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2 Towards an End to HCV Epidemic in Egypt Prof. Gamal Esmat
Now let us move on to talk about the epidemiology of hepatitis C. Prof. Gamal Esmat Prof. Hepatology &Vice President of Cairo University, Egypt Member of WHO Strategic Committee for Viral Hepatitis

3 Global Prevalence of Hepatitis C

4 HCV burden in Egypt HCV prevalence in years old, DHS Egypt, 2008 (n=11,126) HCV Ab prevalence: 14.7% Overall HCV viremia: 9.94% 8 million Ch HCV Estimated new infections per year Guerra et al., J Viral Hepatitis, 2011 Breban et al., J Viral Hepatitis, 2012

5 Liver diseases related mortality in Egypt

6 Age and gender distribution of anti-HCV prevalence, Egypt ,2008
Chris Estes, unpublished data

7 Annual mortality due to liver related and background cause, 2013-2030
Chris Estes, unpublished data

8 Expanded graph of viremic cases by disease stage for cirrhosis, decompensated cirrhosis, and hepatocellular carcinoma, Chris Estes, unpublished data

9 Geographic HCV prevalence
National Survey 1996 SUDAN EGYPT Upper Egypt 19.4% (95% CI: ) Middle Egypt 26.5% (95% CI: ) Alexandria 5.9% (95% CI: ) Lower Egypt 28.4% (95% CI: ) Cairo 8.2% (95% CI: ) LIBYA Red Sea Frank et al., (2000)

10 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: Angelico et al, J Hepatol 1997; 26: 10

11 National Committee for the Control of Viral Hepatitis
Egyptian National Control Strategy for Viral Hepatitis April 2008 Arab Republic of Egypt, Ministry of Health and Population National Committee for the Control of Viral Hepatitis

12 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 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

13 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

14 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

15 Self-reported prevalence of HCV infection
(Egypt Demographic and Health Survey 2008)

16 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.

17 Prevalence of Hepatitis C, Egypt 2008

18 Prevalence of Hepatitis C by Age in Egypt 2009

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21 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

22 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)

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24 Opening of 23 national treatment centres, 2007-2013
Total number of patients treated with PEG-IFN ( ): 350,000 Annual number of new patients treated: 45,000 Annual budget from the Ministry of Health: 90 million $

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26 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

27 Patients’ Gender Patients’ Age and BMI Ministry of Health, Egypt
National Committee for Control of Viral Hepatitis National HCV Treatment Program Patients’ Gender Patients’ Age and BMI Mean (SD) 40 (10) Age 27 (4) BMI

28 Method of Payment Ministry of Health, Egypt Ministry of Health, Egypt
National Committee for Control of Viral Hepatitis National HCV Treatment Program Method of Payment

29 Response Rates of treated patients
Ministry of Health, Egypt Ministry of Health, Egypt National Committee for Control of Viral Hepatitis National HCV Treatment Program Response Rates of treated patients

30 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 >90% governmental funding SVR >55% Data for > patients to answer a lot of questions.

31 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.

32 New Era in HCV 4 Management
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33 Evolution of HCV therapy
PegIFN alfa + RBV represents a significant improvement over previous IFN-based regimens Manns p1351 fig 1 67–79%* 54–63% 45–47% 38–43% 31–35% 13–19% 6% IFN 24 wk (daily) IFN 48 wk 3 times/wk IFN/RBV 24 wk IFNα/RBV 48 wk IFNα/RBV 48 wk pIFNα/RBV 48 wk pIFNα/RBV + 1st gen DAA 24 wk 1992 2001–20111 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– Tran TT. Am J Manag Care 2012;18(14 Suppl):S340–9. 33

34 But what does the future hold?
Manns p1351 fig 1 ? ? IFN 24 wk (daily) IFN 48 wk 3 times/wk IFN/RBV 24 wk IFNα/RBV 48 wk IFNα/RBV 48 wk pIFNα/RBV 48 wk pIFNα/RBV + 1st gen DAA 24 wk ? ? 1992 2001–20111 20122 Beyond? 1. Adapted from Manns MP, et al. Gut 2006;55:1350– Tran TT. Am J Manag Care 2012;18(14 Suppl):S340–9. 34

35 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 .

36 Evolution of HCV Treatment

37 Better understanding of therapeutic targets

38 Several potential innovative drug targets in HCV
IFN-lambda A type III interferon with a restricted distribution of receptors contributing to a favourable adverse event profile7 BMS Cyclophilin A Host protein involved in HCV replication through interaction with NS5A and the HCV polymerase Alisporivir5,* SCY-6351 c NS2 NS3 NS5A NS5B E1 E2 NS3/4A NS5A NS5B A 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 MK ACH-806/GS-91321 Daclatasvir4 Ledipasvir4 ABT-2672 PPI-6686 AZ-6894 BMS PPI-4614 Nucleos(t)ide analogue Sofosbuvir10 Mericitabine15 VX-13520 Non-nucleoside analogue BI ABT-3332 ABT-07217 BMS Tegobuvir12 Setrobuvir12 VX-22219 Filibuvir12 *On clinical hold, Novartis press release 1. Rehman S, et al. Genet Vaccines Ther 2011;9: Gish R & Meanwell NA. Clin Liver Dis 2011;15:627– Coelmont L, et al. PLoS One 2010;5:e Miller DM, et al. Ann N Y Acad Sci 2009;1182: Poordad F, et al. AASLD 2012, abstract Gane E, et al. EASL 2012, poster Delang L, et al. Viruses 2010;2:826– ct2/show/NCT Wedemeyer H, et al. Hepatology 2013 January 24. [Epub ahead of print]. doi: /hep [Accessed April 10, 2013].

39 In different patient types
Many studies have looked at different ways of combining these compounds Alfa RBV NS5A In different patient types NS5A Alfa RBV NS3/4A Different genotypes Treatment-naive Null-responders to prior therapy Intolerant to previous therapy RBV Alfa NS3/4A Lambda RBV Lambda RBV NS5A NS5A NS3/4A NS5B (non-nuc inhibitor) NS5B (nuc inhibitor) RBV NS5A NS3/4A NS3/4A Lambda RBV 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

40 IFN/RBV-containing regimens

41 PILLAR and ASPIRE: Efficacy of simeprevir and alfa/RBV
GT1, treatment-naive or experienced NS3/4A TRIPLE: Simeprevir (TMC-435) + alfa/RBV for 12, 24 or 48 weeks PILLAR and ASPIRE: Efficacy of simeprevir and alfa/RBV alfa RBV PILLAR: treatment-naive ASPIRE: treatment-experienced Simeprevir Control (alfa/RBV) 14/29 24/39 130/156 50/77 15/ 19 145/99 15/66 n/N 5/7 1/13 0/10 Metavir score 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.

42 Patients with response, %
GT1 or GT4, treatment-naive NS5A TRIPLE: Daclatasvir + alfa/RBV for 24 weeks COMMAND-1: Daclatasvir efficacy (SVR12) in different patient subtypes alfa RBV DCV 20 mg + alfa/RBV Placebo + alfa/RBV DCV 60 mg Patients with response, % GT 1* GT 1a GT 1b GT 4 GT 1 Subtype** 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 DCV, daclatasvir *As randomised; ** Randomised patients with GT1a or GT1b subtype Hézode C, et al. AASLD 2012, abstract 755.

43 NEUTRINO: Efficacy of sofosbuvir + alfa/RBV
GT1, 4, 5, 6, treatment-naive NS5B NEUTRINO: Efficacy of sofosbuvir + alfa/RBV TRIPLE: Sofosbuvir (400 mg QD) + alfa/RBV alfa RBV n/N 295/327 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 Available at announces-sustained-virologic-response-rates-from-two-phase-3-studies-of-sofosbuvir-for-hepatitis-c

44 IFN-free regimens in development

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46 COSMOS: Efficacy of simeprevir and sofosbuvir
GT1, null-responders NS3/4A NS5B TRIPLE: Sofosbuvir and simeprevir ± RBV for 12 or 24 weeks COSMOS: Efficacy of simeprevir and sofosbuvir RBV SMV SOF RBV SMV SOF SMV SOF RBV SMV SOF SMV SOF RBV SMV SOF SMV SOF RBV SMV SOF 12 weeks 24 weeks 12 weeks 24 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.

47 Efficacy in Aviator (M11-652)
GT1, treatment-naive or prior null responders to alfa/RBV NS3/4A NS5A ABT-450/r + ABT ABT-267 +/- RBV for either 8 or 12 weeks Efficacy in Aviator (M11-652) NS5B RBV n = ABT ABT ABT ABT-267 ABT ABT-267 ABT ABT ABT ABT-333 ABT-333 RBV RBV RBV RBV RBV RBV 8 weeks 12 weeks 12 weeks Kowdley KV, et al. AASLD 2012, abstract LB-1.

48 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 % SVR 12 for Experienced 60% In 24 weeks Arm SVR 12 for Naive % SVR 12 for Experienced 93% Ruane et al AASLD 2013

49 Sofosbuvir+ Ribavirin in G4(Egypt)
100 Ch. HCV patients (20 % cirrhotics) in 3 centers. Arm weeks SVR % Arm weeks SVR %. SVR 12 will be available at the end of this month.

50 Sofosbuvir/Ledipasvir Coformulation Cures 95% of Genotype 1 Hepatitis C
February 8, 2014, edition of The Lancet.

51 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).

52 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.

53 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

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56 ALL-ORAL THERAPY WITH DACLATASVIR IN COMBINATION WITH ASUNAPREVIR AND BMS 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.

57 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 ’ mg 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 Ab 1164

58 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

59 The Proof of Concept INF free DAA About 100% efficacy All oral
IFN-free Short duration No resistance Pan-genotypic Well tolerated and safe Affordable??

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61 Egyptian MOH Agreement with Gilead
The course for 3 months will cost 900 $ instead of $ 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.

62 Ideal Drug It is important for patients treatment but more important for control and eradication of any infectious disease

63 Eradication of Schistosomiasis
A success story in EGYPT By 2014

64 In 1980,an estimated 10% of the 200 millions persons infected with Schistomiasis were Egyptians

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66 Prevalence of schistosomiasis in Egypt: 1935-2003
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67 Schistosomal Eradication is expected in Egypt in 2014 due to:
Health education. Availability of Praziquantel (Ideal Drug) in the rural health units. Annual examination and treatment of school children. Mass treatment in the villages with prevalence > 20%. Snail control.

68 Eradication of HCV in Egypt Overcoming barriers

69 Annual mortality assumed at: 50/100,000 Or 5/1000 for HCV positive patients

70 Annual mortality assumed at: 50/100,000 Or 5/1000 for HCV positive patients

71 Deacreae incidence Blood safety. Avoid unneeded injection.
Auto destructive syringes. Infection control. Media awareness. Case detection and treatment by Ideal drug Mass treatment

72 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 ). The treat early strategy would be more effective because it reduces transmission by timely treatment and decreases incidence..

73 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.

74 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.

75 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 to patients Prioritize treatment to most frequent injectors

76 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

77 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.

78 please visit www.gamalesmat.com You can see this presentation and more
78

79 Gamal Esmat


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