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Towards an End to HCV Epidemic in Egypt Prof. Gamal Esmat Prof. Hepatology &Vice President of Cairo University, Egypt Member of WHO Strategic Committee.

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Presentation on theme: "Towards an End to HCV Epidemic in Egypt Prof. Gamal Esmat Prof. Hepatology &Vice President of Cairo University, Egypt Member of WHO Strategic Committee."— Presentation transcript:

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3 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

4 Global Prevalence of Hepatitis C

5 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 new infections per year HCV prevalence in years old, DHS Egypt, 2008 (n=11,126)

6 Liver diseases related mortality in Egypt

7 Age and gender distribution of anti-HCV prevalence, Egypt,2008 Chris Estes, unpublished data

8 Annual mortality due to liver related and background cause, Chris Estes, unpublished data

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of viremic cases by disease stage for cirrhosis, decompensated cirrhosis, and hepatocellular carcinoma, Chris Estes, unpublished data

10 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: ) LIBYALIBYA Red Sea Geographic HCV prevalence National Survey 1996 Frank et al., (2000)

11 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:

12 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

13 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  Expand access to treatment to within 100 km for all Egyptians and Treat 20% of persons needing treatment by 2012 under subsidized schemes

14 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

15 National HCV survey Egypt 2008 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

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

17 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.

18 Prevalence of Hepatitis C, Egypt 2008

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22 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

23 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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25 Opening of 23 national treatment centres, 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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27 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

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

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

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

31 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.

32 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.

33 New Era in HCV 4 Management

34 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. Evolution of HCV therapy 6% 13–19% 38–43% 54–63% 67–79%* IFN 24 wk (daily) IFN 48 wk 3 times/wk IFN/RBV 24 wk IFNα/RBV 48 wk pIFNα/RBV 48 wk pIFNα/RBV + 1st gen DAA 24 wk 31–35% 45–47% – PegIFN alfa + RBV represents a significant improvement over previous IFN-based regimens * in patients with HCV genotype 1

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

36 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)

37 Evolution of HCV Treatment

38 Better understanding of therapeutic targets

39 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 treatment/bi development/pipeline [Accessed April 10, 2013]. NS3/4ANS5ANS5B 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 Boceprevir 1 Telaprevir 1 ABT-450/r 2 Sovaprevir 3 Asunaprevir 11 Simeprevir 9 Faldaprevir 12 Danoprevir 12 GS MK ACH-806/GS Daclatasvir 4 Ledipasvir 4 ABT PPI AZ BMS PPI Nucleos(t)ide analogue Sofosbuvir 10 Mericitabine 15 VX Non-nucleoside analogue BI ABT ABT BMS Tegobuvir 12 Setrobuvir 12 VX Filibuvir 12 Several potential innovative drug targets in HCV *On clinical hold, Novartis press release IFN-lambda A type III interferon with a restricted distribution of receptors contributing to a favourable adverse event profile 7 BMS Cyclophilin A Host protein involved in HCV replication through interaction with NS5A and the HCV polymerase Alisporivir 5, * SCY c E1 E2 NS5A NS5B NS3 NS2

40 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 NS3/4A RBV Alfa NS3/4A NS5A NS3/4A NS5B (non-nuc inhibitor) Lambda RBV NS3/4A Lambda RBV Lambda RBV NS5A Alfa RBV NS3/4A Alfa, peginterferon alfa-2a; lambda, peginterferon lambda-1a; RBV, ribavirin

41 IFN/RBV-containing regimens

42 PILLAR and ASPIRE: Efficacy of simeprevir and alfa/RBV NS3/4A alfaRBV GT1, treatment-naive or experienced TRIPLE: Simeprevir (TMC-435) + alfa/RBV for 12, 24 or 48 weeks PILLAR: treatment-naiveASPIRE: treatment-experienced 14/ 29 24/ / 99 15/ 66 1/13 0/10 Metavir score Poordad F, et al. AASLD 2012, abstract / / 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

43 GT 4 Patients with response, % DCV 20 mg + alfa/RBV Placebo + alfa/RBV DCV 60 mg + alfa/RBV n =95/147 94/146 26/72 63/106 66/11321/5632/4127/315/168/1212/123/6 GT 1aGT 1b GT 1* GT 1 Subtype** DCV, daclatasvir *As randomised; ** Randomised patients with GT1a or GT1b subtype Hézode C, et al. AASLD 2012, abstract 755. NS5A COMMAND-1: Daclatasvir efficacy (SVR 12 ) in different patient subtypes GT1 or GT4, treatment-naive TRIPLE: Daclatasvir + alfa/RBV for 24 weeks alfaRBV

44 NEUTRINO: Efficacy of sofosbuvir + alfa/RBV Gilead Press Release Feb Available at 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 alfaRBV GT1, 4, 5, 6, treatment-naive TRIPLE: Sofosbuvir (400 mg QD) + alfa/RBV NS5B 295/327 n/N

45 IFN-free regimens in development

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47 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 12 weeks24 weeks NS3/4A SMV SOF RBV SMV SOF SMV SOF RBV SMV SOF SMV SOF RBV SMV SOF SMV SOF RBV SMV SOF 12 weeks24 weeks

48 Efficacy in Aviator (M11-652) Kowdley KV, et al. AASLD 2012, abstract LB-1. NS3/4A NS5A RBV NS5B GT1, treatment-naive or prior null responders to alfa/RBV ABT-450/r + ABT ABT-267 +/- RBV for either 8 or 12 weeks ABT-267 ABT-267 ABT-267 ABT-333 ABT-333 ABT-333 RBV RBV RBV 8 weeks12 weeks n =

49 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

50 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

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

52 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).

53 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.

54 PEARL 1 INTERFERON-FREE REGIMENS OF ABT-450/R + ABT-267 WITH OR WITHOUT RIBAVIRIN In Ch HCV GENOTYPE 4 Patients

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57 ALL-ORAL THERAPY WITH DACLATASVIR IN COMBINATION WITH ASUNAPREVIR AND BMS FOR TREATMENT NAÏVE PATIENTS WITH CHRONIC HCV 4 INFECTION

58 Results:

59 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

60 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??

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62 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. 61

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

64 Eradication of Schistosomiasis A success story in EGYPT By 2014

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

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67 Prevalence of schistosomiasis in Egypt:

68 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.

69 Eradication of HCV in Egypt Overcoming barriers

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

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

73 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.. 72

74 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.

75 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.

76 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

77 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

78 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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