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 EsmatProf. Hepatology &Vice President of Cairo University, EgyptMember of WHO Strategic Committee for Viral Hepatitis
4 HCV burden in EgyptHCV prevalence in years old, DHS Egypt, 2008 (n=11,126)HCV Ab prevalence:14.7%Overall HCV viremia:9.94%8 million Ch HCVEstimated new infections per yearGuerra et al., J Viral Hepatitis, 2011Breban et al., J Viral Hepatitis, 2012
10 Genotype 4Genotype 4 predominates throughout the Middle East and parts of Africa, often in association with a high population prevalence as in EgyptMore than 90% of Egyptian HCV isolates belong to genotype 4Phylogenetic analysis of the complete genomic sequence of genotype 4 revealed a closer relationship between genotype 4 and genotype 1 than with other genotypesHabib 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 HepatitisApril 2008Arab Republic of Egypt, Ministry of Health and PopulationNational 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 researchInstitutionalize the National Committee on Viral Hepatitis and the viral hepatitis control program within the Egyptian governmental structureEnsure programmatic sustainabilityImplement 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.
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 programAwareness campaigns to enhance knowledge of modes of transmission and methods of prevention among the general populationImproved 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 centersReductions in the price of drugs, and expanded subsidization of antiviral therapyAttaining optimal clinical management of all patients, (including pediatric patients and persons suffering from advanced liver disease)
24 Opening of 23 national treatment centres, 2007-2013 Total number of patients treated with PEG-IFN ( ): 350,000Annual number of new patients treated: 45,000Annual budget from the Ministry of Health: 90 million $
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 HepatitisNational HCV Treatment ProgramPatients’ GenderPatients’ Age and BMIMean (SD)40 (10)Age27 (4)BMI
28 Method of Payment Ministry of Health, Egypt Ministry of Health, Egypt National Committee for Control of Viral HepatitisNational HCV Treatment ProgramMethod of Payment
29 Response Rates of treated patients Ministry of Health, EgyptMinistry of Health, EgyptNational Committee for Control of Viral HepatitisNational HCV Treatment ProgramResponse Rates of treated patients
30 PositiveGovernmental appreciation of the magnitude of HCV problem in EgyptNational guidelines for treatment of chronic HCVMOHP and universities cooperation.Different specialties cooperationWorking in a teamStarting treatment for more than>90% governmental fundingSVR >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.
33 Evolution of HCV therapy PegIFN alfa + RBV represents a significant improvement over previous IFN-based regimensManns p1351 fig 167–79%*54–63%45–47%38–43%31–35%13–19%6%IFN 24 wk (daily)IFN 48 wk 3 times/wkIFN/RBV 24 wkIFNα/RBV 48 wkIFNα/RBV 48 wkpIFNα/RBV 48 wkpIFNα/RBV + 1st gen DAA 24 wk19922001–2011120122* in patients with HCV genotype 1DAA, 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/wkIFN/RBV 24 wkIFNα/RBV 48 wkIFNα/RBV 48 wkpIFNα/RBV 48 wkpIFNα/RBV + 1st gen DAA 24 wk??19922001–2011120122Beyond?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 (telaprevirand 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 .
38 Several potential innovative drug targets in HCV IFN-lambdaA type III interferon with a restricted distribution of receptors contributing to a favourable adverse event profile7BMSCyclophilin AHost protein involved in HCV replication through interaction with NS5A and the HCV polymeraseAlisporivir5,*SCY-6351cNS2NS3NS5ANS5BE1E2NS3/4ANS5ANS5BA serine protease, essential for post-translational processing of HCV polyproteinsMultifunctional membrane- associated phosphoprotein, essential component of the HCV-RNA replication complexAn HCV-specific, RNA-dependent RNA polymeraseBoceprevir1Telaprevir1ABT-450/r2Sovaprevir3Asunaprevir11Simeprevir9Faldaprevir12Danoprevir12GSMKACH-806/GS-91321Daclatasvir4Ledipasvir4 ABT-2672PPI-6686AZ-6894BMSPPI-4614Nucleos(t)ide analogueSofosbuvir10Mericitabine15VX-13520Non-nucleoside analogueBIABT-3332ABT-07217BMSTegobuvir12Setrobuvir12VX-22219Filibuvir12*On clinical hold, Novartis press release1. 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 compoundsAlfaRBVNS5AIn different patient typesNS5AAlfaRBVNS3/4ADifferent genotypesTreatment-naiveNull-responders to prior therapyIntolerant to previous therapyRBVAlfaNS3/4ALambdaRBVLambdaRBVNS5ANS5ANS3/4ANS5B(non-nuc inhibitor)NS5B(nuc inhibitor)RBVNS5ANS3/4ANS3/4ALambdaRBVAlfa, peginterferon alfa-2a; lambda, peginterferon lambda-1a; RBV, ribavirinThis slide represents just a small selection of studies and regimens in current clinical development – other combinations are therefore possible
41 PILLAR and ASPIRE: Efficacy of simeprevir and alfa/RBV GT1, treatment-naive or experiencedNS3/4ATRIPLE: Simeprevir (TMC-435) + alfa/RBV for 12, 24 or 48 weeksPILLAR and ASPIRE: Efficacy of simeprevir and alfa/RBValfaRBVPILLAR: treatment-naiveASPIRE: treatment-experiencedSimeprevirControl (alfa/RBV)14/2924/39130/15650/7715/19145/9915/66n/N5/71/130/10Metavir scoreMetavir scoreTotal alfa/RBV duration was response guided (24 or 48 weeks) in PILLAR, or 48 weeks in ASPIREPoordad F, et al. AASLD 2012, abstract 83.
42 Patients with response, % GT1 or GT4, treatment-naiveNS5ATRIPLE: Daclatasvir + alfa/RBV for 24 weeksCOMMAND-1: Daclatasvir efficacy (SVR12) in different patient subtypesalfaRBVDCV 20 mg + alfa/RBVPlacebo+ alfa/RBVDCV 60 mgPatients with response, %GT 1*GT 1aGT 1bGT 4GT 1 Subtype**n =95/14794/14626/7263/10666/11321/5632/4127/315/168/1212/123/6DCV, daclatasvir*As randomised; ** Randomised patients with GT1a or GT1b subtypeHézode C, et al. AASLD 2012, abstract 755.
43 NEUTRINO: Efficacy of sofosbuvir + alfa/RBV GT1, 4, 5, 6, treatment-naiveNS5BNEUTRINO: Efficacy of sofosbuvir + alfa/RBVTRIPLE: Sofosbuvir (400 mg QD) + alfa/RBValfaRBVn/N295/32717% of patients compensated cirrhosis, 89% GT1 and 35 patients were GT4, 5 & 6Relapse accounted for the virologic failuresSVR = 60% in predefined historic controls (p < 0.001)2% discontinued treatment due to AEsTreatment regimen: sofosbuvir (400 mg QD) + alfa (180 µg/week) + RBV (1000–1200 mg/day) 12 weeksGilead Press Release Feb Available at announces-sustained-virologic-response-rates-from-two-phase-3-studies-of-sofosbuvir-for-hepatitis-c
46 COSMOS: Efficacy of simeprevir and sofosbuvir GT1, null-respondersNS3/4ANS5BTRIPLE: Sofosbuvir and simeprevir ± RBV for 12 or 24 weeksCOSMOS: Efficacy of simeprevir and sofosbuvirRBVSMVSOFRBVSMVSOFSMVSOFRBVSMVSOFSMVSOFRBVSMVSOFSMVSOFRBVSMVSOF12 weeks24 weeks12 weeks24 weeksRVR is based on patients with available data at week 4 (2 patients discontinued before week 4)RVR, rapid virological response; SMV, simeprevir; SOF, sofosbuvirLawitz E, et al. CROI 2013, oral 155LB.
47 Efficacy in Aviator (M11-652) GT1, treatment-naive or prior null responders to alfa/RBVNS3/4ANS5AABT-450/r + ABT ABT-267 +/- RBV for either 8 or 12 weeksEfficacy in Aviator (M11-652)NS5BRBVn =ABT ABT ABT ABT-267ABT ABT-267ABT ABT ABT ABT-333ABT-333RBV RBV RBV RBVRBV RBV8 weeks12 weeks12 weeksKowdley KV, et al. AASLD 2012, abstract LB-1.
48 Sofosbuvir+ Ribavirin in G4 In study done on 70 Egyptians (G4) living in USA20% of them are cirrhotics.In 12 weeks ArmSVR 12 for Naive %SVR 12 for Experienced 60%In 24 weeks ArmSVR 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 DesignThis 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 ResultsIn 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 PatientsTreatment-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
56 ALL-ORAL THERAPY WITH DACLATASVIR IN COMBINATION WITH ASUNAPREVIR AND BMS FOR TREATMENT NAÏVE PATIENTS WITH CHRONIC HCV 4 INFECTIONMethods: 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 RibavirinEmerging 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-freeShort durationNo resistancePan-genotypicWell tolerated and safeAffordable??
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 DrugIt 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
66 Prevalence of schistosomiasis in Egypt: 1935-2003 66
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 drugMass treatment
72 Quantifying Epidemic Severity in Egypt R0 theory R0: the expected number of secondary cases that an infected individual causes in a fullysusceptible 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 RateThere 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 epidemicThere 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 injectionrates.Prioritizing access to treatment by injection rate maybe highly effective in curbing down the epidemic.
75 HCV in EGYPT from Control to Eradication To decrease HCV prevalence to< 2 % in Egyptin 10 years(Mathematical modeling)Effective treatment SVR > 90%Annual treatment of to patientsPrioritize treatment to most frequent injectors
76 SummaryA 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 careThe way forward lies in working togetherActive 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.
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