Transcript www.gamalesmat.com

Towards an End to HCV Epidemic in Egypt
Prof. Gamal Esmat
Prof. Hepatology &Vice President of Cairo University, Egypt
Member of WHO Strategic Committee for Viral Hepatitis
www.gamalesmat.com
Global Prevalence of Hepatitis C
HCV burden in Egypt
HCV prevalence in 15-59 years old, DHS Egypt, 2008
(n=11,126)
HCV Ab prevalence:
14.7%
Overall HCV viremia:
9.94%
8 million Ch HCV
 Estimated 150 000
new infections per year
Guerra et al., J Viral Hepatitis, 2011
Breban et al., J Viral Hepatitis, 2012
Liver diseases related mortality in Egypt
Age and gender distribution of anti-HCV
prevalence, Egypt ,2008
60.0%
HCV Prevalence
50.0%
40.0%
30.0%
20.0%
10.0%
0.0%
Males (2008)
Females (2008)
Chris Estes, unpublished data
Annual mortality due to liver related and
background cause, 2013-2030
180,000
160,000
Mortality
140,000
120,000
100,000
80,000
60,000
40,000
20,000
-
Background Mortality
Liver Related Mortality
Chris Estes, unpublished data
Viremic Cases (by Disease Stage)
Total Viremic Cases
Expanded graph of viremic cases by disease stage for
cirrhosis, decompensated cirrhosis, and hepatocellular
carcinoma, 1950-2030.
700,000
600,000
500,000
400,000
300,000
200,000
100,000
-
Cirrhosis
Decomp Cirrhosis
HCC
Chris Estes, unpublished data
Geographic HCV prevalence
National Survey 1996
Alexandria 5.9%
(95% CI: 4.2-7.7)
Cairo
8.2% (95% CI: 6.7-9.8)
L
I
B
Y
A
Lower Egypt
28.4%
(95% CI: 27.1-29.2)
Middle Egypt
26.5%
(95% CI: 23.7-29.4)
Upper Egypt
19.4%
(95% CI: 17.2-21.6)
EGYPT
SUDAN
Red
Sea
Genotype 4
Genotype 4 predominates throughout the
Middle East and parts of Africa, often in
association with a high population prevalence
as in Egypt
More than 90% of Egyptian HCV isolates
belong to genotype 4
Phylogenetic analysis of the complete genomic
sequence of genotype 4 revealed a closer
relationship between genotype 4 and genotype
1 than with other genotypes
Habib et al, Hepatology 2001; 33: 248-253
Angelico et al, J Hepatol 1997; 26: 236-43
Egyptian National Control Strategy for
Viral Hepatitis
2008-2012
April 2008
Arab Republic of Egypt, Ministry of Health and Population
National Committee for the Control of Viral Hepatitis
The main goals of the National
Control Strategy
 Accurately track prevalence and incidence of
HBV and HCV.
 Reduce the prevalence of chronic HBV and
HCV infection in the 15-30 age group by 20% of
2008 levels by 2012.
 Expand access to treatment to within 100 km for
all Egyptians and Treat 20% of persons needing
treatment by 2012 under subsidized schemes
The main goals of the National
Control Strategy( cont.)
 Continue to produce high-quality scientific
research
 Institutionalize the National Committee on
Viral Hepatitis and the viral hepatitis control
program within the Egyptian governmental
structure
 Ensure programmatic sustainability
 Implement effective monitoring & evaluation
to ensure good use of funds
Priority area 1
National HCV survey
Egypt 2008
Population-level surveys to ascertain
national prevalence rates that can be
broken down by age, sex, and region
Self-reported prevalence of HCV
infection
www.measuredhs.com (Egypt Demographic and Health Survey 2008)
Hepatitis C testing
 Household survey in 28 governorates.
 Total of 12,780 women and men aged 15 – 59
consented to blood sampling.
 ELISA test used to determine presence of antibodies.
 Real time PCR testing for HCV RNA for all antibody
positive samples to detect active infections.
Prevalence of Hepatitis C, Egypt 2008
17
18
16
15
14
12
12
10
11
8
9
6
7
4
2
0
Total
Women
HCV antibody
Men
HCV RNA
45
40
39
40
35
29
30
23
23
25
25
17
20
14
15
12
10
4
6
5
13
8
7
5
0
3
15-19
3
20-24
3
25-29
30-34
35-39
HCV antibody
40-44
45-49
HCV RNA
50-54
55-59
60
HCV Prevalence National Surveys 1996 vs 2008
Men 15-60 Ys
Men 1996
Men 2008
49.3
50
42.4
40
30.3
39.9 40.0 43.9
35
43.5
33.6
30
24.6
19.3
20
10.4
10
13.1 14.3
10.7
5.5
4.4
15-19
20-24
8
0
25-29
30-34
35-39
40-44
45-49
50-54
55-59
HCV Prevalence National Surveys 1996 vs 2008
Women 15-60 Ys
40
35
35
Women 1966
Women 2008
29.4
30
28.1
25.1
28.3
23.6
25
27.1
30.3
26.9
21.2
20
16.5
13.3
15
10
9.7
9.6
5.5
5
10.2
4.6
2.7
0
15-19
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
Priority area 2: Prevention
 Enhanced infection control in MOHP and
other government hospitals and clinics,
(private and non-governmental facilities)
 Anti-HBV vaccination of high-risk groups and
full coverage rates under the childhood
vaccination program
 Awareness campaigns to enhance
knowledge of modes of transmission and
methods of prevention among the general
population
 Improved injection safety in non-medical
settings
Priority area 3: Patient
treatment
 Availability for Counseling and Management for
all HCV positive patients.
 Improved access to treatment, including the
opening of new treatment centers
 Reductions in the price of drugs, and expanded
subsidization of antiviral therapy
 Attaining optimal clinical management of all
patients, (including pediatric patients and persons
suffering from advanced liver disease)
Opening of 23 national treatment centres, 2007-2013
• Total number of patients treated with PEG-IFN (2007-2013): 350,000
• Annual number of new patients treated: 45,000
• Annual budget from the Ministry of Health: 90 million $
National Network for Treatment
Centers (NNTC)
A Network for all patients’ data from the
Viral Hepatitis Treatment Centers nationwide, was established with the main
server located in National Hepatology
Institute in Cairo.
When fully functioning, the NNTC will have
full data for pre-enrollment and treatment
of 300,000 HCV patients
Ministry
Ministryof
ofHealth,
Health, Egypt
Egypt
National Committee for Control of Viral
Hepatitis Program
National HCV Treatment
Patients’ Gender
Patients’ Age and BMI
Mean (SD)
Age
40 (10)
BMI
27 (4)
Ministry
Ministryof
ofHealth,
Health, Egypt
Egypt
National Committee for Control of Viral Hepatitis
National HCV Treatment Program
Method of Payment
Health
Insurance
1%
Cash
11%
Governmental
support
88%
Ministry of Health, Egypt
National Committee for Control of Viral Hepatitis
National HCV Treatment Program
Response Rates of treated patients
Percent
88.5
90
80
70
60
50
40
30
20
10
0
68
62
54
EVR
Week 24
respone
ETR
SVR
Positive
Governmental appreciation of the magnitude of HCV
problem in Egypt
National guidelines for treatment of chronic HCV
MOHP and universities cooperation.
Different specialties cooperation
Working in a team
Starting treatment for more than 300 000
>90% governmental funding
SVR >55%
Data for >300 000 patients to answer a lot of
questions.
HIO Treatment Program for HCV
Same guidelines as NCCVH.
Mostly by Reiferon Retard(biosimilar).
More than 25 centers.
About 8000 patients annually.
Better F/U and better availability of SVR.
Less research and less published data.
New Era in HCV 4 Management
www.gamalesmat.com
Evolution of HCV therapy
PegIFN alfa + RBV
represents a significant
improvement over
previous IFN-based
regimens
100
PegIFN alfa + RBV
represents a
significant
improvement over
previous IFN-based
regimens
SVR24 (%)
80
67–79%*
54–63%
60
38–43%
40
45–47%
31–35%
13–19%
20
6%
0
IFN 24 wk
(daily)
1992
IFN 48 wk
3 times/wk
IFN/RBV
24 wk
IFNα/RBV
48 wk
2001–20111
IFNα/RBV
48 wk
pIFNα/RBV pIFNα/RBV +
48 wk
1st gen DAA
24 wk
20122
* in patients with HCV genotype 1
DAA, direct-acting antiviral; IFN, interferon; RBV, ribavirin; SVR, sustained virologic response
1. Adapted from Manns MP, et al. Gut 2006;55:1350–59. 2. Tran TT. Am J Manag Care 2012;18(14 Suppl):S340–9.
http://www.metrolic.com/human-evolution-102891/
But what does the future hold?
?
100
?
SVR24 (%)
80
60
40
20
0
IFN 24 wk
(daily)
1992
IFN 48 wk
3 times/wk
IFN/RBV
24 wk
IFNα/RBV
48 wk
2001–20111
IFNα/RBV pIFNα/RBV pIFNα/RBV +
48 wk
48 wk
1st gen DAA
24 wk
20122
1. Adapted from Manns MP, et al. Gut 2006;55:1350–59. 2. Tran TT. Am J Manag Care 2012;18(14 Suppl):S340–9.
http://www.metrolic.com/human-evolution-102891/
?
?
2013
Beyond?
Protease inhibitors (FDA approval in 2011)
• These antiviral drugs have only been developed and
investigated for genotype-1 HCV.
• The first two HCV protease inhibitors (telaprevir
and boceprevir) were approved for genotype-1 HCV, in
some countries.
• Not pangenotypic, genotypes 1 and 2 being most
susceptible and genotypes 4 and 5 most resistant .
Evolution of HCV Treatment
Better understanding of therapeutic targets
Several potential innovative drug targets in HCV
NS2
c
E1
NS3/4A
A serine protease,
essential for posttranslational processing
of HCV polyproteins
Boceprevir1
Telaprevir1
ABT-450/r2
Sovaprevir3
Asunaprevir11
Simeprevir9
Faldaprevir12
Danoprevir12
GS-945113
MK-517214
ACH-806/GS-91321
NS3
NS5A NS5B
IFN-lambda
A type III interferon with a
restricted distribution of receptors
contributing to a favourable
adverse event profile7
E2
NS5A
NS5B
Multifunctional membraneAn HCV-specific, RNA-dependent
associated phosphoprotein,
RNA polymerase
essential component of the
HCV-RNA replication complex
Daclatasvir4
Nucleos(t)ide
Non-nucleoside
Ledipasvir4
analogue
analogue
2
10
ABT-267
Sofosbuvir
BI-20712716
PPI-6686
Mericitabine15
ABT-3332
4
20
AZ-689
VX-135
ABT-07217
BMS-8243934
BMS-79132518
PPI-4614
Tegobuvir12
Setrobuvir12
VX-22219
Filibuvir12
BMS-9141438
Cyclophilin A
Host protein involved in HCV
replication through interaction
with NS5A and the HCV
polymerase
Alisporivir5,*
SCY-6351
*On clinical hold, Novartis
press release
1. Rehman S, et al. Genet Vaccines Ther 2011;9:11. 2. http://clinicaltrials.gov/ct2/show/NCT01464827. 3. http://ir.achillion.com/releasedetail.cfm?releaseid=6989383. 4. Gish R
& Meanwell NA. Clin Liver Dis 2011;15:627–39. 5. Coelmont L, et al. PLoS One 2010;5:e13678. 6. http://clinicaltrials.gov/ct2/show/NCT01448200. 7. Miller DM, et al. Ann N Y
Acad Sci 2009;1182:807. 8. http://clinicaltrials.gov/show/NCT01309932. 9.Poordad F, et al. AASLD 2012, abstract 83. 10. Gane E, et al. EASL 2012, poster 1113.
11. http://clinicaltrials.gov/ct2/show/NCT01030432. 12 . Delang L, et al. Viruses 2010;2:826–66. 13. http://www.gilead.com/research. 14. http://clinicaltrials.gov/
ct2/show/NCT01353911. 15. Wedemeyer H, et al. Hepatology 2013 January 24. [Epub ahead of print]. doi: 10.1002/hep.26274. 16. http://www.pipelinereport.org/browse/hcvtreatment/bi-207127. 17. http://www.pipelinereport.org/browse/hcv-treatment/abt-072. 18. http://clinicaltrials.gov/show/NCT01193361. 19. http://www.vrtx.com/researchdevelopment/pipeline. 20. http://news.bms.com/press-release/financial-news/bristol-myers-squibbpresent-new-data-hepatitis-c-and-hepatitis-b-compo. [Accessed April 10, 2013].
Many studies have looked at different ways of
combining these compounds
NS5A
Alfa
RBV
In different patient
types
• Different genotypes
• Treatment-naive
• Null-responders to
prior therapy
• Intolerant to previous
therapy
Alfa, peginterferon alfa-2a; lambda, peginterferon lambda-1a; RBV, ribavirin
This slide represents just a small selection of studies and regimens in current clinical development – other combinations are therefore possible
IFN/RBV-containing regimens
GT1, treatment-naive or experienced
NS3/4A
TRIPLE: Simeprevir (TMC-435) + alfa/RBV for 12, 24 or 48 weeks
alfa
PILLAR and ASPIRE: Efficacy of simeprevir
and alfa/RBV
PILLAR: treatment-naive
100
79
80
SVR24 (%)
ASPIRE: treatment-experienced
100
83
65
72
80
Simeprevir
73
Control
(alfa/RBV)
62
60
60
40
48
40
23
20
0
20
130/
n/N 156
50/
77
Overall
•
15/
19
5/7
F3
Metavir score
0
145/
99
15/
66
Overall
14/
29
8
1/13
24/
39
0/10
F3
F4
Metavir score
Total alfa/RBV duration was response guided (24 or 48 weeks) in PILLAR, or
48 weeks in ASPIRE
Poordad F, et al. AASLD 2012, abstract 83.
RBV
GT1 or GT4, treatment-naive
NS5A
TRIPLE: Daclatasvir + alfa/RBV for 24 weeks
alfa
COMMAND-1: Daclatasvir efficacy (SVR12) in
different patient subtypes
Patients with response, %
100
DCV 20 mg
+ alfa/RBV
100
Placebo
+ alfa/RBV
DCV 60 mg
+ alfa/RBV
RBV
87
78
80
65
67
64
59
60
58
50
38
36
40
31
20
0
n=
GT 1*
95/147
94/146 26/72
GT 1a
GT 1b
GT 1 Subtype**
63/106 66/113 21/56
DCV, daclatasvir
*As randomised; ** Randomised patients with GT1a or GT1b subtype
Hézode C, et al. AASLD 2012, abstract 755.
32/41 27/31
GT 4
5/16
8/12
12/12
3/6
GT1, 4, 5, 6, treatment-naive
NS5B
TRIPLE: Sofosbuvir (400 mg QD) + alfa/RBV
alfa
NEUTRINO: Efficacy of sofosbuvir + alfa/RBV
100
90
89
97
80
SVR12 (%)
80
60
40
20
n/N 295/327
0
Overall
•
•
•
•
GT1
GT4, 5 and 6
Cirrhotic
17% of patients compensated cirrhosis, 89% GT1 and 35 patients were GT4, 5 & 6
Relapse accounted for the virologic failures
SVR = 60% in predefined historic controls (p < 0.001)
2% discontinued treatment due to AEs
Treatment regimen: sofosbuvir (400 mg QD) + alfa (180 µg/week) + RBV (1000–1200 mg/day) 12 weeks
Gilead Press Release Feb 4. 2013. Available at http://www.gilead.com/news/press-releases/2013/2/gileadannounces-sustained-virologic-response-rates-from-two-phase-3-studies-of-sofosbuvir-for-hepatitis-c
RBV
IFN-free regimens in
development
GT1, null-responders
NS5B
NS3/4A
TRIPLE: Sofosbuvir and simeprevir ± RBV for 12 or 24 weeks
RBV
COSMOS: Efficacy of simeprevir and sofosbuvir
RVR
SVR
100
SVR4
85
100
82
96 96
SVR8
100 100
93 93
80
67 67
57
60
80
Patients (%)
Patients (%)
67
40
60
40
20
20
0
0
SMV
SOF
RBV
SMV
SOF
12 weeks
SMV
SOF
RBV
SMV
SOF
24 weeks
SMV
SOF
RBV
12 weeks
RVR is based on patients with available data at week 4 (2 patients discontinued before week 4)
RVR, rapid virological response; SMV, simeprevir; SOF, sofosbuvir
Lawitz E, et al. CROI 2013, oral 155LB.
SMV
SOF
SMV
SOF
RBV
SMV
SOF
24 weeks
GT1, treatment-naive or prior null responders to alfa/RBV
NS3/4A
NS5A
NS5B
RBV
ABT-450/r + ABT-333 + ABT-267 +/- RBV for either 8 or 12 weeks
Efficacy in Aviator (M11-652)
Treatment-naive
Null responders
98
100
88
85
90
100
87
93
80
SVR12 (ITT), %
SVR12 (ITT), %
80
89
60
40
20
60
40
20
n = 80
41
79
79
79
0
45
45
0
ABT-450 ABT-450 ABT-450 ABT-450 ABT-450
ABT-267
ABT-267 ABT-267 ABT-267
ABT-333 ABT-333
ABT-333 ABT-333
RBV
RBV
RBV
RBV
8 weeks
Kowdley KV, et al. AASLD 2012, abstract LB-1.
12 weeks
ABT-450 ABT-450
ABT-267 ABT-267
ABT-333
RBV
RBV
12 weeks
Sofosbuvir+ Ribavirin in G4
• In study done on 70 Egyptians (G4) living in USA
20% of them are cirrhotics.
• In 12 weeks Arm
SVR 12 for Naive
80%
SVR 12 for Experienced 60%
• In 24 weeks Arm
SVR 12 for Naive
100%
SVR 12 for Experienced 93%
Ruane et al AASLD 2013
Sofosbuvir+ Ribavirin in G4(Egypt)
• 100 Ch. HCV patients (20 % cirrhotics) in 3 centers.
• Arm 1
12 weeks SVR 12 80%
• Arm 2 24 weeks SVR 4 94%.
SVR 12 will be available at the end of this month.
Sofosbuvir/Ledipasvir Coformulation
Cures 95% of Genotype 1 Hepatitis C
February 8, 2014, edition of The Lancet.
Study Design
• This open-label study enrolled 2 cohorts at a single
center in Texas.
• Cohort A included 60 treatment-naive individuals without
liver cirrhosis.
• Cohort B included 40 people, about half with cirrhosis,
who did not achieve a cure with pegylated interferon and
ribavirin plus one of the first-generation HCV protease
inhibitors, boceprevir (Victrelis) or telaprevir (Incivek).
Results
• In Cohort A, 95% of treatment-naive patients treated with
sofosbuvir/ledipasvir for 8 weeks and 95% taking the 2-drug
regimen for 12 weeks achieved SVR12.
• The SVR12 rate was 100% for participants taking
sofosbuvir/ledipasvir plus ribavirin for 8 weeks.
• In Cohort B, 95% of patients taking sofosbuvir/ledipasvir alone
and 100% taking sofosbuvir/ledipasvir plus ribavirin for 12 weeks
achieved SVR12.
• Two patients (1 treatment-naive and 1 treatment-experienced)
had post-treatment viral relapse, both of whom had HCV subtype
1a and were not taking ribavirin.
PEARL 1 INTERFERON-FREE REGIMENS
OF ABT-450/R + ABT-267 WITH OR WITHOUT
RIBAVIRIN
In Ch HCV GENOTYPE 4 Patients
ALL-ORAL THERAPY WITH DACLATASVIR IN COMBINATION
WITH ASUNAPREVIR AND BMS-791325 FOR TREATMENT
NAÏVE PATIENTS WITH CHRONIC HCV 4 INFECTION
Results:
Ribavirin
•Emerging data show that RBV continues
to have an important role in interferon-free
DAA regimens.
•When two agents with a low barrier to
resistance are combined, the addition of
RBV accelerates the HCV-RNA level
decline, delays selection of resistance and
results in a greater proportion of patients
achieving an RVR, as well as reducing the
incidence of relapse after therapy and
thereby improving SVR
INF free DAA
The Proof of Concept
• About 100% efficacy
• All oral
• IFN-free
• Short duration
• No resistance
• Pan-genotypic
• Well tolerated and safe
• Affordable??
Egyptian MOH Agreement with Gilead
•The course for 3 months will cost 900 $
instead of 84 000 $ in USA.
•Manufactured outside Egypt but with
different color and written on it(to be sold
only in Egypt ).
•Renewal of the agreement every year.
•Will be available after 3 months after (fast
track) registration in Egypt.
Ideal Drug
It is important for patients treatment
but more important for control and
eradication of any infectious
disease
Eradication of Schistosomiasis
A success story in EGYPT
By 2014
• In 1980,an estimated 10% of the 200 millions persons
infected with Schistomiasis were Egyptians
Prevalence of schistosomiasis
in Egypt: 1935-2003
%
40
35
30
25
20
15
10
5
0
1980
1985
1990
1995
2000
2005
Schistosomal Eradication is expected in
Egypt in 2014 due to:
1. Health education.
2. Availability of Praziquantel (Ideal Drug) in the
rural health units.
3. Annual examination and treatment of school
children.
4. Mass treatment in the villages with prevalence
> 20%.
5. Snail control.
Eradication of HCV in Egypt
Overcoming barriers
Number of Patients with Hepatitis C in Egypt
Current Incidence (2.5/1000)
16,000,000
12,000,000
8,000,000
4,000,000
2013
2014
2015
2016
2017
2018
2019
2020
2021
2022
2023
2024
2025
2026
2027
2028
2029
2030
2031
2032
2033
2034
2035
2036
2037
2038
2039
2040
2041
2042
2043
2044
2045
2046
2047
2048
2049
2050
2051
2052
2053
2054
0
Current therapy 50% Efficacy, 50,000/yr
DAA, 90% Efficacy, 250,000/yr
Current therapy 50% Efficacy, 100,000/yr
Annual mortality assumed at: 50/100,000 Or 5/1000 for HCV positive patients
Number of Patients with Hepatitis C in Egypt
90% Reduction in Incidence (0.25/1000)
16,000,000
12,000,000
8,000,000
4,000,000
2013
2014
2015
2016
2017
2018
2019
2020
2021
2022
2023
2024
2025
2026
2027
2028
2029
2030
2031
2032
2033
2034
2035
2036
2037
2038
2039
2040
2041
2042
2043
2044
2045
2046
2047
2048
2049
2050
2051
2052
2053
2054
0
Current therapy 50% Efficacy, 50,000/yr
DAA, 90% Efficacy, 250,000/yr
Current therapy 50% Efficacy, 100,000/yr
Annual mortality assumed at: 50/100,000 Or 5/1000 for HCV positive patients
Deacreae incidence
•Blood safety.
•Avoid unneeded injection.
•Auto destructive syringes.
•Infection control.
•Media awareness.
• Case detection and treatment by Ideal drug
Quantifying Epidemic Severity in Egypt
R0 theory
•R0: the expected number of secondary cases
that an infected individual causes in a fully
susceptible population during their entire
infectious period.
•R0 of the untreated HCV epidemic in the
Egyptian community is 3.50 (95% CI 2.95-4.03).
• The treat early strategy would be more effective
because it reduces transmission by timely
treatment and decreases incidence..
High Injection Rate
•There is high heterogeneity in health care
access in Egypt; 5% of the population takes
more than 50% of all injections (2008 DHS).
•The epidemic is maintained by <5% of the
population, consisting mostly of individuals with
high injection rates.
• Prioritizing access to treatment early and by
injection rate may be highly effective in
reducing incidence.
Egypt HCV epidemic
• There is high heterogeneity in health care access in
Egypt; 5% of the population takes more than 50% of
all injections (2008 DHS).
• The epidemic is maintained by <5% of the population,
consisting mostly of individuals with high injection
rates.
• Prioritizing access to treatment by injection rate may
be highly effective in curbing down the epidemic.
HCV in EGYPT
from Control to Eradication
To decrease HCV prevalence to< 2 % in Egypt
in 10 years(Mathematical modeling)
Effective treatment SVR > 90%
Annual treatment of 250.000 to 300.000 patients
Prioritize treatment to most frequent injectors
Summary
• A range of potent drugs are in development, in
different combinations, and each must be
matched to individual patient types to improve the
current standard of care
• The way forward lies in working together
• Active collaboration is required to achieve this
goal of individualised therapy tailored to the needs
of every patient
Conclusion
We are looking to say Goodbye Interferon
The ideal drug for treatment of HCV will be soon
within our reach.
( oral, short duration, SVR >90% , minimal side
effects and affordable)
• The ideal drug has an important role in prevention.
please visit
www.gamalesmat.com
You can see this presentation and more