Genotype 4, finally cured? Imam Waked Professor of Medicine National Liver Institute Paris, January 12, 215
Disclosures Investigator, speaker, and advisory board member for: Roche, MSD, BMS, Gilead, Janssen, Abbvie Presentation includes use of unlicensed drugs
Genotype 4, finally cured? Outline Epidemiology Therapy Historical: PEG-RBV Current: PEG-RBV Triple therapy IFN Free therapy IFN and RBV Free therapy Subtypes The Final Cure?
HCV Genotype Distribution Globally HCV a global health challenge with ~15-18 Million chronic HCV infections Genotype 1 is the most prevalent in most countries 4; 15% 5; 1% 6; 2% 1; 47% 3; 22% 2; 14% Genotype 4: 12%-15% (15-18 Million) of total global HCV infection 1. Gower, E., et al., J Hepatol 214; 61:S45 S57; 2. Messina J. et al. Hepatology, 215;61:77-87 4
HCV Genotype Distribution Globally Global Total ~15-18 Million <5, -15, 5-7, South America North America Europe Asia and Australia 1-1.5 Million Africa and Middle East 13-15 Million ~85% G-4 distribution restricted to regions: in Egypt, Central Africa, and the Middle East 1. Gower, E., et al., J Hepatol 214; 61:S45 S57; 2. Messina J. et al. Hepatology, 215;61:77-87 5
Genotype 4 Distribution by Country Africa & Middle East Egypt Palestine Libya Saudi Arabia Equatorial Guinea Gabon Lebanon UAE Central African Republic Syria Jordan Kuwait Iraq Congo Ethiopia G-4 is considered endemic, circulated for generations in restricted regions 1. Gower, E., et al., J Hepatol 214; 61:S45 S57; 2. Messina J. et al. Hepatology, 215;61:77-87 6
Genotype 4 Distribution by Country Europe, Asia, North and South America France Belgium Portugal Spain Netherlands Switzerland Greece Italy Germany Austria HCV G-4 is increasing in Europe due to prevalence in PWID and migration Increasing in France (>1%), Spain (>15% in South Spain) and Italy Ireland Czech Republic United Kingdom Slovakia Norway Georgia Denmark Russia Sweden Belarus Finland Poland Turkey North America Hungary Armenia South America Asia, South Estonia Asia Central Lithuania Asia East 1. Gower, E., et al., J Hepatol 214; 61:S45 S57; 2. Messina J. et al. Hepatology, 215;61:77-87 3. Asselah et al. J Hepatol. 212; 56:527-32; 4. Cifuentes C Et al. Enferm Infecc Microbiol Clin 212; 3:452-7; 5. Sariguzel et al. Clin Lab. 213; 59:143-8 Latvia Asia Southeast
Genotype 4, finally cured? Epidemiology Therapy Historical: PEG-RBV Current: PEG-RBV Triple therapy IFN Free therapy IFN and RBV Free therapy Subtypes The Final Cure?
AI447-11 ASV +DCV SVR4 GT 1 Null Responders Genotype 4 PEG-RBV Therapy Real-World Experience for naive HCV patients (PROPHESYS cohort study, n=7,163) Historically, HCV-G4 was considered to respond to PEGRBV better than G1 but lower than G2 and G3 Virologic response (%) 8 71.4 67.9 6.6 6 41.8 41. 4 2 SVR SVR SVR SVR G1 G2 G3 G4 (n = 4,52) (n = 1,25) (n = 1,259) (n = 317) SVR G5/6 (n = 28) Pts with HCV GT4 treated with PegIFNα + RBV for 48 wks Marcellin P, et al. Hepatology 212; 56:239 25.
DAAs with Efficacy Data for HCV-G4 Drugs Drug Target Protease G4 Approved Simeprevir NS5A Daclatasvir Non-nucleoside Asunaprevir Paritaprevir Phase II and III Effective in G4 Danoprevir Ledipasvir PPI-668 Ombitasvir GS-5816 Beclabuvir NS5B Nucleoside Approved for other genotype Effective in G4 Sofosbuvir
PEG-RBV + DAA Triple Therapy for HCV-Genotype 4 DCV 24 wks + PEG-RBV 48 wks Naiive, COMAND 1 8 6 4 2 85,2 87,5 9,5 8 Patients with SVR 24, % SVR-12 SMV 12 wks + PEG-RBV 24-48 wks RESTORE DCV 6 mg + alfa/rbv 33,3 87 8 28 32 52 61 1 3 19 21 64 6 4 5 Placebo + alfa/rbv 58 36 4 38 5 31 2 n/n = 146 72 GT 1 ASN+DCV+PEG-RBV HALLMARK QUAD 8 6 4 2 87 99 98 7 8 G1a SVR 12 (%) Patients with SVR24 (%) G1b 1. Moreno, C., et al. J Hepatol, 214. 3. Jenssen D et al. Liver Intl. 215. G4 113 56 GT 1a 3 16 1 GT 1b 1 6 2 GT 4 SOF + PEG-RBV 12 wks NEUTRINO 96 91 8 6 4 2 296 327 Overall 2 He zode C, et al. Gut, 214. 4. Lawitz, E., et al. N Engl J Med, 213. 27 28 7 7 GT-4 GT-5, GT-6
IFN-Free Therapy in Genotype 4 SOF + RBV in Treatment-Naïve and Experienced US Patients of Egyptian Ancestry Randomized, open-label, single-center study conducted in the US of the safety and efficacy of all-oral SOF + RBV in patients of Egyptian ancestry with HCV GT 4, 6 patients Treatmentnaive Naiive SOF+ RBV (n=14) 8 Experienced 87 79 Treatmentexperienced SOF+ RBV (n=17) SOF + RBV (n=15) Week 24 SOF 4 mg + Weight-based RBV dosing (-12 mg). Male (68%), cirrhosis (23%), HCV RNA (5.7 to 6.1 log1 IU/mL), IL28B non-cc (83%). 12 SVR 12 SOF + RBV (n=14) 6 59 4 2 SOF+RBV well-tolerated for up to 24 weeks of treatment 12 Weeks No discontinuation due to AEs No Grade 4 AEs or lab abnormalities were reported No SOF resistance mutation S282T was found in any patient with virologic failure Ruane P, EASL, 214, P1243 24 Weeks
IFN-Free Therapy in Genotype 4 SOF + RBV in Treatment-Naïve and Experienced Egyptian Patients Naiive Treatmentnaive Treatmentexperienced 8 SOF+ RBV (n=27) 12 SOF 4 mg + Weight-based RBV dosing (-12 mg). Male (67%), cirrhosis (17%), 52% high viral load (>8, IU/ml), IL28B non-cc (81%). 9 77 2 12 wks 24 wks Experienced 2 92 4 4 24 84 6 6 SOF + RBV (n=27) Week 8 Overall SOF+ RBV (n=25) SOF + RBV (n=24) Randomized, open-label, multi-center study conducted in Egypt of the safety and efficacy of all-oral SOF + RBV in Egyptian patients with HCV GT 4, 13 patients 12 wks 24 wks 8 89 7 6 4 Naïve patients, with <=F2 Fibrosis, low viral load (<6, IU): % SVR with 12 wks treatment Esmat G. et al. AASLD 214 2 12 wks 24 wks
IFN- & RBV-Free Therapy in Genotype 4 LED + SOF in Treatment-Naïve and Experienced Patients (SYNERGY) Phase II trial of LDV/SOF for 12 weeks in GT4-infected patients, including 43% with advanced fibrosis LDV/SOF (n=21) 8 9 95 95 95 71 6 LDV = 9 mg12 wks SOF = 4 mg 24 wks 4 2 38% Treatment experienced 1% advanced fibrosis 33% compensated cirrhosis One person stopped treatment after the first dose. Regimen safe and well tolerated, no deaths, SAEs or grade 4 laboratory abnormalities. Most common AEs: fatigue, diarrhea and nausea. Kapoor R, et al. Hepatology 214;6(Suppl):91A.
IFN- & RBV-Free Therapy in Genotype 4 ASV + BCV + DCV in Treatment-Naïve Patients HCV GT4 treatment-naive adults, including those with compensated cirrhosis received triple therapy of ASV, BCV, and DCV for 12 weeks ASV + BCV 75 mg + DCV (n=11) ASV + BCV 15 mg + DCV (n=1) Response (%) 24 wks 12 wks 8 Two patients had missing data at post-treatment Week 12 but subsequently achieved SVR No patient had on-treatment virologic failure or experienced relapse 6 4 2 n N 11 11 1 1 Week 2 11 11 1 1 EOT Hassanein T, et al. J Hepatol. 215; doi: http://dx.doi.org/1.116/j.jhep.214.12.25 11 11 1 1 SVR
IFN- & RBV-Free Therapy in Genotype 4 OMB + PAR/r +/- RBV in Treatment-Naive Patients (PEARL-I) An open-label Phase 2b study (PEARL-I) evaluated the safety and efficacy of 2DAAs with or without RBV for 12 weeks for the treatment of HCV GT4-infected patients Group I N=44 G4 PAR/r + OMB Naiive SVR12 9,9 8 Group 2 PAR/r + OMB N=44 G1b Naiive 6 4 2 Group 3 PAR/r + OMB N=4 G1b Null Responders Group 4 PAR/r + OMB + RBV N=42 G4 Naiive Group 5 N=44 G4 PAR/r + OMB Partial/Null Responders, Relapsers Group 6 N=49 G4 PAR/r + OMB + RBV Partial/Null Responders, Relapsers Pol S, et al. Hepatology 214; 6: 1129A 1
Genotype 4, finally cured? Epidemiology Therapy Historical: PEG-RBV Current: PEG-RBV Triple therapy IFN Free therapy IFN and RBV Free therapy Subtypes The Final Cure?
Genotype 4 Subtypes Egypt 4a Syria 4a Saudi Arabia 4a, 4d Yemen 4a 8 7 6 Response to PEG-RBV 6 5 SVR% 17-21 Subtypes (4a-4w) Cameroun 4f, 4e Congo 4b, 4c Subtypes responded differently to PEG-RBV therapy 4 35 3 Impact of G4 subtype on response to DAA still not known 2 1 4a non 4a 1. Smith DB. et al. Hepatology. 214;59:318-27. 2. Gower, E., et al., J Hepatol 214; 61:S45 S57; 3. Messina J. et al. Hepatology, 215;61:77-87 4. Roulot D et al. J Viral Hepat 27 5. Moucari R et al. Gut 29
Genotype 4, finally cured? Epidemiology Therapy Historical: PEG-RBV Current: PEG-RBV Triple therapy IFN Free therapy IFN and RBV Free therapy Subtypes The Final Cure?
Summary of Currently Available Therapies Triple Therapy with PEG-RBV 96 88 83 Interferon Free 87 <5, % S VR 12 9,9-15, 5-7, Resource Limited Settings? 95 South America North America Europe 1-1.5 Million Asia and Australia Africa and Middle East 12-15 Million 6-8 Million ~85% ~45% Egypt 6-7 Million ~4% 1. He zode C, et al. Gut, 214 4. Ruane P et al. EASL 214, 2. Moreno, C., et al. J Hepatol, 214, 3. Lawitz, E., et al. N Engl J Med, 213. 5. Esmat G el al. AASLD 214, 6. Kapoor et al. AASLD 214, 7. Pol S. et al. Hepatology 214
The Final Cure? Resource Limited Settings? The Egypt Example % S VR 12 Currently: SOF based 88 83 therapy SOF-PEG-RBV 12 wks for IFN eligible patients SOF-RBV 24 wks for IFN ineligible patients Total estimate 6-7 Mill 95% G4 Gilead access program reduced cost drastically National treatment program started October 214 NCCVH Egypt, Data on file 96 87 738, registered for 9,9 evaluation 4, F3 and F4 selected for treatment 15, started treatment, 33% SOF+PEG-RBV 67% SOF+RBV 95 Of those who reached wk4, 99% >2 log1 reduction in viral load 82% RNA <LLQ (<15 IU/ml) 81.3% SOF-RBV
The Final Cure? Resource Limited Settings? The Egypt Example Negotiating and evaluating IFN & RBV free therapies for G4: LED-SOF, SIM-SOF, DCV-SOF, OMB-PAR/r National HCV Control Target: Treat 3-35, a year, 9% SVR, 1-15 yrs 7 6 5 4 3 2 # Cirrhosis Total Infected 6-95% 28 7 6 5 4 3 2 2 63 15-88% 76 Annual HCV-related Mortality214 23 HCC 5 4 16-85% 3 24 2 HCC: 17, cases Prevented between 215 and 23 Mortality: 26, cases prevented between 215 and 23 1. NCCVH data 365 2. Waked I, et al. Arab J Gastro. 214 75
Summary HCV G4 is common, mainly in resource limited settings in Africa and the Middle East Increasing in Western Europe Egypt has 4% of global HCV-G4 patients Current therapies have high cure rates All oral therapies with > 95% SVR and short duration becoming available, promising complete cure With affordable prices, HCV-G4 will be cured, even in the resource limited settings where it is most prevalent 2
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