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Transcript of Towards an End to HCV Epidemic in Egypt Prof. Gamal Esmat Prof. Hepatology &Vice President of Cairo...
Towards an End to HCV Epidemic in Egypt
Prof. Gamal EsmatProf. Hepatology &Vice President of Cairo University, Egypt
Member of WHO Strategic Committee for Viral Hepatitiswww.gamalesmat.com
Global Prevalence of Hepatitis C
HCV burden in Egypt
Guerra et al., J Viral Hepatitis, 2011 Breban et al., J Viral Hepatitis, 2012
HCV Ab prevalence:14.7%
Overall HCV viremia:9.94%
8 million Ch HCV Estimated 150 000 new infections per year
HCV prevalence in 15-59 years old, DHS Egypt, 2008 (n=11,126)
Liver diseases related mortality in Egypt
Age and gender distribution of anti-HCV prevalence, Egypt ,2008
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
HC
V P
reva
len
ce
Males (2008) Females (2008)
Chris Estes, unpublished data
Annual mortality due to liver related and background cause, 2013-2030
-
20,000
40,000
60,000
80,000
100,000
120,000
140,000
160,000
180,000
Mo
rtal
ity
Background Mortality Liver Related Mortality
Chris Estes, unpublished data
Expanded graph of viremic cases by disease stage for cirrhosis, decompensated cirrhosis, and hepatocellular carcinoma, 1950-2030.
-
1,000,000
2,000,000
3,000,000
4,000,000
5,000,000
6,000,000
7,000,000
-
500,000
1,000,000
1,500,000
2,000,000
2,500,000
3,000,000
3,500,000
Total
Virem
ic Ca
ses
Virem
ic Case
s (by
Disea
se Sta
ge)
F0 F1 F2
F3 Cirrhosis Decomp Cirrhosis
HCC Total Viremic
-
100,000
200,000
300,000
400,000
500,000
600,000
700,000
Virem
ic Case
s (by
Disea
se Sta
ge)
Cirrhosis Decomp Cirrhosis HCC
Chris Estes, unpublished data
SUDAN
EGYPT
Upper Egypt19.4%
(95% CI: 17.2-21.6)
Middle Egypt26.5%
(95% CI: 23.7-29.4)
Alexandria 5.9% (95% CI: 4.2-7.7)
Lower Egypt28.4%
(95% CI: 27.1-29.2)
Cairo8.2% (95% CI: 6.7-9.8)
LIBYA Red
Sea
Geographic HCV prevalence National Survey 1996
Frank et al., (2000)
Genotype 4Genotype 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 2008Arab 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 1National 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
Total Women Men0
2
4
6
8
10
12
14
16
18 15
12
17
9
7
11
HCV antibody HCV RNA
Prevalence of Hepatitis C by Age in Egypt 2009
15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-590
5
10
15
20
25
30
35
40
45
4 5 6
1214
23
29
3940
3 3 3
78
1317
23 25
HCV antibody HCV RNA
15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-590
10
20
30
40
50
60
10.4 10.7
19.3
30.3
42.4 39.9 40.0 43.933.6
5.5 4.48
13.1 14.3
24.6
35
49.3
43.5
Men 1996 Men 2008
HCV Prevalence National Surveys 1996 vs 2008 Men 15-60 Ys
15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-590
5
10
15
20
25
30
35
40
9.79.6
16.5
25.128.1
29.4 28.3
26.9
30.3
2.7
5.5 4.6
10.2
13.3
21.223.6
27.1
35
Women 1966 Women 2008
HCV Prevalence National Surveys 1996 vs 2008 Women 15-60 Ys
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 nation-wide, 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
Patients’ Gender
Mean (SD)
40 (10) Age
27 (4) BMI
Ministry of Health, EgyptMinistry of Health, Egypt
National Committee for Control of Viral Hepatitis
Patients’ Age and BMI
National HCV Treatment Program
Method of Payment
Governmental support
88%
Health Insurance
1%
Cash11%
Ministry of Health, EgyptMinistry of Health, Egypt
National Committee for Control of Viral Hepatitis
National HCV Treatment Program
Response Rates of treated patients
0102030405060708090
EVR Week 24 respone
ETR SVR
88.5
6862
54
Perc
ent
Ministry of Health, EgyptMinistry of Health, Egypt
National Committee for Control of Viral Hepatitis
National HCV Treatment Program
PositiveGovernmental 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 Managementwww.gamalesmat.com
DAA, direct-acting antiviral; IFN, interferon; RBV, ribavirin; SVR, sustained virologic response1. 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/
Evolution of HCV therapy
0
20
40
60
80
100
SV
R2
4 (
%)
6%
13–19%
38–43%
54–63%
67–79%*
IFN 24 wk(daily)
IFN 48 wk3 times/wk
IFN/RBV24 wk
IFNα/RBV48 wk
IFNα/RBV48 wk
pIFNα/RBV48 wk
pIFNα/RBV + 1st gen DAA
24 wk
31–35%
45–47%
1992 2001–20111 20122
PegIFN alfa + RBV represents a significant
improvement over previous IFN-based
regimens
PegIFN alfa + RBV represents a
significant improvement over
previous IFN-based regimens
* in patients with HCV genotype 1
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?
0
20
40
60
80
100
SV
R2
4 (
%)
IFN 24 wk(daily)
IFN 48 wk3 times/wk
IFN/RBV24 wk
IFNα/RBV48 wk
IFNα/RBV48 wk
pIFNα/RBV48 wk
?
?
1992 2001–20111 20122 2013 Beyond?
? ?pIFNα/RBV + 1st gen DAA
24 wk
• 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 .
Protease inhibitors (FDA approval in 2011)
Evolution of HCV Treatment
Better understanding of therapeutic targets
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/hcv-treatment/bi-207127. 17. http://www.pipelinereport.org/browse/hcv-treatment/abt-072. 18. http://clinicaltrials.gov/show/NCT01193361. 19. http://www.vrtx.com/research-development/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].
NS3/4A NS5A NS5BA serine protease, essential for post-translational processing of HCV polyproteins
Multifunctional membrane-associated phosphoprotein, essential component of the HCV-RNA replication complex
An HCV-specific, RNA-dependent RNA polymerase
Boceprevir1
Telaprevir1
ABT-450/r2
Sovaprevir3
Asunaprevir11
Simeprevir9
Faldaprevir12
Danoprevir12
GS-945113
MK-517214
ACH-806/GS-91321
Daclatasvir4
Ledipasvir4
ABT-2672
PPI-6686
AZ-6894
BMS-8243934
PPI-4614
Nucleos(t)ide analogueSofosbuvir10
Mericitabine15
VX-13520
Non-nucleoside analogueBI-20712716 ABT-3332
ABT-07217
BMS-79132518
Tegobuvir12
Setrobuvir12
VX-22219
Filibuvir12
Several potential innovative drug targets in HCV
*On clinical hold, Novartis press release
IFN-lambdaA type III interferon with a restricted distribution of receptors contributing to a favourable adverse event profile7
BMS-9141438
Cyclophilin AHost protein involved in HCV replication through interaction with NS5A and the HCV polymerase
Alisporivir5,*SCY-6351
c
E1 E2
NS5A NS5BNS3NS2
Many studies have looked at different ways of combining these compounds
This slide represents just a small selection of studies and regimens in current clinical development – other combinations are therefore possible
In different patient types• Different genotypes
• Treatment-naive
• Null-responders to prior therapy
• Intolerant to previous therapy
NS5B(nuc inhibitor)RBV
Alfa RBV
NS5A
NS5A
NS3/4A
RBV
Alfa
NS3/4A
NS5ANS3/4A
NS5B
(non-nuc
inhibitor)
Lambda
RBV
NS3/4ALambda
RBV
Lambda
RBV
NS5A
NS5A
AlfaRBV
NS3/4A
Alfa, peginterferon alfa-2a; lambda, peginterferon lambda-1a; RBV, ribavirin
IFN/RBV-containing regimens
Overall F30
20
40
60
80
100
83 79
6572
SV
R2
4 (
%)
PILLAR and ASPIRE: Efficacy of simeprevir and alfa/RBV
NS3/4A
alfa RBV
GT1, treatment-naive or experienced
TRIPLE: Simeprevir (TMC-435) + alfa/RBV for 12, 24 or 48 weeks
Overall F3 F40
20
40
60
80
100
73
48
62
23
8
PILLAR: treatment-naive ASPIRE: treatment-experienced
14/29
24/39
145/99
15/66 1/13 0/10
Metavir score Metavir score
Poordad F, et al. AASLD 2012, abstract 83.
130/156
15/19
50/77 5/7
• Total alfa/RBV duration was response guided (24 or 48 weeks) in PILLAR, or 48 weeks in ASPIRE
Simeprevir
Control (alfa/RBV)
n/N
0
20
40
60
80
100
6559
78
676458
87
100
36 3831
50
GT 4
Pat
ient
s w
ith r
espo
nse,
%
DCV 20 mg + alfa/RBV
Placebo+ alfa/RBV
DCV 60 mg+ alfa/RBV
n =95/147 94/146 26/72 63/106 66/113 21/56 32/41 27/31 5/16 8/12 12/12 3/6
GT 1a GT 1bGT 1*GT 1 Subtype**
DCV, daclatasvir*As randomised; ** Randomised patients with GT1a or GT1b subtypeHézode C, et al. AASLD 2012, abstract 755.
NS5A
COMMAND-1: Daclatasvir efficacy (SVR12) in different patient subtypes
GT1 or GT4, treatment-naive
TRIPLE: Daclatasvir + alfa/RBV for 24 weeks
alfa RBV
NEUTRINO: Efficacy of sofosbuvir + alfa/RBV
Gilead Press Release Feb 4. 2013. Available at http://www.gilead.com/news/press-releases/2013/2/gilead-announces-sustained-virologic-response-rates-from-two-phase-3-studies-of-sofosbuvir-for-hepatitis-c
Treatment regimen: sofosbuvir (400 mg QD) + alfa (180 µg/week) + RBV (1000–1200 mg/day) 12 weeks
• 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
alfa RBV
GT1, 4, 5, 6, treatment-naive
TRIPLE: Sofosbuvir (400 mg QD) + alfa/RBVNS5B
Overall GT1 GT4, 5 and 6
Cirrhotic0
20
40
60
80
10090 89
97
80
SV
R1
2 (
%)
295/327n/N
IFN-free regimens in development
0
20
40
60
80
100 96 93
67
10096 93
67
100
SVR
SVR4 SVR8
Pa
tien
ts (
%)
COSMOS: Efficacy of simeprevir and sofosbuvir
GT1, null-responders
TRIPLE: Sofosbuvir and simeprevir ± RBV for 12 or 24 weeks
RBV
NS5B
Lawitz E, et al. CROI 2013, oral 155LB.
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
0
20
40
60
80
100
85
57
82
67
RVR
Pa
tien
ts (
%)
12 weeks 24 weeks
NS3/4A
SMVSOFRBV
SMVSOF
SMVSOFRBV
SMVSOF
SMVSOFRBV
SMVSOF
SMVSOFRBV
SMVSOF
12 weeks 24 weeks
Efficacy in Aviator (M11-652)
Kowdley KV, et al. AASLD 2012, abstract LB-1.
NS3/4A NS5A
RBVNS5B
GT1, treatment-naive or prior null responders to alfa/RBV
ABT-450/r + ABT-333 + ABT-267 +/- RBV for either 8 or 12 weeks
ABT-450 ABT-450 ABT-450 ABT-450 ABT-4500
20
40
60
80
10088 85
90 87
98Treatment-naive
SV
R1
2 (
ITT
), %
ABT-450 ABT-4500
20
40
60
80
10089
93
Null responders
SV
R12
(IT
T),
%
ABT-267 ABT-267 ABT-267 ABT-267 ABT-267 ABT-267ABT-333 ABT-333 ABT-333 ABT-333 ABT-333 RBV RBV RBV RBV RBV RBV
8 weeks 12 weeks 12 weeks
n = 80 41 79 79 79 45 45
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.
49
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
Treatment-naive and Peginterferon/RBV-
experienced patients with chronic HCV GT4 infection
were enrolled. Treatment-naive patients received
ABT-450/r (150/100mg QD) + ABT-267 (25mg QD) ±
weight-based RBV for 12 weeks. Experienced
patients received the RBV-containing regimen for 12
weeks.
EASL 2014 Ab 58
ALL-ORAL THERAPY WITH DACLATASVIR IN COMBINATIONWITH ASUNAPREVIR AND BMS-791325 FOR TREATMENT
NAÏVE PATIENTS WITH CHRONIC HCV 4 INFECTION
Methods: Treatment-naive, HCV GT4-infected patients were
randomly assigned (1:1) to receive a twice-daily regimen of
DCV 30 mg, ASV 200 mg, and ’325 75mg (n = 11) or 150mg
(n = 10) for 12 weeks.
Results:
All patients completed 12 weeks of therapy. HCVRNA was
undetectable in 21/21 (100%) patients at the end of
treatment.
SVR12 was achieved by 10/11 patients in the ’325 75mg
group and 9/10 patients in the ’325 150mg group.
There were no serious adverse events (AEs), grade 3/4 AEs,
or grade 3/4 liver-related lab abnormalities.
The most frequent AEs were headache (29%), insomnia
(19%), nausea (14%), and pain (14%).
EASL 2014 Ab 1164
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.
61
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
0
5
10
15
20
25
30
35
40
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 EgyptOvercoming barriers
Annual mortality assumed at: 50/100,000 Or 5/1000 for HCV positive patients
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
•Mass treatment
Quantifying Epidemic Severity in EgyptR0 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..
72
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 EGYPTfrom 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.
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www.gamalesmat.com
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Gamal Esmat