The Egyptian Plan to Cure HCV Gamal Esmat Professor of Endemic Medicine & Hepatology Vice President of Cairo University for Graduate Studies and Research
Disclosure Advisory Committee Board Member : MSD, Gilead Sc., BMS. Speaking & Teaching Activities: BMS, Roche,MSD,GSK Grants and Research Support: Gilead Sc., Roche, MSD, GSK, BMS,Abbvie, Janssen.
Natural History HCV Spontaneous Cure Acute Hepatitis 25-40% Chronic Hepatitis 60-75 % Liver Cirrhosis in 5 % under the age of 40 and 20 % after 40 (after 20 years of infection) HCC IN 1.6 % Annually Decompensation in 4 % Annually
Epidemiology Country Egypt Cameroon Gabon Nigeria Saudi Arabia Lebanon Syria Southern Spain Southwestern France Southern India Germany Northern Italy Southern Italy HCV genotype 4 prevalence % 91 % 76 % 71 % 60 % 60 % 30 % 30 % 14 % 7.4 % 6.2 % 3.6 % 3.1 % 1.4 % Wantuck et al., Aliment Pharmacol Ther 2014
HCV Prevalence Age and gender distribution of anti-hcv prevalence, Egypt,2008 60.0% 50.0% 40.0% 30.0% 20.0% 10.0% 0.0% Males (2008) Females (2008) Chris Estes, unpublished data
Mortality Annual mortality due to liver related and background cause, 2013-2030 180,000 160,000 140,000 120,000 100,000 80,000 60,000 40,000 20,000 - Background Mortality Liver Related Mortality Chris Estes, unpublished data
Total Viremic Cases Viremic Cases (by Disease Stage) Expanded graph of viremic cases by disease stage for cirrhosis, decompensated cirrhosis, and hepatocellular carcinoma, 1950-2030. 700,000 600,000 500,000 400,000 300,000 200,000 100,000 - Cirrhosis Decomp Cirrhosis HCC Chris Estes, unpublished data
Egyptian Strategy for HCV Control
Ministry of Health, Egypt National Committee for Control of Viral Hepatitis(NCCVH) 26 Treatment centers covering all the governorates. Total no of patients treated with PEG-IFN (2006-2014): 350,000 No. of new patients annually now is: 45,000
Percent Ministry of Health, Egypt National Committee for Control of Viral Hepatitis National HCV Treatment Program Response Rates of treated patients with Peg/RBV 90 80 70 60 50 40 30 20 10 0 88.5 68 62 54 EVR Week 24 respone ETR SVR
Several potential innovative drug targets in HCV c E1 E2 NS2 NS3 NS5A NS5B IFN-lambda A type III interferon with a restricted distribution of receptors contributing to a favourable adverse event profile 7 NS3/4A NS5A NS5B A serine protease, essential for posttranslational processing of HCV polyproteins Boceprevir 1 Telaprevir 1 ABT-450/r 2 Sovaprevir 3 Asunaprevir 11 Simeprevir 9 Faldaprevir 12 Danoprevir 12 GS-9451 13 MK-5172 14 ACH-806/GS-9132 1 Multifunctional membraneassociated phosphoprotein, essential component of the HCV-RNA replication complex Daclatasvir 4 Ledipasvir 4 ABT-267 2 PPI-668 6 AZ-689 4 BMS-824393 4 PPI-461 4 An HCV-specific, RNA-dependent RNA polymerase Nucleos(t)ide analogue Sofosbuvir 10 Mericitabine 15 VX-135 20 Non-nucleoside analogue BI-207127 16 ABT-333 2 ABT-072 17 BMS-791325 18 Tegobuvir 12 Setrobuvir 12 VX-222 19 Filibuvir 12 BMS-914143 8 Cyclophilin A Host protein involved in HCV replication through interaction with NS5A and the HCV polymerase Alisporivir 5, * SCY-635 1 *On clinical hold, Novartis press release 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/hcvtreatment/bi-207127. 17. http://www.pipelinereport.org/browse/hcv-treatment/abt-072. 18. http://clinicaltrials.gov/show/nct01193361. 19. http://www.vrtx.com/researchdevelopment/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].
Approved molecules acting on HCV G4 Egypt MOH Registration ongoing Drug Name ABT-267; ABT450/r (Viekira-2D) Drug Category NS5A Inhibitor; Protease Inhibitor Company AbbVie ongoing Registered Registered Daclatasvir (BMS-790052) (Daklinza) Sofosbuvir (GS-7977) (Sovaldi) Simeprevir (TMC435) (Olysio) NS5A Inhibitor Polymerase Inhibitor Protease Inhibitor BMS Gilead Janssen
Characteristics of DAA DAA PI 1 st generation PI 2 nd generation NS5A Inh. 1 s t generation NS5A Inh. 2 nd generation NS5B nucleos(t)ide inh. NS5B non nucleos(t)ide inh. Efficacy Resistance profile Pangenotypic efficacy Adverse events Drug-drug interaction Good profile Average profile Least favorable profile Schinazi, et al. Liver Int 2014;34 Suppl 1:69-78
Many studies have looked at different ways of combining these compounds Alfa NS5A RBV In different patient types Different genotypes Treatment-naive Null-responders to prior therapy Intolerant to previous therapy 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
Sofo+RBV Study Patients Regimen Duration Response Sofosbuvir and Ribavirin for Hepatitis C Genotype 1 in Patients With Unfavorable Treatment Characteristics Osinusi (2013) JAMA Sofosbuvir plus ribavirin in the treatment of chronic HCV genotype 4 infection in Egyptian patients Ruane (2013) Hepatology Egyptian study No: 60 treatment-naive patients genotype 1 with bad predictors: (African-American, high BMI, low frequency of IL28B CC, viral load and advanced fibrosis) 60 patients Egyptians G4 Treatment naive and - experienced G4 100 patients Treatment naive and - experienced A: 10 non cirrhotic B: 50 All stages of fibrosis: 25 (weight based RBV) 25 (low dose RBV: 600) Sofosbuvir + RBV Sofosbuvir + RBV 12 weeks 12 weeks Or 24 weeks 12 weeks Or 24 weeks SVR 24 Non cirrhotic: 90% Wight based RBV: 68% Low dose RBV: 48% 12 weeks SVR12 68% 24 weeks SVR12 93%: 12 weeks SVR12 77% 24 weeks SVR12 90%
Sofo+IFN+RBV Study Patients Regimen Duration Response ATOMIC Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an openlabel, randomised, multicentre phase 2 trial Kowdley et al (2013) Lancet 316 naïve genotype-1 A (N:52): sofosbuvir +P+R B (N: 109, with 11 of them genotype 4): sofosbuvir +P+R C (N: 155): 12 weeks of sofosbuvir +P+R followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir +R 12 w 24 weeks 24 weeks (12 +12) SVR 24 A: 89% B: 89% C: 87% NEUTRINO Sofosbuvir for previously untreated chronic hepatitis C infection Lawitz (2013) NEJM G1, 4, 5, 6 Naïve n = 327 (G1 79%) Sofosbuvir + PegIFN + RBV 12 weeks Total 90% (295/327) G1a 92% (206/225) G1b 82% (54/66) G4 96% (27/28) G5/6 100% (7/7) Cirrhosis 80% (43/54)
Sofo and other DAA combination trials Response Duration Regimen Patients Study Cirrhotic TTT failure: With RBV: 100% SVR12 Without RBV: 70% SVR 12 Non cirrhotic naïve: 6 weeks ttt: 68% SVR 12 8 weeks ttt; 100% SVR 12 8 weeks with RBV: 100% 8 weeks without RBV: 95% 12 without RBV: 95% SVR12 in prior null responders with F0-F2 fibrosis were 93% (in both 12 and 24 weeks). In cirrhotics: SVR 4: 100% (in both null responders and naïve) 24 weeks. 12 weeks 8 weeks for 12 or 24 weeks Sofosbuvir+ ledipasvir With or without RBV Sofosbuvir+ ledipasvir With or without RBV Sofosbuvir+simeprevir with or without RBV G1 prior null responders with compensated cirrhosis and in naive, noncirrhotic patients G 1 treatment-naive, noncirrhotic G1 Noncirrhotic and cirrhotic, treatment-naıve and prior null responder Electron (1) Once daily sofosbuvir/ledipasvir fixed dose combination with or without ribavirin LONESTAR (2) Sofosbuvir and ledipasvir fixeddose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an openlabel, randomized, phase 2 trial COSMOS (3) SVR results of a oncedaily regimen of simeprevir (TM435) plus sofosbuvir (GS-7977) with of without ribavirin in cirrhotic and noncirrhotic HCV genotype 1 treatment naıve and prior null responder patients 1) Gane (2013), Hepatology 2) Lawitz (2013), Lance, 3) Jacobson (2013), Hepatology
SVR12 (%) SOF + RBV: In genotype 4 This study done on 60 Egyptians (G4) living in USA 20% of them are cirrhotics. 21/31 27/29 11/14 14/14 10/17 13/15 12 Week SOF + RBV All 24 Week SOF + RBV Ruane PJ, et al. EASL 2014. P1243 Ruane PJ, et al. AASLD 2013. Abstract 1090 12 Week SOF + RBV Treatment naïve 24 Week SOF + RBV 12 Week SOF + RBV 24 Week SOF + RBV Treatment experienced Ruane PJ, et al. EASL 2014. P1243
Sofosbuvir+ Ribavirin in G4 (Egypt) Naïve %84 Arm 1 (12 wks) Overall %77 Exper %70 100 patients (20% C, 3 centers) Naïve %92 Arm 2 (24 wks) Overall %90 Exper %89 (Esmat, et al AASLD.2014)
In 51 patients GT4, received SOF + RBV for 12 weeks, SVR in 39 (77%) Pts who were treatment naïve, Fibrosis stage<f3, and baseline viremia <600,000 IU were 9 pts. All showed SVR (100%) Pts who were either treatment experienced, and/or fibrosis stage >F2 and viremia level >600,000 IU showed SVR (71%) (12 pts of whom 8 were treatment experienced) P value 0.01 (S)
0= naïve, Fibrosis <F3, viremial<600,000 IU 1= treatment experienced, and/or fibrosis F3, viremial >600,000 IU
SVR 12 % SOF STUDIES 100 90 80 70 60 50 40 30 20 10 0 96 100 92 87 89 84 79 70 59 OVERALL NAÏVE TE NAÏVE TE NAÏVE TE NAÏVE TE NEUTRINO1 SOF/PR WK2 12 SOF/RBV WK2 24SOF/RBV W12SOF/RBV WK24SOF/RBV 1. Lawitz et al. DDW 2013. 2. Ruane et al. EAS L2014. Poster 1242. 3. Esmat et al,aasld. 2014 EGYPTIAN
SVR (%) Current and future regimens containing the new DAAs for genotype 4 patients Phase III Phase IIb Naive Naive Experienced Naive Experienced Naive Experienced Naive Experienced Naive 100 100 Experienced No data for DCV/PR 27/28 11/14 10/17 14/14 13/15 29/35 41/72 42/42 37/37 12/12 SOF/PR 1 NEUTRINO SOF/RBV 2 12 wk 1. Lawitz et al. DDW 2013. 2. Ruane et al. EAS L2014. Poster 1242. 3. Moreno et al. EASL 2014. Poster 1319. 4.Hézode et al.easl2014. 4. Hézode et al. AASLD 2012. Poster 755. SOF/RBV 2 24 wk SMV/PR* 3 RESTORE ABT-450/r + Ombitasvir +RBV* 4 PEARL-I (SVR4 only in experienced) DCV 60 mg/pr* 5 COMMAND-1
EASL Guidelines: Treatment of HCV GT 4 infection Treatment Options Recommendation status: Regimen Comments by authors Option 1 B1: PR + SOF 12 wks appears the most efficacious and the easiest to use Evaluated in TN Neutrino SVR 96% 27/28 No data in TE Option 2 Option 3 Option 4 IFN intolerant or ineligible Option 5 Option 6 B1: PR+ SMV 12 wks + additional PR for either 12 or 36 wks (12 wks SMV + PR; 24 wks total duration for TN & relapsers including cirrhosis and 48 wks for Prior partials and nulls including those with cirrhosis) B1: PR + DAC 60mg 24 wks B2: 12 wks TT + additional PR for either 12 or 36 wks: (24 wks total duration for TN & relapsers including cirrhosis and 48 wks for Prior partials and nulls including those with cirrhosis) C2:R + SOF 24 wks B2: SOF+SMV 12 wks Consider adding RBV in patients with predictors of poor response or in pts with cirrhosis B2: SOF +DAC (60mg) 12 wks TN or 24wks TE Consider adding RBV in patients with predictors of poor TN: SVR 89% 31/35 Prior Relapsers: SVR 86% 19/22 Non Responders 57% 41/72 Theoretically effective, few data available SVR 100% in 12/12 COMMAND 1 trial only preliminary data is available in Egyptian pts TN 12 wks treatment: SVR 79% 11/14 TN 24 wks treatment: SVR 100% 14/14 TE 12 wks treatment: SVR 59% 10/17 TE 24 wks treatment: SVR 93% 14/15 no data with this combination- it is likely that data from Cosmos can be extrapolated no data with this combination- it is likely that data can be extrapolated
Eradication of HCV in Egypt Overcoming the Barriers
Number of Patients with Hepatitis C in Egypt Current Incidence (2.5/1000) 16,000,000 12,000,000 8,000,000 4,000,000 0 2038 2039 2040 2041 2042 2043 2044 2045 2046 2047 2048 2049 2050 2051 2052 2053 2054 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033 2034 2035 2036 2037 Current therapy 50% Efficacy, 50,000/yr Current therapy 50% Efficacy, 100,000/yr DAA, 90% Efficacy, 250,000/yr Annual mortality assumed at: 50/100,000 Or 5/1000 for HCV positive patients
Number of Patients with Hepatitis C in Egypt 90% Reduction in Incidence (0.25/1000) 16,000,000 12,000,000 8,000,000 4,000,000 0 2038 2039 2040 2041 2042 2043 2044 2045 2046 2047 2048 2049 2050 2051 2052 2053 2054 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033 2034 2035 2036 2037 Current therapy 50% Efficacy, 50,000/yr Current therapy 50% Efficacy, 100,000/yr DAA, 90% Efficacy, 250,000/yr Annual mortality assumed at: 50/100,000 Or 5/1000 for HCV positive patients
Overcome the Barriers Ideal drug Decrease incidence Mass treatment
Ideal Drug It is important for patients treatment but more important for control and eradication of any infectious disease
Decrease incidence Blood safety. Avoid unneeded injection. Auto destructive syringes. Infection control. Media awareness. Case detection and treatment by Ideal drug
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 250.000 to 300.000 patients Decrease incidence by prioritize treatment to most frequent injectors J.viral hepatitis,2014
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