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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. Frequent curability of diverse populations without IFN. IFN-free DAA combinations (GT1). Ribavirin. Suppression of HCV with DAA combination (PI + NI). Potential approval of other DAAs with IFN (eg, faldaprevir). Proof of concept for DAA (PI).
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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 Frequent curability of diverse populations without IFN IFN-free DAA combinations (GT1) Ribavirin Suppression of HCV with DAA combination (PI + NI) Potential approval of other DAAs with IFN (eg, faldaprevir) Proof of concept for DAA (PI) Telaprevir and boceprevir Interferon 1990 2000 2005 2010 2011 2012 2013 2014 2015- Curability of HCV without interferon • Approval of simeprevir and sofosbuvir with IFN • First approved IFN-free therapy: SOF + RBV for GT2/3 Pegylated interferons
DAAs 2013 100 2011 90+ PegIFN 2001 RBV 80 Standard IFN 70+ 1998 55 60 1991 42 39 SVR (%) 40 34 16 20 6 0 DAA + RBV ± PegIFN IFN 12 mos IFN/RBV 6 mos IFN/RBV 12 mos PegIFN 12 mos PegIFN/ RBV 12 mos IFN 6 mos PegIFN/ RBV/ DAA Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting, April 27-28, 2011, Silver Spring, MD.
Direct-Acting Antiviral Agents Core E1 E2 NS2 NS3 NS4B NS5A NS5B 3’UTR 5’UTR p7 Protease Polymerase Ribavirin NS3Protease Inhibitors NS5AReplication Complex Inhibitors NS5BNUC Inhibitors NS5BNon-NUC Inhibitors Telaprevir BoceprevirSimeprevir 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-791325 PPI-383 GS-9669 TMC647055
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 1 Treatment Naive No IFN Eligible? Yes Sofosbuvir 400 mg/d PEG + RBV x 12 wks Sofosbuvir 400 mg/d Simeprevir 150 mg/d ± RBV x 12 wks Alternative Regimens • Simeprevir 150 mg/d x 12 wks • + PEG + RBV x 24 wks • GT1b • GT1a Q80K neg Sofosbuvir 400 mg/d + RBV x 24 wks RBV : 1000-1200 mg/day AASLD treatment recommendations.
AASLD 对经治的基因1型慢丙肝的治疗指南 Genotype 1 Treatment Experienced Prior Protease Inhibitor? No Yes/No 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 Alternative Regimens Sofosbuvir 400 mg/d + RBV ± PEG x 24 wks • Simeprevir 150 mg/d x 12 wks + PEG + RBV x 48 wks • GT1b • GT1a Q80K neg Sofosbuvir 400 mg/d x 12 wks + PEG + RBV x 12 wks RBV dose: 1000-1200 mg/day AASLDtreatment recommendations.
AASLD对经治的基因2型慢丙肝的指标指南 *Pts with cirrhosis may benefit by extension of therapy to 16 wks. AASLD/IDSA treatment recommendations.
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 score
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;27:1081-1085. 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 *Treatment duration: 24 weeks; all others 12 weeks.†Genotype 1b HCV-infected patients only 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. Gastroenterol. 2014;146:420-429. 5. Poordad F, et al. N Engl J Med. 2014;[Epub ahead of print].
Summary • Cirrhotic patients are the most in need for HCV treatment • Child-Pugh A patients should be strongly advised to undergo 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
EASL HCV Guidelines 2014: Genotype 1 *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. J Hepatology. 2014;60:392-420.
EASL HCV Guidelines 2014: Genotype 2-6 *In settings where recommended options are not available, treatment with pegIFN/ribavirin remains acceptable. EASL. J Hepatology. 2014;60:392-420.
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 recommendation; 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 recommendation; 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) WHO 2014. Guidelines for the screening, care and treatment of persons with hepatitis C infection.
