WHAT DID WE DO IN FRANCE - Virology...

WHAT DID WE DO IN FRANCE ?

(and perspectives…)

Daniel Dhumeaux, Henri Mondor hospital

Créteil, France

daniel.dhumeaux@gmail.com Frankfurt, Sept.10, 2015

The French masterplan : successive steps

1st national sero-

prevalence survey

1st national

programme

(HCV)

1994

Episodes of transmission in

health-care settings

High

prevalence

in DUs

law relative to

public health

policy

20041999 2002

2nd national

programme

(HCV+HBV)

Conference on

Hep C treatment

- National

seroprevalence

survey in DUs

- 2nd national sero-

prevalence survey

Hepatology

reference centre

implementation

2009-2012

3rd national

programme

(HCV+HBV)

Surveillance

19961997

The French masterplan : successive steps

1st national sero-

prevalence survey

1st national

programme

(HCV)

1994

Episodes of transmission in

health-care settings

High

prevalence

in DUs

law relative to

public health

policy

20041999 2002

2nd national

programme

(HCV+HBV)

Conference on

Hep C treatment

- National

seroprevalence

survey in DUs

- 2nd national sero-

prevalence survey

Hepatology

reference centre

implementation

2009-2012

3rd national

programme

(HCV+HBV)

Surveillance

1996 1997

The 30 HBV/HCV expert centers in France

The French masterplan : successive steps

1st national sero-

prevalence survey

1st national

programme

(HCV)

1994

Episodes of transmission in

health-care settings

High

prevalence

in DUs

law relative to

public health

policy

20041999 2002

2nd national

programme

(HCV+HBV)

Conference on

Hep C treatment

- National

seroprevalence

survey in DUs

- 2nd national sero-

prevalence survey

Hepatology

reference centre

implementation

2009-2012

3rd national

programme

(HCV+HBV)

Surveillance

19961997

The French masterplan : successive steps

1st national sero-

prevalence survey

1st national

programme

(HCV)

1994

Episodes of transmission in

health-care settings

High

prevalence

in DUs

law relative to

public health

policy

20041999 2002

2nd national

programme

(HCV+HBV)

Conference on

Hep C treatment

- National

seroprevalence

survey in DUs

- 2nd national sero-

prevalence survey

Hepatology

reference centre

implementation

2009-2012

3rd national

programme

(HCV+HBV)

Surveillance

19961997

The French masterplan : successive steps

1st national sero-

prevalence survey

1st national

programme

(HCV)

1994

Episodes of transmission in

health-care settings

High

prevalence

in DUs

law relative to

public health

policy

20041999 2002

2nd national

programme

(HCV+HBV)

Conference on

Hep C treatment

- National

seroprevalence

survey in DUs

- 2nd national sero-

prevalence survey

Hepatology

reference centre

implementation

2009-2012

3rd national

programme

(HCV+HBV)

Surveillance

19961997

The French masterplan : successive steps

1st national sero-

prevalence survey

1st national

programme

(HCV)

1994

Episodes of transmission in

health-care settings

High

prevalence

in DUs

law relative to

public health

policy

20041999 2002

2nd national

programme

(HCV+HBV)

Conference on

Hep C treatment

- National

seroprevalence

survey in DUs

- 2nd national sero-

prevalence survey

Hepatology

reference centre

implementation

2009-2012

3rd national

programme

(HCV+HBV)

Surveillance

19961997

French medicine agencies

French national authority

of health

Ministry department in charge

of addiction prevention

National

committee

French national stake-houlders

- More than 1,000 medicinal products assessed since 1994

- Availability 10 to 12 months before market authorization

application

- Therapeutic areas

. Oncology-haematology

. Central nervous system diseases

. Metabolic disorders

. Infectious diseases including HIV infection and

and viral hepatitis

- Implemented in 1994

The French of authorization for temporary use (ATU)

French ATU for hepatitis C virus infection

. Boceprevir or telaprevir + peginterferon

+ ribavirin (CUPIC cohort)

. Sofosbuvir + ribavivin

. Simeprevir + peginterferon + ribavirin

. Sofosbuvir + daclatasvir

. Sofosbuvir + ledipasvir

. Paritaprevir/r + ombitasvir + dasabuvir

The French masterplan : successive steps

1st national sero-

prevalence survey

1st national

programme

(HCV)

1994

Episodes of transmission in

health-care settings

High

prevalence

in DUs

law relative to

public health

policy

20041999 2002

2nd national

programme

(HCV+HBV)

Conference on

Hep C treatment

- National

seroprevalence

survey in DUs

- 2nd national sero-

prevalence survey

Hepatology

reference centre

implementation

2009-2012

3rd national

programme

(HCV+HBV)

Surveillance

19961997

2014 French ministry guidelines

for the management of patients

with hepatitis B and C

Coordinator : Daniel Dhumeaux

Operators : ANRS and AFEF

- Specific national committee for implementationand

monitoring (November 2014, French Ministry of Health)

- Initiated by the French Minister of Health

Management of patients with hepatitis B or C

virus infection. Report of recomendations

- Conducted beween April 2013 and May 2014

- Organized into expert groups on 22 themes

(from epidemiology to research), associated with

an independent committee for validation and synthesis

(200 people, including patients associations,

180 recommentations)

Defining strategic therapy

Sofosbuvir +

ribavirin

Daclatasvir +

asunaprevir +

beclabuvir

All-oral DAA availability in Europe

2015 2016

Sofosbuvir +

ledipasvir

Sofosbuvir +

daclastasvir

Sofosbuvir +

simeprevir

Paritaprevir/r +

dasabuvir +

ombitasvir

Grasoprevir +

elbasvir

Defining strategic therapy

Two planned successive steps

2014 French ministery guidelines

for the management of patients

with hepatitis B and C

- Treat first patients with chronic hepatitis C :

. with fibrosis score of ≥ F2

. whatever the stage of fibrosis, with

extrahepatic manifestations, patients on a list

of organ transplantation, women who like to

get pregnant, and with the aim to collectively reduce

transmssion and epidemis, drugs users and prisoners.

Liver biopsy

n=2,110

Stage F3

n=336 (16%)

Stage F4

n=300 (14%)

Stage F2

n=618 (29%)

Cohort 2004-2011

n=14,256

Decomp. 27.7%

HCC 8.3%

Death 23.7%

Decomp. 10.1%

HCC 2.7%

Death 10.4%

Decomp. 3.6%

HCC 1.0%

Death 4.9%

Moorman et al. AASLD, Nov.2014 (Abstr. 174)

Morbidity and mortality of HCV infection at the

time of DAA (follow-up : 4 years)

Lee et al. J Infect Dis 2012;206:469-77

HCV chronic infection-induced mortality

Effects of HCV treatment on cardiovascular events

Nahon et al. JFHOD Paris, March 19 2015

Defining strategic therapy

The second step

Treating all patients

. HCV infection may induce long term severe hepatic

complications.

. HCV infection may induce (long term ?) severe

extrahepatic complications.

. Efficient oral treatment with low side effects and

expected low duration of administration may

prevent or treat these complications.

. Collectively, treating all patients is the best way for

reducing tansmission risk and limiting epidemics.

2014 French ministery guidelines

for the management of patients

with hepatitis B and C

- Treat first patients with chronic hepatitis C :

- with fibrosis score of ≥ F2

- whatever the stage of fibrosis, with

extrahepatic manifestations, patients on a list

of organ transplantation, women who like to

get pregnant, drugs users, and prisoners.

- Then (2016?), provide treatment to all infected patients.

Burden of HCV infection in France

Infected patients

Treated patients (up to 2014)

Cured patients

Residual infected patients

200,000

70,000

35,000

165,000

Screened

100,000

To be screened

65,000

In treating 15,000 new patients each year, disease control

could be achieved within 10 years

Deuffic-Burban et al. Submitted for publication

Budgetary impact Treatment if ≥F2, with priority to>F3

< 20,000 patients treated /year

Decisions about price and reimbursement take

place at the level of each member state,

« considering the potential role/use of this

medicine in the context of the national health

system of that country ».

Reducing the cost of treatment

Costs of treatment have to be reduced

Screening

50

100

0

-

-

-

HCV screening rates in European countries

65%

40% 40%33%

37%30%

50%

(%)

Screening

Evaluation

Treatment

Screening strategies according to

epidemiological studies

- USA : 1945-1965 birth cohort screening

- France…

- Canada : 1945-1975 birth cohort screening

Estimated proportion of persons between 18 to 60

year-old unaware of their HBV or HCV chronic

infection according to gender in France

Men MenWomen Women

HBV HCV

0

100

50 -

-

-

75%

25%

10%

90%

(%)

Proposed screening strategy in France

- All men between 18-60 years old

- Including combined detection of HBV, HCV

and HIV

To screen and treat

Licensing Agreements to Increase Access to

Hepatitis C Treatments

http://www.gilead.com/news/press-releases/2014/9/gilead-announces

-generic-licensing-agreements-to-increase-access-to-hepatitis-c-treatments

developing-countries

Licensing Agreements to Increase Access to

Hepatitis C Treatments in Developing Countries

SVR

(%)

4 weeks 6 weeks 8 weeks6 weeksNo cirrhosis Cirrhosis

100

50

0

95%

80%87%

39%

Grasoprevir +elbasuvir + sofosbuvir in patients

with naïve patients with genotype1

Lawitz et al. AASLD 2014, Abstr. LB-33

31 30 20 19

Hepatitis C worldwide

. Annual mortality : 350,000

. Prevalence of viremic people : 130 millions

. Prevalence of infected people : 170 millions

-

-

-

IFN24 IFN48 IFN-RBV24IFN-RBV48 PEG IFN-

RBV48

PEG IFN-

RBV-DAA1

0

50

100

Advances in therapy (hepatitis C virus genotype 1)

SVR

(%)

7%2%

16%

75%

40%

28%

90%

DAA

Cumulative treatment rate in 21 country, according

to national sources of prevalence

Lettmeier et al. J Hepatol 2008

Decisions about price and reimbursement take

place at the level of each member state,

« considering the potential role/use of this

medicine in the context of the national health

system of that country ».

Criteria for granting ATU

1. The product is a medicinal product (not a preparation)

3. There is no market authorisation application

2. ATU is given for treatment (not for investigation)

6. There is no available alternative therapeutic method

7. Efficacy and safety are presumed and benefit is

expected for the patient

4. The patient cannot be included in a clinical trail

5. The disease is serious and/or rare

Two types of ATU : nominative and cohort ATU

Nominative ATU

. For one patient, on a name

patient basis

. On the request and

responsibility of the clinician

. ATU for the duration of

treatment

. Usually follow-up of patients

and data collection according

to a protocol for therapeutic use

Cohort ATU

. For a group of patients

. Applied by the company

commitment to submit a

marketing autorisation

. ATU for one-year duration,

renewal possible

. Always follow-up of patients

and data collection according

to a protocol of therapeutic use

The ATU system : success and limits

- The ATU system is extremely useful for covering public

health needs :

. It is strongly supported by patients ans physicians

. It is contolled by competent authorities (*)

- The risks are (a) to slow down clinical trials and

marketing autorisation applications, (b) to overestimate

efficacy and to underestimate safety

- Regarding nominative ATU :

. Too many

. Complex system

. No strong regulatory long term status (no mandatory

marketing authorisation application)

(*) ansm : agence nationale de sécurité du médicament et des produits de santé

N NN Engl J Med 2014, April 10

Screening strategies according to

epidemiological studies

- USA : 1945-1965 birth cohort screening

- France :

. men between 18 and 60-year old

. combined detection of HCV, HBV and HIV

- Canada : 1945-1975 birth cohort screening

Screening strategies according to

epidemiological studies

- USA : 1945-1965 birth cohort screening

- France…

- Canada : 1945-1975 birth cohort screening

Screening rate of hepatitis C in European countries

Deuffic-Burban et al. Gastroenterology 2012; 143:974-85

Deuffic-Burban et al. Gastroenterology 2012;143:974-85

2014 French ministery guidelines

for the management of patients

with hepatitis B and C

- Treat first patients with chronic hepatitis C :

- with fibrosis score of ≥ F2

- whatever the stage of fibrosis, with

extrahepatic manifestations, patients on a list

of organ transplantation, women who like to

get pregnant, drugs users, and prisoners.

Premature ovarian senescence in HCV-positive

women of child-bearing age

Antimullerian hormone

(AMH)

ControlControl HCVHCV

AMH levels indicative of

ovarian failure (i.e. <0.8ng/ml)

15

5

10

0

-

-

-

-

13.0

3.210

30

20

0

-

-

-

-

28.0

9.7

(ng/ml)

Karampatou et al. AASLD, Boston 2014

Epidemiologie inter-régionale de l’hépatite C

Paritaprevir/r + ombitasvir + dasabuvir + ribavirin

Side effects

Side effects

Fatigue

Nausea

Pruritus

Insomnia

Diarrhea

33D+RBV

Placebo

0 20 40 60 80 100

Feld et al. N Engl J Med 2014

Headache

Cognitive emotional and functional brain impairment

(«brain fog») in hepatitis C chronic infection.

Afdal et al. AASLD 2014 (Abstr. 48)

1. DAA treatment induced an increase in basal

ganglia n-acetyl aspartate (NAA)/creatine (Cr) ratio

in all patients at magnetic resonance spectroscopy.

Effect of sofosbuvir-ledipasvir ± ribavirin in 14

patients with genotype 1 and F0-F1 fibrosis

2. The effect was more apparent in patients

not receiving ribavirin.

3. Some of the changes in basal ganglia correlated

with changes in the emotiotonal function domain of

CLDQ-HCV and in the mental health scale of SF-36.

Patient-reported outcomes (PRO) after 12 weeks

of treatment by sofosfuvir and ledipasvir

Younoussi et al. EASL 2014 (Abstr. P1324)

0.95

0.65

0.80

Quality

of life

Proposed screening strategy in France

- All men between 18-60 years old

- including combined detection of HBV, HCV

and HIV

Proposed screening strategy fo HBV

and HCV in France

2. Extend testing to all men between 18-60

years old

3. Propose combined detection of HBV, HCV

and HIV

1. Reinforce the strategy of targeted testing

based on risk of contamination

Yonoussi et al. AASLD, Boston 2014

Patient-reported outcomes (PRO) after 12 weeks

of treatment by sofosfuvir and ledipasvir

Treating

« THE FRENCH EXPERIENCE »

Daniel Dhumeaux, Henri Mondor hospital

Créteil, France

daniel.dhumeaux@gmail.com Glasgow, Dec.11, 2014

Wiesse et al. Hepatology 2014

Sofosbuvir DaclatasvirSimeprevir

New direct-acting antivirals

(May 2014)(Jan. 2014) (Sept.2014)

High genetic barrier

of resistance

Low genetic barrier

of resistance Low barrier genetic

of resistance

Genotypes 1,2,4 Genotype 1b All genotypes

Sofosbuvir+

ledipasvir

(Nov. 2014)

Low genetic barrier

of resistance

All genotypes (suboptimal in GT3)

Sofosbuvir +

ribavirin

All-oral DAA availability in Europe

Now

Sofosbuvir +

ledipasvir

Sofosbuvir +

daclastasvir

Sofosbuvir +

simeprevir

http://www.gilead.com/news/press-releases/2014/9/gilead-announces

-generic-licensing-agreements-to-increase-access-to-hepatitis-c-treatments

developing-countries

Licensing Agreements to Increase Access to

Hepatitis C Treatments in Developing Countries

Deuffic-Burban et al. Gastroenterology 2012;143:974-85

Sofosbuvir DaclatasvirSimeprevir

New direct-acting antivirals

(May 2014)(Jan. 2014) (Sept.2014)

High genetic barrier

of resistance

Low genetic barrier

of resistance Low barrier genetic

of resistance

Genotypes 1,2,4 Genotype 1b All genotypes

Sofosbuvir+

ledipasvir

(Nov. 2014)

Low genetic barrier

of resistance

All genotypes (suboptimal in GT3)

Sofosbuvir DaclatasvirSimeprevir

New direct-acting antivirals

(May 2014)(Jan. 2014) (Sept.2014)

High genetic barrier

of resistance

Low genetic barrier

of resistance Low barrier genetic

of resistance

Genotypes 1,2,4 Genotype 1b All genotypes

Sofosbuvir+

ledipasvir

(Nov. 2014)

Low genetic barrier

of resistance

All genotypes (suboptimal in GT3)

Five-year of death (all causes) or hepatocellular

carcinima in HCV patients with ( ) or without ( ) SVR.

Meta-analysis of 129 studies in 23,309 patients

Hill et al. AASLD 2014 (Abstr.44)

General Cirrhotic CoinfectedCoinfectedCirrhotic General

Patients

(%)

15

0

5

10

-

-

-

-

10.5 11.3

4.53.6

1.3

10.0

2.9

9.3

13.9

5.3

0.9

10.0

Death Hepatocellular carcinoma

Decisions about price and reimbursement take

place at the level of each member state,

« considering the potential role/use of this

medicine in the context of the national health

system of that country ».

Screening strategies according to

epidemiological studies

- USA : 1945-1965 birth cohort screening

- France :

. all men between 18 and 60-year old

. combined detection of HCV, HBV and HIV

- Canada : 1945-1975 birth cohort screening

Five-year of death (all causes) or hepatocellular

carcinima in HCV patients with ( ) or without ( ) SVR.

Meta-analysis of 129 studies in 23,309 patients

Hill et al. AASLD 2014 (Abstr.44)

General Cirrhotic CoinfectedCoinfectedCirrhotic General

Patients

(%)

15

0

5

10

-

-

-

-

10.5 11.3

4.53.6

1.3

10.0

2.9

9.3

13.9

5.3

0.9

10.0

Death Hepatocellular carcinoma

Kwong et al. PLUS ONE 2012;7:e44103

Impact of infectious diseases on healthThe Ontario Burden of Infectious Diseases Study (ONBOIDS)

Health-adjusted life year (HALY)

Hepatitis B Hepatitis C

Prevalence Anti-HCV Ab:0.84%

Annual mortality

Proportion of

sceened people

Number of infected

people 280 000

HCV RNA:0.53%

InVS 2004

HBsAg:0.65%

57%45%

230 000

2 6001 300

Marcellin et al. J Hepatol 2008;48:200-7

Hepatitis B Hepatitis C

Prevalence Anti-HCV Ab:0.84%

Annual mortality

Proportion of

sceened people

Number of infected

people 280 000

HCV RNA:0.53%

InVS 2004

HBsAg:0.65%

57%45%

230 000

2 6001 300

Marcellin et al. J Hepatol 2008;48:200-7

Hepatitis B Hepatitis C

Prevalence Anti-HCV Ab:0.84%

Annual mortality

Proportion of

sceened people

Number of infected

people 280 000

HCV RNA:0.53%

InVS 2004

HBsAg:0.65%

57%45%

230 000

2 6001 300

Marcellin et al. J Hepatol 2008;48:200-7

Lee et al. J Infect Dis 2012;206:469-77

HCV chronic infection-induced mortality

HCV chronic infection-induced mortality

Lee et al. J Infect Dis 2012;206:469-77

Effects of treatment in patients with HCV cirrhosis

Nahon et al. JFHOD Paris, March 19 2015

Deuffic-Burban et al. Submitted for publication

Budgetary impact Treatment if ≥F2, with priority to>F3

< 20,000 patients treated /year

Deuffic-Burban et al. Submitted for publication

Budgetary impact Treatment if ≥F2, with priority to>F3

< 20,000 patients treated /year

All patients Child-Pugh B Child-Pugh C

Sofosbuvir + ledipasvir + ribavirin in patients with

decompensated cirrhosis

Flamm et al. AASLD Boston 2014, Abstr. 239

100

50

0

-

--

87%89%

87%89%

86%

90%

SVR12

(%)12w

24w

SOF + LDV +RBV

(12 weeks)

SOF + LDV

(24 weeks)

96% 97%

Bourlière et al. AASLD 2014, LB-6

100

50

0

SVR12

(%)

-

-

-

Effect of sofosbuvir + ledispasvir ± ribavirin in

cirrhotic patients with failure to

previous first-generation protease inhibitor regimen

Fighting against hepatitis C

French national stake-holders

7

National

institute

of health & medical

Research

INSERM

National

Health

insurance

CNAM

French medicines

Agency

ANSM

Ministry department in charge

of addiction prevention

MILDT

National

Agency

for viral hepatitis

research

ANRS

Patients &

professionalsAssociations

Other Ministries

( economy,

employment,

housing, justice)

French national

authority for health

HAS

Ministry

of Social Affairs

and Health

Institute for

public health

surveillance

InVS

National

institute

for prevention &

health education

INPES

National

society

of blood

transfusion

EFS

Experts

Follow-up &

ProspectiveCommittee

≈

Health

regional agencies

ARS