traitement de l’hépatite c sans interféron patrick marcellin
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Traitement de l’Hépatite C Sans Interféron Patrick Marcellin. Hepatitis C. Where we are: The achievements. Hepatitis C: progress is accelerating. The conclusion of the PHC 2009. Cure = 100% in 10 years. Progress is accelerating. Earlier ? 2015 ?. - PowerPoint PPT PresentationTRANSCRIPT
Traitement de l’Hépatite C
Sans Interféron
Patrick Marcellin
Hepatitis C
Where we are:The achievements
Hepatitis C: progress is accelerating
Cure = 100% in 10 years
The conclusion of the PHC 2009
Progress is accelerating
Earlier ?
2015 ?
Where we areBetter understanding of therapeutic targets
Protease Inhibitors
Polymerase Inhibitors
NS5A Inhibitors
Where we areBetter efficacy with triple therapy (G1)
20
40
60
80
2002BI
2012TRI
0
70%
40%+30%
Jacobson et al. NEJM 2012Poordad NEJM 2012
SVR = CURE
Undetectable HCV RNA in serum: 100%
Undectable HCV RNA in liver: ≈100%
Undectable HCV RNA in PBMCs: 100%
Marcellin et al. Annals of Intern Madicine 1997Maylin et al. Gastroenterology 2009
Cure = improved prognosis
HCC in 300 cirrhotics
Cardoso et al. J Hepatol 2010
0
0.2
0.4
0.6
0.8
1.0
SVR (+)
SVR (-)
p < 0.001
2 4 6 8 12
Time since last treatment (years)
10
0
Cure = improved prognosis
Survival in 300 cirrhotics
0
0,2
0,4
0,6
0,8
1,0SVR (+)
SVR (-)
p < 0.001
2 4 6 8 10Time since last treatment (years)
0,0
Cardoso et al. J Hepatol 2010
Reinforced screening and access to therapy=decrease in HCV-related mortality
Deuffic-Durban et al. EASL 2011
Percentage of decreased mortality modelisation 2012 – 2021 France
PEG-IFN + RBV
Tritherapy PEG IFN + RBV + PI
Tritherapy + reinforced screening
+ improved access to therapy
0
20
40
60
80
100
- 83 %
- 19 %
%
Where we are:the limitations
Where we are: limitations
Insufficient screening
Undiagnosed Pool2.5 million
Diagnosed Pool0.9 million
Undiagnosed Pool1.8 million
Diagnosed Pool1.6 million
Where we are: limitations
170 million people HCV infected worldwide
US4M
Brazil7M
Europa5M
Russia3M
Egypt12M
India10M
China43M
Korea1M
Japan2M
Vietnam7M
Pakistan9M
Where we are: limitations
Insufficient access to treatmentInsufficient access to treatment
Where we are: limitations
0
20
40
60
80
100
Catégorie 1
Access to treatment: the bottle necks
Diagnosed Managed Treated Cured
Where we are: limitations
US4M
Brazil7M
Europa5M
Russia3M
Egypt12M G4
India10M G3
China43M
Korea1M
Japan2M
Vietnam7M G6
Pakistan9M G3
High prevalence of G non1 in high prevalence countries
Where we are:The hope is becoming reality
Ideal Therapy
100% efficacy IFN-free All oral Short duration No resistance Pan-genotypic Well tolerated and safe Low cost
Where we go
Lok et al. NEJM 2012
0
20
40
60
80
100
BMS-790052 + BMS-650032 + PEG IFN + RBV
36
90%
BMS-790052 + BMS-650032
Quadruple therapy: PEG-IFN+ RBV+ NS5AI + PIin G1 null responders: IFN free
danoprevir + mericitabine + ribavirine in non responders G 1
n/N
Partial Responders Null Responders
%
Feld JJ, AASLD 2012
39
55
0
20
40
60
80
100
17/319/23
SVR 12
IFN-free ongoing trials: summary First drug (company) Second drug Third drug Fourth drugBoehringer ingelheimFaldaprevir (BI201335)
BI207127 Ribavirin
Protease inhibitor NS5B NNI
Abbott
ABT-450/r ABT 267 ABT 333 RibavirinProtease inhibitor NS5B NNI NS5A inhibitor
Gilead/BMS Ribavirin
Sofosbuvir (GS 7977) GS 5885
NS5B NI NS5A inhibitor
BMS
Asunasprevir Daclastavir + Ribavirin
Protease inhibitor NS5A inhibitor
Vertex
Telaprevir VX 222 Ribavirin
Protease inhibitor NS5B
0
500
1000
1500
2000
2500
3000
1980 1985 1990 1995 2000 2005 2010 2015 2020 2025
YearsYears
inci
den
ce
an
nu
ell
e d
e l
a m
ort
ali
té l
iée
au
VH
Cin
cid
enc
e a
nn
ue
lle
de
la
mo
rta
lité
lié
e a
u V
HC
Without treatment
With bitherapy PEG IFN + RBV
-14%
-32%
G1/4
G2/3
Impact of treatment on mortality
Deuffic-Durban et al. J Hepatol 2007
Reinforced screening and access to therapy=decrease in HCV-related mortality
Deuffic-Durban et al. EASL 2011
PEG-IFN + RBV
Tritherapy PEG IFN + RBV + PI
Tritherapy + reinforced screening
+ improved access to therapy
Percentage of decreased mortality modelisation 2012 – 2021 France
0
5
10
15
20
25
+ 83 %
+ 19 %
Where we go:IFN free Therapy
Where we go
Lok et al. NEJM 2012
0
20
40
60
80
100
BMS-790052 + BMS-650032 + PEG IFN + RBV
36
90%
BMS-790052 + BMS-650032
Quadruple therapy: PEG-IFN+ RBV+ NS5AI + PIin G1 null responders: IFN free
danoprevir + mericitabine + ribavirine in non responders G 1
n/N
Partial Responders Null Responders
%
Feld JJ, AASLD 2012
39
55
0
20
40
60
80
100
17/319/23
SVR 12
Faldaprevir + BI 207127 + RBV (naive G1)
Zeuzem S, et al. Gatroenterology 2011
40
6773
82
100 100
0
20
40
60
80
100
Day 15 Day 22 Day 29
Patie
nts
with
HCV
RN
A <2
5 IU
/mL
(%)
400 mg TID BI 207127 + BI 201335 + RBV600 mg TID BI 207127 + BI 201335 + RBV
6/15 14/17 17/1710/15 11/15 17/17
ABT-450/r + ABT-333 + ABT-267 + RBV
Kowdley et al. AASLD 2012
SVR
12 (
ITT)
8WNaîve patient
12WNaïve Patients
12WNull Responders
0
20
40
60
80
100 87
85
98
89
93
SVR 12 (ITT)
Sofosbuvir (GS 7977) + GS 5885 + RBV
Gane et al. AASLD 2012
HCV RNA < 15 UI/ml
HCV
RN
A <
15 U
I/m
l
SOF + RBV0
20
40
60
80
100 88
10
100 100
Naive Null responders
SOF + GS-5885 + RBV
Naive Null responders
Faldaprevir + BI 207127 + RBV (naive G1)
Zeuzem S, et al. Gatroenterology 2011
40
6773
82
100 100
0
20
40
60
80
100
Day 15 Day 22 Day 29
Patie
nts
with
HCV
RN
A <2
5 IU
/mL
(%)
400 mg TID BI 207127 + BI 201335 + RBV600 mg TID BI 207127 + BI 201335 + RBV
6/15 14/17 17/1710/15 11/15 17/17
ABT-450/r + ABT-333 + ABT-267 + RBV
Kowdley et al. AASLD 2012
SVR
12 (
ITT)
8WNaîve patient
12WNaïve Patients
12WNull Responders
0
20
40
60
80
100 87
85
98
89
93
SVR 12 (ITT)
Sofosbuvir (GS 7977) + GS 5885 + RBV
Gane et al. AASLD 2012
HCV RNA < 15 UI/ml
HCV
RN
A <
15 U
I/m
l
SOF + RBV0
20
40
60
80
100 88
10
100 100
Naive Null responders
SOF + GS-5885 + RBV
Naive Null responders
The Proof of Concept
100% efficacy
All oral
IFN-free
Short duration
No resistance
Pan-genotypic
Well tolerated and safe
Low cost??
Hepatitis C: progress is accelerating
Cure = 100% in 2-3 years One pill a day
The conclusion of the PHC 2009
Where we are: limitations
Insufficient access to treatmentInsufficient access to treatment