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WHAT DID WE DO IN FRANCE ?
(and perspectives…)
Daniel Dhumeaux, Henri Mondor hospital
Créteil, France
[email protected] 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
[email protected] 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