Presentation on theme: "Towards an End to HCV Epidemic in Egypt"— Presentation transcript:
1 Towards an End to HCV Epidemic in Egypt New Treatment for HCV G4Towards an End to HCV Epidemic in EgyptNow let us move on to talk about the epidemiology of hepatitis C.
2 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].
3 Characteristics of DAA PI 1st generationPI 2nd generationNS5A Inh. 1st generationNS5A Inh. 2nd generationNS5Bnucleos(t)ide inh.NS5B non nucleos(t)ide inh.EfficacyResistance profilePangenotypic efficacyAdverse eventsDrug-drug interactionGood profileAverage profileLeast favorable profileSchinazi, et al. Liver Int 2014;34 Suppl 1:69-78
4 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
5 Sofo+RBV Response Duration Regimen Patients Study SVR 24 Non cirrhotic: 90%Wight based RBV: 68%Low dose RBV: 48%12 weeksA: 10 non cirrhoticB: 50 All stages of fibrosis:25 (weight based RBV)25 (low dose RBV: 600)No: 60treatment-naive patientsgenotype 1with bad predictors: (African-American, high BMI, low frequency ofIL28B CC, viral load and advanced fibrosis)Sofosbuvir and Ribavirin for Hepatitis C Genotype 1 in Patients With Unfavorable Treatment CharacteristicsOsinusi (2013)JAMA12 weeks SVR %24 weeks SVR %:Or 24 weeksSofosbuvir + RBV60 patientsEgyptiansG4Treatment naive and -experiencedSofosbuvir plus ribavirin in the treatment of chronic HCV genotype 4 infection in Egyptian patientsRuane (2013)Hepatology12 weeks SVR %24 weeks SVR %G patientsEgyptian study
6 Sofo+IFN+RBV Response Duration Regimen Patients Study SVR 24 A: 89% C: 87%12 w24 weeks24 weeks (12 +12)A (N:52): sofosbuvir +P+RB (N: 109, with 11 of them genotype 4): sofosbuvir +P+RC (N: 155): 12 weeks of sofosbuvir +P+R followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir +R316 naïvegenotype-1ATOMICSofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentrephase 2 trialKowdley et al (2013)LancetTotal 90% (295/327)G1a 92% (206/225)G1b 82% (54/66)G4 96% (27/28)G5/6 100% (7/7)Cirrhosis 80% (43/54)12 weeksSofosbuvir + PegIFN+ RBVG1, 4, 5, 6Naïven = 327(G1 79%)NEUTRINOSofosbuvir for previously untreated chronic hepatitis C infectionLawitz (2013)NEJM
7 Sofo and other DAA combination trials StudyPatientsRegimenDurationResponseElectron (1)Once daily sofosbuvir/ledipasvir fixed dose combination with or without ribavirinG1prior null responders with compensated cirrhosisand in naive, noncirrhotic patientsSofosbuvir+ ledipasvirWith or without RBV12 weeksCirrhotic TTT failure:With RBV: 100% SVR12Without RBV: 70% SVR 12Non cirrhotic naïve:6 weeks ttt: 68% SVR 128 weeks ttt; 100% SVR 12LONESTAR (2)Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomized, phase 2 trialG 1treatment-naive, noncirrhotic8 weeks8 weeks with RBV: 100%8 weeks without RBV: 95%12 without RBV: 95%COSMOS (3)SVR results of a oncedailyregimen of simeprevir (TM435) plus sofosbuvir (GS-7977) with of without ribavirin in cirrhotic and noncirrhotic HCV genotype 1 treatment naıve and prior null responder patientsNoncirrhotic and cirrhotic,treatment-naıve and prior null responderSofosbuvir+simeprevirwith or without RBVfor 12 or24 weeksSVR12 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.Gane (2013), Hepatology 2) Lawitz (2013), Lance, 3) Jacobson (2013), Hepatology
8 Treatment experienced SOF + RBV: In genotype 4This study done on 60 Egyptians (G4) living in USA20% of them are cirrhotics.SVR12 (%)11/1414/1410/1713/1521/3127/2912 Week SOF + RBV24 Week SOF + RBV12 Week SOF + RBV24 Week SOF + RBV12 Week SOF + RBV24 Week SOF + RBVTreatment naïveTreatment experiencedAllRuane PJ, et al. EASL P1243Ruane PJ, et al. EASL P1243Ruane PJ, et al. AASLD Abstract 1090
9 Sofosbuvir+ Ribavirin in G4 (Egypt) 100 patients (20% C, 3 centers)Arm 1 (12 wks)Arm 2 (24 wks)(Esmat, et al AASLD.2014)
10 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)
11 0= naïve, Fibrosis <F3, viremial<600,000 IU 1= treatment experienced, and/or fibrosis ≥F3, viremial >600,000 IU
12 SOF STUDIES EGYPTIAN 1. Lawitz et al. DDW 2013. 2. Ruane et al. EAS L2014. Poster 1242.3. Esmat et al,AASLD. 2014EGYPTIAN
13 Non invasive detection of hepatic fibrosis Fib-4 Formula
14 Non invasive detection of hepatic fibrosis Fibroscan
15 Non invasive diagnosis of Advanced hepatic fibrosis(>F2) AUCNo of patientsBest cutoffsensitivityspecificityPPVNPVaccuracyLR+LR-*Fib-40.71368411.450.690.630.280.901.90.49♠Fibroscan0.822319.50.870.680.930.866.520.20Fib-4Fibroscan>1.45≤1.45Wait or Do liver biopsyDo not treat≤9.5Treat>9.5*National Committee for control of viral hepatitis, NNTC data , Jan 2014♠ Esmat et al, Arab Journal of Gastroenterology 14 (2013) 109–112
16 PEARL 1 INTERFERON-FREE REGIMENS OF ABT-450/R + ABT-267 WITH OR WITHOUT RIBAVIRIN In 135 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.Hezode EASL 2014 Ab 58
19 ABT-450/r + Ombitasvir +RBV*4 Current and future regimens containing the new DAAs for genotype 4 patientsPhase IIIPhase IIbNaiveNaiveExperiencedNaiveExperiencedNaiveExperiencedNaiveExperiencedNaive100100ExperiencedNo data forDCV/PRSVR (%)27/2811/1410/1714/1413/1529/3542/4237/3712/1212/1241/72SOF/PR1 NEUTRINOSOF/RBV212 wkSOF/RBV224 wkSMV/PR*3 RESTOREABT-450/r + Ombitasvir +RBV*4PEARL-I(SVR4 only in experienced)DCV 60 mg/PR*5 COMMAND-11. Lawitz et al. DDW 2013.2. Ruane et al. EAS L2014. Poster 1242.3. Moreno et al. EASL Poster 1319.4.Hézode et al.EASL2014.4. Hézode et al. AASLD Poster 755.
20 EASL Guidelines: Treatment of HCV GT 4 infection Treatment OptionsRecommendation status: RegimenComments by authorsOption 1B1: PR + SOF 12 wks„appears the most efficacious and the easiest to use “Evaluated in TN Neutrino SVR 96% 27/28No data in TEOption 2B1: 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)TN: SVR 89% 31/35Prior Relapsers: SVR 86% 19/22Non Responders 57% 41/72Option 3B1: PR + DAC 60mg 24 wksB2: 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)Theoretically effective, few data available SVR 100% in 12/12 COMMAND 1 trialOption 4IFN intolerant or ineligibleC2:R + SOF 24 wks„only preliminary data is available in Egyptian pts“TN 12 wks treatment: SVR 79% 11/14TN 24 wks treatment: SVR 100% 14/14TE 12 wks treatment: SVR 59% 10/17TE 24 wks treatment: SVR 93% 14/15Option 5B2: SOF+SMV 12 wksConsider adding RBV in patients with predictors of poor response or in pts with cirrhosis„no data with this combination- it is likely that data from Cosmos can be extrapolated“Option 6B2: SOF +DAC (60mg) 12 wks TN or 24wks TE„no data with this combination- it is likely that data can be extrapolated“
23 Eradication of HCV in Egypt Overcoming the Barriers
24 Annual mortality assumed at: 50/100,000 Or 5/1000 for HCV positive patients
25 Annual mortality assumed at: 50/100,000 Or 5/1000 for HCV positive patients
26 Overcome the BarriersIdeal drugDecrease incidenceMass treatment
27 Ideal DrugIt is important for patients treatment but more important for control and eradication of any infectious disease
28 Decrease incidence Blood safety. Avoid unneeded injection. Auto destructive syringes.Infection control.Media awareness.Case detection and treatment by Ideal drug
29 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 patientsDecrease incidence by prioritize treatment to most frequent injectorsJ.viral hepatitis,2014
31 Priority for treatment will be directed towards patients with F3 and F4. No differentiation in treatment priority will be established based on the previous treatment experience.
32 Assessment of fibrosis stage will be performed by using a combination of both Fibroscan results and FIB 4 score. F3-4 stage will be considered if both Fibroscan result is more than 9.5 and FIB4 score is more than If both results are below these cut-off values, patient will not be assigned as a treatment priority . If one of these two methods is above the cut-off value while the other is below, performing liver biopsy or re-assessment after one year is recommended to rule out the fibrosis stage of the patient.
33 Upper GI endoscopy is mandatory in the following circumstances: a. Histological evidence of cirrhosis by liver biopsyb. Fibroscan > 19.2 K.Pac. Platelet count < 100,000
34 Patients who are eligible to receive Interferon (according to the currently used inclusion/exclusion criteria for combined IFN/RBV treatment)will be treated with daily Sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly PEG for 12 weeks.Recommended regimen for patients who are not eligible to receive IFN is daily Sofosbuvir (400 mg) plus weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 24 weeks
35 Otherwise, waiting for new DAAs combination is advised. Inclusion criteria for treatment will be expanded to adapt for more advanced liver fibrosis patients (who will be treated with Interferon free regimen) as defined with the presence of one or more of the following;Child score up to 8Total bilirubin ≤ 3Albumin ≥ 2.5Platelet count ≥ 50,000Prtothrombin concentration ≥ 50%Hemoglobin concentration ≥ 10 mgOtherwise, waiting for new DAAs combination is advised.
36 Patients with more decompensated liver disease will be excluded from treatment until enough data will be available and this will be applied to:Child C patients with scores ≥ 9Presence of ascites (except after control)Patients with HCC except after successful radical curative intervention (4 months after resection or successful local ablation) evident by triphasic CT.Presence of large risky esophageal varices (except after prophylactic management)
37 Age limits for treatment legibility will be above 18 years and below 70 years for all patients while BMI will be accepted up to 35.The same rules will be applied for all patients regardless the source of payment and there will be no role for patients' preferences in deciding the treatment regimen.
38 For special population groups; priority for treatment will be offered for post liver transplantation, post kidney transplantation patients and combined HCV/HBV infection regardless the fibrosis stage. Other groups like Pediatric age group and kidney disease patients will be kept for discussion after the availability of enough data.
39 Patients with documented extra-hepatic manifestations will be prioritized for treatment according to the same guidelines.Treatment experienced patients should not start evaluation for new treatment regimens except after 6 months from cessation of interferon therapy.