慢性丙肝的治疗进展
山东省千佛山医院
肝病科 安勇
慢性丙肝的治疗进展
Suppression of
HCV with DAA
combination
(PI + NI)
Ribavirin
Interferon
1990
Proof
of concept
for DAA (PI)
2000
2005
Pegylated
interferons
Telaprevir
and
boceprevir
2010
2011
IFN-free DAA
combinations (GT1)
Frequent
curability of
diverse
populations
without IFN
2012
Curability of
HCV without
interferon
Potential
approval of
other DAAs
with IFN
(eg, faldaprevir)
2013
2014
2015-
 Approval of simeprevir
and sofosbuvir with IFN
 First approved IFN-free
therapy: SOF + RBV for
GT2/3
DAAs
2011
100
PegIFN
80
90+
2001
RBV
Standard
IFN
2013
70+
1998
55
60
1991
42
40
34
39
16
20
6
0
IFN
6 mos
IFN
12 mos
IFN/RBV
6 mos
IFN/RBV
12 mos
PegIFN
12 mos
PegIFN/
RBV
12 mos
DAA
PegIFN/
+ RBV
RBV/
DAA ± PegIFN
Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee
Meeting, April 27-28, 2011, Silver Spring, MD.
直接抗病毒药物（DAAs）
5’UTR
Core
E1
E2
p7
Direct-Acting Antiviral Agents
NS2
NS3
NS4B
NS5A
Protease
Ribavirin
NS3
Protease Inhibitors
Telaprevir
Boceprevir
Simeprevir
Asunaprevir
ABT-450
MK-5172
Faldaprevir
Sovaprevir
ACH-2684
3’UTR
NS5B
Polymerase
NS5A
Replication
Complex Inhibitors
Daclatasvir
Ledipasvir
Ombitasvir
MK-8742
GS-5885
GS-5816
ACH-3102
PPI-668
GSK2336805
Samatasvir
NS5B
NUC Inhibitors
NS5B
Non-NUC Inhibitors
Sofosbuvir
VX-135
IDX21437
ACH-3422
Dasabuvir
BMS-791325
PPI-383
GS-9669
TMC647055
DAAs的特点
Characteristic
Protease
Inhibitor*
Protease
Inhibitor**
NS5A
Inhibitor
Nuc
Polymerase
Inhibitor
Non-Nuc
Polymerase
Inhibitor
Resistance
profile
Pangenotypic
efficacy
Antiviral
potency
Adverse
events
Good profile
Average profile
*First generation. **Second generation.
Least favorable profile
AASLD 对基因1型慢丙肝初治患者的治疗指南
Genotype 1
Treatment Naive
IFN Eligible?
Yes
Sofosbuvir 400 mg/d
PEG + RBV x 12 wks
No
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
AASLD treatment recommendations.
Sofosbuvir 400 mg/d
+ RBV x 24 wks
RBV : 1000-1200 mg/day
AASLD 对经治的基因1型慢丙肝的治疗指南
Genotype 1
Treatment Experienced
Yes/No
Prior Protease Inhibitor?
Sofosbuvir 400 mg/d
x 12 wks + PEG +
RBV x 12-24 wks
No
Sofosbuvir 400 mg/d
Simeprevir 150 mg/d
± RBV
x 12 wks
Alternative Regimens
Sofosbuvir 400 mg/d
+ RBV ± PEG x 24 wks
RBV dose: 1000-1200 mg/day
AASLDtreatment recommendations.
Sofosbuvir
400 mg/d x 12 wks +
PEG + RBV x 12 wks
Simeprevir 150 mg/d x
12 wks + PEG + RBV
x 48 wks
GT1b
GT1a Q80K neg
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
Population
Treatment naive and
previous relapsers,
genotype 2
Recommended Regimen
Duration
Sofosbuvir 400 mg +
RBV 1000-1200 mg/day
12 wks
AASLD对经治的基因2型慢丙肝的指标指南
Population
Recommended Regimen
Duration
Sofosbuvir 400 mg +
RBV 1000-1200 mg/day
12 wks*
Nonresponse to previous
treatment with pegIFN/RBV
*Pts with cirrhosis may benefit by extension of therapy to 16 wks.
Population
Alternative Regimen
Nonresponse to previous
Sofosbuvir 400 mg + pegIFN +
treatment with pegIFN/RBV
RBV 1000-1200 mg/day
with IFN eligibility
AASLD/IDSA treatment recommendations.
Duration
12 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
score
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;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
SVR12 %
Regimen
Tx Naive
Tx Exp
PI Failure
Sofosbuvir + ledipasvir[1,2]
---
70 (N = 10)
91 (N = 11)
Sofosbuvir + ledipasvir + RBV[1,2]
---
100 (N = 25)
100 (N = 11)
Sofosbuvir + ledipasvir + GS-9669[1]
---
100 (N = 26)
---
90 (N = 203)†
82 (N = 205)†
---
Daclatasvir + asunaprevir + BMS-791325 75 mg[4]
94 (N = 16)
---
---
Daclatasvir + asunaprevir + BMS-791325 150
mg[4]
89 (N = 18)
---
---
ABT-450/ritonavir/ombitasvir + dasabuvir +
RBV[5]
94 (N = 86)
87-97 (N = 122)
---
ABT-450/ritonavir/ombitasvir + dasabuvir +
RBV[5]*
95 (N = 74)
95-100 (N = 98)
---
Daclatasvir + asunaprevir[3]*
*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
Guidelines
EASL HCV Guidelines 2014: Genotype 1
Genotype
Options for Therapy
PegIFN/ribavirin + sofosbuvir: 12 wks (A1)
PegIFN/ribavirin + simeprevir†: 12 wks, followed by 12 wks of pegIFN/ribavirin in
previously untreated pts and prior relapsers (A1), or 36 wks of pegIFN/ribavirin
in previous partial responders and null responders (B1)
Genotype 1*
PegIFN/ribavirin + daclatasvir (genotype 1b only; B1): 12 wks followed by 12 wks
of pegIFN/ribavirin alone or a further 12 wks of pegIFN/ribavirin + daclatasvir
(response-guided therapy) (B2)
Sofosbuvir + ribavirin: 24 wks for interferon-intolerant pts only, where no other
interferon-free option available (B2)
Sofosbuvir + simeprevir: 12 wks (ribavirin may be added for previous
nonresponders & cirrhotics) (B1)
Sofosbuvir + daclatasvir: 12 wks in previously untreated pts; 24 wks in
treatment-experienced patients (including TVR/BOC-experienced patients)
(ribavirin may be added in previous nonresponders and cirrhotics) (B1)
*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
Genotype
Options for Therapy
Sofosbuvir + ribavirin: 12 wks (16-20 weeks in cirrhotic patients, especially treatment experienced)
Genotype 2* (A1)
PegIFN/ribavirin + sofosbuvir: 12 wks for cirrhotic and/or treatment-experienced patients (B1)
Sofosbuvir + ribavirin: 24 wks (unsuitable for treatment-experienced cirrhotics, no specific
alternative proposed) (A2)
Genotype 3*
PegIFN/ribavirin + sofosbuvir: 12 wks (A2)
Sofosbuvir + daclatasvir: 12 wks (24 wks for treatment-experienced patients) (B1)
PegIFN/ribavirin + sofosbuvir 12 weeks (B1)
PegIFN/ribavirin + simeprevir: 12 wks, followed by 12 wks of pegIFN/ribavirin in previously
untreated patients & prior relapsers (B1), or 36 wks of pegIFN/ribavirin in previous partial
responders & null responders (B1)
PegIFN/ribavirin + daclatasvir: 12 wks followed by 12 wks of pegIFN/ribavirin alone or a further 12
Genotype 4* wks of pegIFN/ribavirin + daclatasvir (response-guided therapy) (B1)
Sofosbuvir + ribavirin: 24 wks for interferon-intolerant patients (C2)
Sofosbuvir + simeprevir: 12 wks (ribavirin may be added in previous nonresponders and cirrhotics)
(B2)
Sofosbuvir + daclatasvir: 12 wks in previously untreated patients; 24 wks in treatment-experienced
patients (ribavirin may be added in previous nonresponders and cirrhotics) (B2)
PegIFN/ribavirin + sofosbuvir 12 wks (B1)
Genotype
*In settings where recommended options are not available, treatment with pegIFN/ribavirin remains acceptable.
5/6*
Sofosbuvir + ribavirin: 24 wks for interferon-intolerant patients (C2)
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.