Microsoft PowerPoint - HCV SZ Nov 2015

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1 司徒伟基临床助理教授香港大学内科学系内科顾问医生香港大学深圳医院 Dr. Wai-Kay Seto MBBS MD FRCP FHKCP FHKAM Clinical Assistant Professor The University of Hong Kong, Hong Kong Consultant HKU-Shenzhen Hospital, Shenzhen

2 HBV 与 HCV 的分别 HBV HCV Host cell Host cell HCV RNA Host DNA cccdna H Host DNA H Integrated DNA Nucleus Nucleus 需长期抑制病毒复制确切的病毒清除

3 丙肝中国 anti-hcv 阳性病人 : 29,791,212 Lavanchy et al Clin Microbiol Infect 2011 Wei et al Gastroenterology 2014

6%/yr Alcohol use, obesity, co infection

4 HCV: 自然病史 HCV exposure Chronic 85% Cirrhosis 10 15% Decompensation 6.4%/yr HCC 3.4%/yr Resolved 15% Transplant/death 4.6%/yr Alcohol use, obesity, co infection with HIV or HBV accelerate HCV progression % = percent of previous group; ESLD, End-Stage Liver Disease. Di Bisceglie AM, et al. Hepatology. 2000;31: ; Chen SL, Morgan TR. Int J Med Sci. 2006;3:47 52; 4 Alazawi, et al. Aliment pharmacol Ther. 2010;32:

5 丙肝 : 越迟感染越多并发症年纪越大 :? 减少抗氧化功效? 脂肪肝增加 Minola et al Blood 2002

6 HCV 基因型 Wei et al Gastroenterology 2014

7 HCV- 基因型 : 广东省数据 HCV Genotype Mean age: 34.4 years Fu et al J Viral Hepat 2011

8 基因型只影响治疗, 不影响病情基因型 1 基因型 6 Seto WK et al J Hepatol 2010

9 Safety challenges with peginterferon/ribavirin therapy: development of adverse events over time Anemia 1,2 Neutropenia 1,3 Thrombocytopenia 1,3 Severity Flu like symptoms 1,3 Fatigue 1 Psychiatric side effects (depression) 4, Duration of interferon therapy (weeks) 1. Smith J. Pharmacotherapy 2008; 28: ; 2. McHutchison JG, et al. Am J Gastro 2007; 102: ; 3. Russo M & Fried M. Gastroenterol 2003; 124: ; 4. Kraus M, et al. World J Gastroenterol 2005; 11: ; 9 5 Fontana R et al Am J Gastroenterol 2008;

10 Cure rate 100% 75% 50% 25% 0% 普通干扰素 24 weeks 4% 丙肝治疗的未来已到! 普通干扰素 48 weeks 9% 普通干扰素利巴韦林 48 weeks 27% 新代干扰素利巴韦林 48 weeks 45% yrs 2004 蛋白酶抑制剂新代干扰素利巴韦林 24 weeks 75% 2011 ( 欧美 ) Combo DAA 1 st DAA + 2 nd DAA 无干扰素 12 wks % 2015 ( 欧美 )

11 丙肝病毒基因排列 Seto WK et al. (2013) Hepatitis viruses and hepatocellular carcinoma. In Cancer and Inflammation Mechanism: Chemical, Biological and Clinical Aspects

丙肝病毒复制 : 细胞核以外 Moradpour, D et al. Replication of hepatitis C virus Nature Review Microbiol. 2007:5;453-463. O'Leary JG, Davis GL. Hepatitis C.

12 丙肝病毒复制 : 细胞核以外 Moradpour, D et al. Replication of hepatitis C virus Nature Review Microbiol. 2007:5; O'Leary JG, Davis GL. Hepatitis C. In: Feldman M, Friedman LS, Brandt LJ, eds. Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management. 9th ed. Philadelphia, PA: Saunders, Elsevier Inc.; 2010:

13 达卡他韦 (Daclatasvir) Asunaprevir Viekira Pak (Ombitasvir / Paritaprevir / Dasabuvir and Ritonavir) 索非布韦 (Sofosbuvir) 雷迪帕韦 (Ledipasvir) Grazoprevir Elbasvir

14 Daclatasvir and Asunaprevir NS5A NS3/4A

15 达卡他韦 Daclatasvir NS5A 基因型 1B Asunaprevir NS3/4A 6 个月 307 以前没治疗 205 IFN 治疗失败 235 不适合或不耐受 IFN 治疗 Manns et al Lancet 2014

16 100% 90% 80% 82% 82% 85% 84% 60% 40% 20% 0% 以前没治疗以前治疗失败不耐受以前治疗没肝硬化肝硬化 Manns et al Lancet 2014

17 治疗成功因素轻微副作用 : 头痛, 腹泻 ( 与安慰剂组相等 ) 不良事件需要停药 :1% 转氨酶上升 ( 轻微, 可逆 ) Manns et al Lancet 2014

19 DCV 及 ASV 建议 24 周基因型 1B(1A 没效 ) NS5A 基因突变检查有用

20 Viekira Pak Ombitasvir (NS5A) Paritaprevir (NS3/4A) Ritonavir Dasabuvir (NS5B) Feld JJ et al New Engl J Med 2014

N Engl J Med 2014;370:1983 1992; 3. Feld J, et al.

21 Viekira Pak: 非肝硬化 HCV-1 1 Andreone P et al. Gastroenterology 2014;147: e1; 2. Ferenci P et al. N Engl J Med 2014;370: ; 3. Feld J, et al. N Engl J Med 2014;370: ; 1 4. Zeuzem S et al. N Engl J Med 2014;370:

Viekira Pak HCV-1 功效 1. Ferenci P, et al. N Eng J Med 2014;370:1983 92.

22 Viekira Pak HCV-1 功效 1. Ferenci P, et al. N Eng J Med 2014;370: viekira pak [package insert]. Hong Kong, AbbVie Limited; Dec 2014.

HCV-1 非肝硬化 : 不需要利巴韦林 1. Andreone P et al. Gastroenterol 2014;147:359 365. 2. Ferenci P, et al.

23 HCV-1 非肝硬化 : 不需要利巴韦林 1. Andreone P et al. Gastroenterol 2014;147: Ferenci P, et al. N Eng J Med 2014;370: *Prior pegifn/ RBV treatment #Two patients data was missing at post-treatment week 12

24 Viekira Pak:HCV-1 肝硬化 Dedicated randomised phase III trial of 380 GT1 peg-ifn/rbv treatment-naïve and -experienced HCV patients with compensated cirrhosis Randomised, open-label phase III trial in 380 patients GT1 patients were pegifn/ribavirin experienced; 137 of which were prior null responders (62%) 1 2 Primary analysis: SVR12 (HCV RNA <LLOQ [25 IU/mL] 12 weeks post-treatment) 1 1. Poordad F et al. N Engl J Med 2014:370; viekira pak [package insert]. Hong Kong. AbbVie Limited; Dec 2014.

TURQUOISE-II: SVR12 rates in treatment-naïve and - experienced cirrhotic patients remain high even in difficult to treat populations 100 80 88.6 94.2 98.

25 TURQUOISE-II: SVR12 rates in treatment-naïve and - experienced cirrhotic patients remain high even in difficult to treat populations viekira pak + RBV 12-week arm 24-week arm SVR12, % Patients / /121 67/68 51/51 GT 1a GT 1b In GT1b patients, the SVR rates were high for both 12- and 24-week arms In GT1a patients, the SVR rate was higher in the 24 week arm 2

26 TURQUOISE-II: demonstrated low study discontinuation due to AE *1 patient with a non-treatment emergent death (occurring 80 days after last dose of study treatment), not attributed to viekira pak or RBV 2 Hepatic decompensation events were rare (4 patients, 1.1%) 2 None were considered related to study drug viekira pak + RBV 1 Event, n (%) 12-week arm (N = 208) 24-week arm (N = 172) Any AE 191 (91.8) 156 (90.7) Any serious AE 13 (6.2) 8 (4.7) Any AE leading to study drug discontinuation 4 (1.9) 4 (2.3) Death* 1 (0.5) 0 1. Poordad F et al. N Engl J Med 2014:370; Poordad F et al. Presented at the 2014 International Liver Congress/49 th Annual Meeting of the European Association for the Study of the Liver, 9 13 April 2014, London, UK. 2

27 Viekira Pak (ombitasvir, paritaprevir, dasabuvir and ritonavir) 要加上利巴韦林

28 肝硬化 : 可否没利巴韦林 Lawitz et al Gastroenterology 2015

29 可以! /47 50/52 Treatment-naive Treatment-experienced Cirrhosis Lawitz et al Gastroenterology 2015

30 Viekira Pak 建议基因型 1A 及 1B 12 周肝硬化 : 需加利巴韦林

31 VIEKIRA PAK 药物相互作用

Harvoni: Sofosbuvir and Ledipasvir Ledipasvir Picomolar potency against HCV GT 1a and 1b 1 Effective against NS5B RAV S282T 2 Once-daily, oral, 90 mg LDV NS5A inhibitor Sofosbuvir Potent antiviral

32 Harvoni: Sofosbuvir and Ledipasvir Ledipasvir Picomolar potency against HCV GT 1a and 1b 1 Effective against NS5B RAV S282T 2 Once-daily, oral, 90 mg LDV NS5A inhibitor Sofosbuvir Potent antiviral activity against HCV GT 1 6 High barrier to resistance Once-daily, oral, 400-mg tablet SOF - NS5B nucleotide polymerase inhibitor Ledipasvir/Sofosbuvir STR Once-daily, oral fixed-dose (90/400 mg) combination tablet No food effect >2000 patients treated LDV NS5A inhibitor SOF - NS5B nucleotide polymerase inhibitor

33 LDV/SOF 第三期临床研究 (ION-1, ION-2, ION-3) 基因型 1A 及 1B Wk 0 Wk 8 Wk 12 Wk 24 LDV/SOF + RBV ION-1 ION-2 LDV/SOF LDV/SOF + RBV ION-3 LDV/SOF LDV/SOF + RBV LDV/SOF ION-1 treatment naïve: N = 865 ION-2 treatment experienced: N = 440 ION-3 treatment naïve: N = 647 N=1952 total patients Afdhal N et al New Engl J Med 2014 Kowdley KV et al New Engl J Med 2014

34 ION-1 (LDV/SOF±RBV) ION-1( 从未治疗 ) 临床效果 LDV/SOF 12 weeks LDV/SOF + RBV 12 weeks LDV/SOF 24 weeks LDV/SOF + RBV 24 weeks Patients with HCV RNA < LLOQ (%) / / / / / / / / / / / /217 Week 4 EOT SVR 12 On treatment All four treatment arms met the primary endpoint of superiority over the historical response rate of 60% (P < for all comparisons) 16% had NS5A RAVs at baseline, with 96% achieving SVR Error bars represent 95% confidence intervals. Afdhal N, et al. N Engl J Med 2014;

35 ION-1 (LDV/SOF±RBV x 12 or 24 weeks) 肝硬化 vs 没肝硬化 Absence of Cirrhosis Cirrhosis SVR12 (%) /179 32/33 178/178 33/33 181/182 31/32 179/179 36/36 LDV/SOF LDV/SOF + RBV LDV/SOF LDV/SOF + RBV 12 Weeks 24 Weeks Error bars represent 95% confidence intervals Afdhal N, et al. N Engl J Med 2014;

36 ION-2 (LDV/SOF±RBV x 12 or 24 weeks) ION-2( 曾经治疗 ) 临床效果 LDV/SOF 12 weeks LDV/SOF + RBV 12 weeks LDV/SOF 24 weeks LDV/SOF + RBV 24 weeks Patients with HCV RNA < LLOQ (%) * / / / / / / / / / / / /111 Week 4 EOT SVR 12 On treatment All four treatment arms met the primary endpoint of superiority over the historical response rate of 25% (P<0.001 for all comparisons) 14% had NS5A RAVs at baseline, with 89% achieving SVR Error bars represent 95% confidence intervals Afdhal N, et al. N Engl J Med 2014;

37 ION-2 (LDV/SOF±RBV x 12 or 24 weeks) 肝硬化 vs 没肝硬化 Absence of Cirrhosis Cirrhosis SVR12 (%) /87 19/22 89/89 18/22 86/87 22/22 88/89 22/22 LDV/SOF LDV/SOF + RBV LDV/SOF LDV/SOF + RBV 12 Weeks 24 Weeks Error bars represent 95% confidence intervals Afdhal N, et al. N Engl J Med 2014;

38 ION-3 (LDV/SOF±RBV x 8 or 12 weeks) 8 周治疗 : 只建议非肝硬化及 HCVRNA 少过 6,000,000 IU/mL P=0.52 Patients with HCV RNA < LLOQ (%) / / / / / /216 On treatment P=0.70 P= / / /216 Week 4 EOT SVR 12 8 weeks of LDV/SOF was non-inferior to 8 weeks of LDV/SOF + RBV and 12 weeks LDV/SOF 18% had NS5A RAVs at baseline, with 90% achieving SVR Error bars represent 95% confidence intervals Kowdley K, et al. N Engl J Med 2014

39 基因型 1A 及 1B 12 周 : Harvoni 建议从未治疗病人曾经治疗非肝硬化病人 24 周 : 曾经治疗肝硬化病人 8 周 : 只建议非肝硬化及 HCVRNA 少过 6,000,000 IU/mL

40 Sofosbuvir 基因型 2/3 临床研究 Week FISSION Treatment Naïve SOF 400mg QD + RBV, n=256 SVR12 PEG IFN+RBV, n=243 FUSION Treatment Experienced SVR12 GT 2/3 SOF 400mg QD + RBV, n=103 PBO SVR12 All Oral Therapy SOF 400mg QD + RBV, n=98 POSITRON PEG-IFN-unable SVR12 SOF 400mg QD + RBV, n=207 SVR12 PBO, n=71 *PEG-IFN 180 μg/wk, RBV mg/d; PEG-IFN 180 μg/wk, RBV mg/d for SOF+RBV arms and 800 mg/d for PEG-IFN+RBV arm Jacobson IM, et al. N Engl J Med 2014

41 HCV-2/3 结果 Efficacy Endpoints: SVR 12 FISSION Treatment Naive Overall Genotype 2 Genotype 3 SOF + RBV x 12 weeks 67% 97% 56% FUSION Treatment Experienced Overall Genotype 2 Genotype 3 SOF + RBV x 12 weeks 50%* 86% 30% SOF + RBV x 16 weeks 73%* 94% 62% POSITRON IFN Unable Overall Genotype 2 Genotype 3 SOF + RBV x 12 weeks 78% 93% 61% Jacobson IM, et al. N Engl J Med 2014

42 BOSON: SOF Based Regimens in TN/TE NC/CC GT 3 HCV-3:24 周才有效 SOF + RBV 16 weeks SOF + RBV 24 weeks SOF + PegIFN + RBV 12 weeks SVR12 (%) /70 65/72 68/71 12/21 94/112 18/22 21/23 83/100 41/54 44/54 10/1149/52 17/36 26/34 30/35 TN No no Cirrhosis cirrhosis TN Cirrhosis cirrhosis TE No no Cirrhosis cirrhosis TE Cirrhosis cirrhosis Treatment Naïve Treatment Experienced Higher SVR12 rates with SOF+PegIFN+RBV compared to SOF+RBV for 16 or 24 weeks 86% SVR12 in GT 3 TE with cirrhosis treated with SOF+PegIFN+RBV > 80% in all other subgroups treated with 24 weeks SOF+RBV; consistent with earlier Phase 3 studies Error bars represent 95% confidence intervals. Zeuzem et al New Engl J Med 2014

43 HCV-2 / -3 建议 HCV-2: 没肝硬化 : 12 周索非布韦及利巴韦林 12 周索非布韦及达卡他韦肝硬化 : 16 周索非布韦及利巴韦林 12 周索非布韦及达卡他韦 HCV-3 24 周索非布韦及利巴韦林周索非布韦及达卡他韦

44 HCV-4 LDV/SOF Multicenter study in TN/TE GT 4 patients in France Week N=44 LDV/SOF SVR12 Naïve n=22 Experienced n=22 Mean age, years (range) 52 (21 69) 50 (30 62) Male, n (%) 11 (50) 17 (77) White, n (%) 19 (86) 17 (77) Cirrhosis, n (%) 1 (5) 9 (41) IL28B non-cc, n (%) 15 (68) 21 (95) Mean HCV RNA, log 10 IU/mL (range) 6.0 ( ) 6.3 ( ) GT 4a, n (%) 13 (59) 12 (55) GT 4d, n (%) 5 (23) 5 (23) GT 4b, 4f, 4m, 4o, 4r, n (%) 4 (18) 5 (23) SVR12 (%) /22 20/22 31/34 10/10 TN TE No Yes Treatment Status Cirrhosis No subjects D/C study due to AEs Abergel, EASL, 2015, O056

45 HCV-6: LDV/SOF SVR 96% Gane EJ et al Gastroenterology 2015

46 ION-4: All-Oral LDV/SOF STR x 12 weeks in HCV/HIV Co-infection (Phase 3) HCV/HIV 共同感染 Overall Naïve vs Experienced Cirrhosis Status SVR12 (%) / / / /268 63/67 LDV/SOF 12 Weeks 0 0 Naïve Experienced No Cirrhosis Cirrhosis Among those who were treatment-experienced with cirrhosis, 98% (46/47) achieved an SVR12 Naggie et al New Engl J Med 2015

47 SOLAR-1: LDV/SOF + RBV in Post-Transplant 肝移植后 (HCV-1) 100 LDV/SOF + RBV 12 Weeks LDV/SOF + RBV 24 Weeks SVR12, % /55 55/56 25/26 24/25 22/26 15/18 3/5 2/3 F0 F3 CTP A CTP B CTP C SVR rates were similar with 12 or 24 weeks of LDV/SOF + RBV Reddy, AASLD, 2014, Oral #8

48 SOLAR-1 LDV/SOF + RBV CTP B/C 肝硬化 LDV/SOF + RBV 12 Weeks LDV/SOF + RBV 24 Weeks SVR12 (%) /30 24/27 19/22 18/20 CTP B CTP C SVR rates were similar with 12 or 24 weeks of LDV/SOF + RBV Charlton M et al Gastroenterology 2015

49 未来对肾脏友善的药物 ( 有机会 2016 初美国 FDA 通过 ) Grazoprevir (NS3/4A) Elbasvir (NS5A)

50 Grazoprevor Elbasvir 12 周 % SVR 12 % Virologic Failure Parameter (N = 138) (N = 138) GT1, 4, 6-infected Subjects 135/138 (97.8%) 2/138 (1.4%) Genotype 1a 73/76 (96.1%) 2/76 (2.6%) 1b/other 56/56 (100%) 0 4 6/6 (100%) HIV Co-infection 35/35 (100%) -- CKD 4/5 (mfas population) 6/6 (100%) Pending analyses: Efficacy among patients with low platelet count (more severe cirrhosis) Phase 3b studies Lawitz E et al Lancet 2015

51 Grazoprevir Elbasvir CKD 4/5 功效 122 Subjects Enrolled 116 (95%) Primary Efficacy Pop n SVR 12 : 115/116 (99.1%) 1 failure: Non-cirrhotic, Relapse (GT1b) 6 (5%) Early Non-Virology Stop 2 pts: Loss to follow-up 2 pts: Withdrawal by Subject or Physician 1 pt: Non-drug-related death 1 pt: Non-compliance SVR 12 (FAS): 115/122 (94.3%) Roth D et al Lancet 2015

52 丙肝新药的挑战 HCV-3 ( ) 肝移植后 HIV 共感染 Child s B 肝硬化 ( ) Child s C 肝硬化 ( ) 慢性肾病 ( 未来 : ) 血透病人 ( 未来 : ) 肾移植后?? 再感染病人??

53 达卡他韦 (Daclatasvir) Asunaprevir HCV-1B 6 个月 SVR<90% Viekira Pak (Ombitasvir / Paritaprevir / Dasabuvir and Ritonavir) HCV-1A/1B/4 肝硬化需要 RBV 药物相互作用索非布韦 (Sofosbuvir) 雷迪帕韦 (Ledipasvir) 每天一粒 Harvoni HCV-1/4/5/6 SOF+RBV HCV-2 HCV/HIV 肝移植后 Grazoprevir Elbasvir??2016 每天一粒 HCV-1/4/6 CKD?CTP-B/C

54 不久的将来 : 不用检查基因型? 基因型 1,2,4,5, % 基因型 3 95% Child s B 94%( 加利巴韦林 ) Feld JJ et al New Engl J Med in press Curry MP et al New Engl J Med in press Foster GR et al New Engl J Med in press

55 丙肝新药的最大挑战 Harvoni 每天经费

56 丙肝新药 2015 第三季销售 ( 亿美金 ) 亿美金 Harvoni Sovaldi Viekira Pak Daclatasvir / Asunaprevir

57 索非布韦 + 达卡他韦 in HCV GT 1, 2 or 3 Phase 2: Study AI Virologic Response Phase 2, parallel-group, randomized, open-label study of SOF + DCV ± RBV for 12 or 24 weeks in treatment-naïve HCV GT 1, 2 or 3, and PI-failure (TVR, BOC) HCV GT 1 patients with no evidence of cirrhosis TN, GT 1 (n = 126) SOF SOF + DCV SOF + DCV SOF + DCV + RBV SOF + DCV SOF + DCV + RBV SVR12 100% (15/15) 100% (14/14) 100% (15/15) 100% (41/41) 95% (39/41) PI-Failure, GT 1 (n = 41) SOF + DCV SOF + DCV + RBV 100% (21/21) 95% (19/20) TN, GT 2 or 3 (n = 44) SOF SOF + DCV SOF + DCV SOF + DCV + RBV 88% (14/16) 100% (14/14) 86% (12/14) Weeks Primary endpoint: SVR12 SVR12 was achieved in 98% of GT 1 patients, 92% of GT 2 patients, and 89% GT 3 patients Sulkowski M, et al. N Engl J Med 2014;370: 突破厂家的限制

58 理想价钱 Sofosbuvir: USD $136 (12 weeks) Daclatasvir USD $30 (12 weeks) Hill et al Clin Infect Dis 2014

59 总结寻找完美组合!!

60 谢谢!

61 司徒伟基临床助理教授香港大学内科学系内科顾问医生香港大学深圳医院 Dr. Wai-Kay Seto MBBS MD FRCP FHKCP FHKAM Clinical Assistant Professor The University of Hong Kong, Hong Kong Consultant HKU-Shenzhen Hospital, Shenzhen

plx-005/04

plx-005/04 (HCV) (HCC) 3 2 HCV HCV Flaviviridae) RNA 6 HCV ( 1a 2b 3c ) 1 HCV 70% HCV quasispecies HCV HCV ORF 10 NS NS3 / NS5B RNA RNA HCV HCV 100 5min 60 10h WHO HCV 3% 1.7 HCV 3.5 -HCV 3.2% -HCV 3.6% 2.9% 2.5%