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1、山东省千佛山医院 肝病科 安勇,慢性丙肝的治疗进展,慢性丙肝的治疗进展,Interferon,Ribavirin,Pegylated interferons,Proof of concept for DAA (PI),Suppression of HCV with DAA combination (PI + NI),Telaprevir and boceprevir,Curability of HCV without interferon,Frequent curability of diverse populations without IFN,Approval of simeprevir
2、and sofosbuvir with IFN First approved IFN-free therapy: SOF + RBV for GT2/3,IFN-free DAA combinations (GT1),Potential approval of other DAAs with IFN (eg, faldaprevir),1990 2000 2005 2010 2011 2012 2013 2014 2015-,Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee
3、Meeting, April 27-28, 2011, Silver Spring, MD.,SVR (%),IFN 6 mos,PegIFN/ RBV 12 mos,IFN 12 mos,IFN/RBV 12 mos,PegIFN 12 mos,2001,1998,2011,Standard IFN,RBV,PegIFN,1991,DAAs,PegIFN/ RBV/ DAA,IFN/RBV 6 mos,6,16,34,42,39,55,70+,0,20,40,60,80,100,DAA + RBV PegIFN,90+,2013,直接抗病毒药物（DAAs）,Direct-Acting Ant
4、iviral Agents,3UTR,5UTR,Core,E1,E2,NS2,NS4B,NS3,NS5A,NS5B,p7,Telaprevir Boceprevir Simeprevir Asunaprevir ABT-450 MK-5172 Faldaprevir Sovaprevir ACH-2684,Daclatasvir Ledipasvir Ombitasvir MK-8742 GS-5885 GS-5816 ACH-3102 PPI-668 GSK2336805 Samatasvir,Sofosbuvir VX-135 IDX21437 ACH-3422,Dasabuvir BMS
5、-791325 PPI-383 GS-9669 TMC647055,NS5B NUC Inhibitors,NS3 Protease Inhibitors,NS5A Replication Complex Inhibitors,Ribavirin,NS5B Non-NUC Inhibitors,Polymerase,Protease,DAAs的特点,Good profile,Average profile,Least favorable profile,*First generation. *Second generation.,AASLD 对基因1型慢丙肝初治患者的治疗指南,Genotype
6、 1 Treatment Naive,Sofosbuvir 400 mg/d PEG + RBV x 12 wks,Sofosbuvir 400 mg/d Simeprevir 150 mg/d RBV x 12 wks,IFN Eligible?,Yes,No,Simeprevir 150 mg/d x 12 wks + PEG + RBV x 24 wks GT1b GT1a Q80K neg,Sofosbuvir 400 mg/d + RBV x 24 wks,AASLD treatment recommendations.,Alternative Regimens,RBV : 1000
7、-1200 mg/day,AASLD 对经治的基因1型慢丙肝的治疗指南,Genotype 1 Treatment Experienced,Sofosbuvir 400 mg/d x 12 wks + PEG + RBV x 12-24 wks,Sofosbuvir 400 mg/d Simeprevir 150 mg/d RBV x 12 wks,Prior Protease Inhibitor?,Yes/No,No,Simeprevir 150 mg/d x 12 wks + PEG + RBV x 48 wks GT1b GT1a Q80K neg,Alternative Regimens
8、,RBV dose: 1000-1200 mg/day,Sofosbuvir 400 mg/d + RBV PEG x 24 wks,Sofosbuvir 400 mg/d x 12 wks + PEG + RBV x 12 wks,AASLDtreatment recommendations.,初治基因1型慢丙肝患者,经治基因1型慢丙肝患者,Genotype 2,基因2型慢丙肝PEG-INF+RBV优化治疗方案,基因2/3型慢丙肝患者,AASLD 对初治的基因2型慢丙肝的治疗指南,AASLD对经治的基因2型慢丙肝的指标指南,AASLD/IDSA treatment recommendatio
9、ns.,*Pts with cirrhosis may benefit by extension of therapy to 16 wks.,Cirrhotic Patients,Cirrhosis: A Continuous Spectrum of Disease,ESLD,Child-Pugh B,Portal hypertension high risk,Cirrhosis treatment candidate,Liver disease is not optimally represented by Child-Pugh stage (A, B, or C) or MELD scor
10、e,18,19,PegIFN/RBV 治疗HCV肝硬化患者,绝大部分患者需要治疗(5年生存率为 50%) SVR 率 情况 基因1-4型 7% 16%1,2 基因2/3型 44% 57% 1,2 治疗的局限性 感染风险及感染相关死亡风险高1 Child-Pugh C (MELD 18)患者中药物不良反应发生率高3 治疗获益 治疗随访中失代偿发生率降低1,4 应答患者的死亡率降低1,4,1. Iacobellis A, et al. J Hepatol. 2007;46:206-212. 2. Iacobellis A, et al. Aliment Pharmacol Ther. 2009;2
11、7:1081-1085. 3. Forns X, et al. J Hepatol. 2003;39:389-396. 4. Fattovich G, et al. Gastroenterology. 1997;112:463-472.,丙肝肝硬化患者无干扰素治疗,1. Gane EJ, et al. AASLD 2013. Abstract 73. 2. Lawitz. E et al. AASLD 2013, Abstract 215. 3. Manns M, et al. EASL 2014. Abstract 166. 4. Everson GT, et al. Gastroenter
12、ol. 2014;146:420-429. 5. Poordad F, et al. N Engl J Med. 2014;Epub ahead of print.,*Treatment duration: 24 weeks; all others 12 weeks. Genotype 1b HCV-infected patients only,Summary,Cirrhotic patients are the most in need for HCV treatment Child-Pugh A patients should be strongly advised to undergo
13、therapy More advanced cirrhosis should be treated with caution on a case-by-case basis Newest DAA + pegIFN/RBV combinations increase SVR in cirrhotic patients IFN-free DAA regimens demonstrate significant potency in cirrhotic patients,Guidelines,EASL HCV Guidelines 2014: Genotype 1,EASL. J Hepatolog
14、y. 2014;60:392-420.,*In settings where recommended options are not available, treatment with pegIFN/ribavirin + TVR or BOC remains acceptable. Not recommended in pts with genotype 1a and detectable Q80K polymorphism.,EASL HCV Guidelines 2014: Genotype 2-6,EASL. J Hepatology. 2014;60:392-420.,*In set
15、tings where recommended options are not available, treatment with pegIFN/ribavirin remains acceptable.,WHO HCV Guidelines 2014: Recommendations on HCV Treatment,All adults and children with chronic HCV infection, including people who inject drugs, should be assessed for antiviral treatment (strong r
16、ecommendation; moderate quality of evidence) PegIFN + RBV recommended rather than standard nonpegylated IFN with RBV (strong recommendation; moderate quality of evidence) TVR or BOC, in combination with pegIFN/RBV, suggested for GT1 chronic HCV infection rather than pegIFN/RBV alone (conditional rec
17、ommendation; moderate quality of evidence) Sofosbuvir, in combination with RBV with or without pegIFN (depending on HCV genotype), recommended for GT1-4 HCV infection rather than pegIFN/RBV alone (and rather than no treatment for persons who cannot tolerate IFN) (strong recommendation; high quality of evidence) Simeprevir, in combination with pegIFN/RBV, recommended for GT1b HCV infection and genotype 1a HCV infection without the Q80K polymorphism, rather than pegIFN/RBV alone (strong recommendation; high quality of evidence),
