 20 n/N = 209/257 67/134 202/235 7/22 0 Overall 24 wks 48 wks SMV Arm: Total Duration of RGT Manns M, et al. EASL 2013. Abstract 1413.

  36. QUEST-2: SVR12 by Subtype and Fibrosis Level • Higher rates of SVR12 with SMV, irrespective of HCV genotype or cirrhosis • Baseline Q80K mutation not a predictor of response (unlike in QUEST-1) SMV + P/RP/R 100 82 82 80 80 65 53 60 51 46 SVR12 (%) 40 40 20 86/107 26/57 123/150 41/77 189/231 61/119 11/17 6/15 n/N = 0 GT 1a GT 1b No Cirrhosis Cirrhosis Manns M, et al. EASL 2013. Abstract 1413.

  37. Summary of Simeprevir • RGT met in 85-91% of patients; 86-91% had SVR • Q80K polymorphism in G1a affected SVR in QUEST-1 and in pooled analysis • Safety profiles similar between groups through first 12 wks of treatment • No increase in anemia with SMV; slightly higher rash or photosensitivity • Mild, transient bilirubin increases with SMV; other liver parameters did not change Jacobson I, et al. EASL 2013. Abstract 1425; Manns M, et al. EASL 2013. Abstract 1413.

  38. NEUTRINO: Sofosbuvir + P/R for 12 Wks in Treatment-Naïve GT 1/4/5/6 HCV Patients • Open-label, single-arm study of sofosbuvir 400 mg QD + P/R for 12 wks in treatment-naive patients with GT 1/4/5/6 HCV • 17% had cirrhosis; 89% had GT 1, 9% had GT 4, < 1% had GT 5, 2% had GT 6 HCV 99 99 100 90 80 60 HCV RNA < LLOQ (%) 40 20 n/N = 321/325 326/327 295/327 0 Wk 4 EOT SVR12 P/R: pegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/day Lawitz E, et al. NEJM 2013;368:1878-87.

  39. NEUTRINO: SVR12 With Sofosbuvir + P/R According to Genotype and Fibrosis Level SVR12 According to Fibrosis Level SVR12 According to Genotype 100 96 100 100 92 89 80 80 80 60 60 SVR12 (%) SVR12 (%) 40 40 20 20 252/273 43/54 261/292 27/28 7/7 n/N = 0 0 GT 1 GT 4 GT 5,6 No Cirrhosis Cirrhosis Lawitz E, et al. NEJM 2013;368:1878-87.

  40. FISSION: Sofosbuvir/RBV vsPegIFN/RBV in Treatment-Naïve GT 2/3 HCV Patients • Randomized, controlled, open-label phase III noninferiority trial • 20% to 21% had cirrhosis; 72% had GT 3 HCV Stratified by HCV GT (2 vs 3), HCV RNA (< vs ≥ 106 IU/mL), cirrhosis (yes vs no) Wk 12 Wk 24 Sofosbuvir 400 mg QD + RBV 1000-1200 mg/day (n = 256) Treatment-naive patients with GT 2/3 HCV(N = 499) PegIFN alfa-2a 180 µg/wk + RBV 800 mg/day (n = 243) Gane E, et al. EASL 2013. Abstract 5.

  41. FISSION: Sofosbuvir/RBV Noninferior to P/R in Tx-Naïve GT 2/3 HCV Patients PegIFN + RBV Sofosbuvir + RBV 99 99 99 100 92 P < .001 80 67 67 67 60 HCV RNA < LLOQ (%) 40 20 n/N = 249/250 158/236 242/244 207/224 NA 188/190 170/253 162/243 0 Wk 4 Wk 12 Wk 24 SVR12 On Treatment Gane E, et al. EASL 2013. Abstract 5.

  42. FISSION: SVR12 According to Genotype and Fibrosis Level PegIFN + RBV Sofosbuvir + RBV 98 100 91 82 80 71 62 61 60 SVR12 (%) 40 34 30 20 n/N = 58/59 44/54 10/11 8/13 89/145 99/139 13/38 11/37 0 No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis Genotype 2 Genotype 3 Gane E, et al. EASL 2013. Abstract 5.

  43. FISSION: Better Tolerability Profile With Sofosbuvir/RBV vsPegIFN/RBV • Grade ≥ 3 AEs: 7% with SOF/RBV vs 19% for pegIFN/RBV • Discontinuations due to AEs: 1% for SOF/RBV vs 11% for pegIFN/RBV Gane E, et al. EASL 2013. Abstract 5.

  44. FUSION: Sofosbuvir + RBV for 12 or 16 Wks in Tx-Experienced GT 2/3 HCV Pts • Randomized, double-blind, placebo-controlled phase III trial • 62% to 64% had GT 3 HCV, 33% to 35% had cirrhosis, 75% to 76% were previous relapsers Stratified by HCV GT (2 vs 3), cirrhosis (yes vs no) Wk 12 Wk 16 Sofosbuvir 400 mg QD + RBV 1000-1200 mg/day (n = 103) Placebo Treatment-experienced pts with GT 2/3 HCV (N = 201) Sofosbuvir 400 mg QD + RBV 1000-1200 mg/day (n = 98) Nelson D, et al. EASL 2013. Abstract 6.

  45. FUSION: Overall Efficacy Outcomes of Sofosbuvir + RBV in GT 2/3 Sofosbuvir + RBV 12 wks Sofosbuvir + RBV 16 wks 100 100 98 97 100 80 73 60 50 HCV RNA < LLOQ (%) 40 20 97/100 93/95 100/100 95/95 50/100 69/95 n/N = 0 Wk 4 End of Treatment SVR12 Nelson D, et al. EASL 2013. Abstract 6.

  46. FUSION: SVR12 With Sofosbuvir + RBV by Genotype and Fibrosis Level Sofosbuvir + RBV 12 wks Sofosbuvir + RBV 16 wks 100 96 100 100 78 80 80 63 60 61 60 60 SVR12 (%) SVR12 (%) 37 40 40 19 20 20 n/N = 25/26 23/23 6/10 7/9 14/38 25/40 5/26 14/23 0 0 No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis Genotype 2 Genotype 3 Nelson D, et al. EASL 2013. Abstract 6.

  47. POSITRON: Sofosbuvir + RBV for 12 Wks in GT 2/3 IFN-Unwilling/Intolerant/Ineligible • Randomized, double-blind, placebo-controlled phase III trial Stratified by cirrhosis (yes vs no) Wk 12 Sofosbuvir 400 mg QD + RBV 1000-1200 mg/day (n = 207) IFN unwilling, intolerant, or ineligible pts with GT 2/3 HCV (N = 278) Placebo (n = 71) Jacobson I, et al. EASL 2013. Abstract 61.

  48. POSITRON: Virologic Response in GT 2/3 IFN-Unwilling/Intolerant/Ineligible Overall Outcomes No cirrhosis Cirrhosis 100 99 92 94 100 100 78 80 80 68 60 60 HCV RNA < LLOQ (%) SVR12 (%) 40 40 21 20 20 202/204 202/202 161/207 n/N = 85/92 16/17 57/84 3/14 0 0 Wk 4 EOT SVR12 GT 2 GT 3 • SVR12 0% for placebo Jacobson I, et al. EASL 2013. Abstract 61.

  49. Topline Summary of Sofosbuvir Trials 1. Lawitz E, et al. EASL 2013. Abstract 1411. 2. Gane E, et al. EASL 2013. Abstract 5.3. Nelson D, et al. EASL 2013. Abstract 6. 4. Jacobson I, et al. EASL 2013. Abstract 61.

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