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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 ?.

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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 ?


Where we areBetter understanding of therapeutic targets

Protease

Inhibitors

NS5A

Inhibitors

Polymerase

Inhibitors


80

70%

60

+30%

40%

40

20

0

2002

BI

2012

TRI

Where we areBetter efficacy with triple therapy (G1)

Jacobson et al. NEJM 2012

Poordad 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 1997

Maylin et al. Gastroenterology 2009


1.0

0.8

SVR (-)

0.6

p < 0.001

0.4

0.2

SVR (+)

0

0

2

4

6

8

10

12

Time since last treatment (years)

Cure = improved prognosis

HCC in 300 cirrhotics

Cardoso et al. J Hepatol 2010


1,0

SVR (+)

0,8

p < 0.001

SVR (-)

0,6

0,4

0,2

0,0

0

2

4

6

8

10

Time since last treatment (years)

Cure = improved prognosis

Survival in 300 cirrhotics

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

%

100

- 19 %

80

- 83 %

60

40

20

0

PEG-IFN + RBV

Tritherapy PEG IFN + RBV + PI

Tritherapy + reinforced screening + improved access to therapy


Where we are:

the limitations


Where we are: limitations

Insufficient screening

Undiagnosed Pool2.5 million

Undiagnosed Pool1.8 million

Diagnosed Pool0.9 million

Diagnosed Pool1.6 million


Where we are: limitations

Russia3M

Korea1M

US4M

Europa5M

Japan2M

China43M

Pakistan9M

Egypt12M

Vietnam7M

India10M

Brazil7M

170 million people HCV infected worldwide


Where we are: limitations

Insufficient access to treatment


Where we are: limitations

Access to treatment: the bottle necks

Diagnosed

Managed

Treated

Cured


Where we are: limitations

Russia3M

Korea1M

US4M

Europa5M

Japan2M

China43M

Pakistan9M G3

Egypt12M G4

Vietnam7M G6

India10MG3

Brazil7M

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

Quadruple therapy: PEG-IFN+ RBV+ NS5AI + PIin G1 null responders: IFN free

%

100

90

80

60

36

40

20

0

BMS-790052 + BMS-650032 + PEG IFN + RBV

BMS-790052 + BMS-650032

Lok et al. NEJM 2012


danoprevir + mericitabine + ribavirine in non responders G 1

SVR 12

%

100

80

55

60

39

40

20

n/N

9/23

17/31

0

Partial Responders

Null Responders

Feld JJ, AASLD 2012


IFN-free ongoing trials: summary


Impact of treatment on mortality

Without treatment

With bitherapy PEG IFN + RBV

3000

2500

-14%

G1/4

2000

incidence annuelle de la mortalité liée au VHC

1500

-32%

G2/3

1000

500

0

1980

1985

1990

1995

2000

2005

2010

2015

2020

2025

Years

Deuffic-Durban et al. J Hepatol 2007


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

25

20

+ 83 %

15

+ 19 %

10

5

0

PEG-IFN + RBV

Tritherapy PEG IFN + RBV + PI

Tritherapy + reinforced screening + improved access to therapy


Where we go:

IFN free Therapy


Where we go

Quadruple therapy: PEG-IFN+ RBV+ NS5AI + PIin G1 null responders: IFN free

%

100

90

80

60

36

40

20

0

BMS-790052 + BMS-650032 + PEG IFN + RBV

BMS-790052 + BMS-650032

Lok et al. NEJM 2012


danoprevir + mericitabine + ribavirine in non responders G 1

SVR 12

%

100

80

55

60

39

40

20

n/N

9/23

17/31

0

Partial Responders

Null Responders

Feld JJ, AASLD 2012


Faldaprevir + BI 207127 + RBV (naive G1)

400 mg TID BI 207127 + BI 201335 + RBV

600 mg TID BI 207127 + BI 201335 + RBV

100

100

100

82

80

73

67

60

Patients with HCV RNA <25 IU/mL (%)

40

40

20

6/15

14/17

10/15

17/17

11/15

17/17

0

Day 15

Day 22

Day 29

Zeuzem S, et al. Gatroenterology 2011


ABT-450/r + ABT-333 + ABT-267 + RBV

SVR 12 (ITT)

98

93

100

87

89

80

85

60

SVR 12 (ITT)

40

20

0

8W

Naîve patient

12WNaïve Patients

12WNull Responders

Kowdley et al. AASLD 2012


Sofosbuvir (GS 7977) + GS 5885 + RBV

HCV RNA < 15 UI/ml

100

100

100

88

80

60

HCV RNA < 15 UI/ml

40

10

20

0

SOF + RBV

SOF + GS-5885 + RBV

Naive

Null responders

Naive

Null responders

Gane et al. AASLD 2012


Faldaprevir + BI 207127 + RBV (naive G1)

400 mg TID BI 207127 + BI 201335 + RBV

600 mg TID BI 207127 + BI 201335 + RBV

100

100

100

82

80

73

67

60

Patients with HCV RNA <25 IU/mL (%)

40

40

20

6/15

14/17

10/15

17/17

11/15

17/17

0

Day 15

Day 22

Day 29

Zeuzem S, et al. Gatroenterology 2011


ABT-450/r + ABT-333 + ABT-267 + RBV

SVR 12 (ITT)

98

93

100

87

89

80

85

60

SVR 12 (ITT)

40

20

0

8W

Naîve patient

12WNaïve Patients

12WNull Responders

Kowdley et al. AASLD 2012


Sofosbuvir (GS 7977) + GS 5885 + RBV

HCV RNA < 15 UI/ml

100

100

100

88

80

60

HCV RNA < 15 UI/ml

40

10

20

0

SOF + RBV

SOF + GS-5885 + RBV

Naive

Null responders

Naive

Null responders

Gane et al. AASLD 2012


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

The conclusion of the PHC 2009

  • Cure = 100% in 2-3 years

  • One pill a day


Where we are: limitations

Insufficient access to treatment


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