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Chris Estes, unpublished data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Chris Estes, unpublished data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Chris Estes, unpublished data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.

please visit

www.gamalesmat.com

You can see this presentation and more

Gamal Esmat