SVR12 by HCV Genotype

HCV Treatment in the Era of DAA

Prof. Gamal Esmat Prof. Hepatology & Vice President of Cairo University, Egypt Member of WHO Strategic Committee for Viral Hepatitis www.gamalesmat.com Global genotype distribution

. Under auspices of Ministry of Health.

. Implemented in association with DHS Egypt and MACRO international.

. Funding from USAID and UNICEF.

. Hepatitis C testing undertaken at the central Laboratory of MOH. . Household survey in 28 governorates.

. ELISA test used to determine presence of antibodies.

. Real time PCR testing for HCV RNA for all antibody positive samples to detect active infections. National Survey (DHS) 2015 (1 -59 years)

2015(1-59 Y) HCV Ab 6.3% HCV PCR 4.4% Percentage of women and men with an active hepatitis C infection by age, Egypt 2015

30 27.8 25 23.7

20 17.6 16.1 15 women 12.4 men 10 10.8 10.4

7.1 6.9 7.3 5 4.7 5.3 3.1 3.2 1.5 1.9 0 0.69 19-15 24-20 29-25 34-30 39-35 44-40 49-45 54-50 59-55 Trends in Percentage of population age 15-59 testing positive HCV Ab, Egypt 1996-2008-2015 Chart Title 1996 2008 2015

25.8 22.9 20.1 16.6 14.2 11.8 12 10 9

total Women Men Evolution of HCV treatment and SVR rates 1989 2011 2013 2014/15 95–100 100 Number Column1 Genotype 2/genotype 3 85–97 80–90 61–79 76–82 80 66–79

60 31–44 42–46 40 33–36 18–39 6–19 11–19 10–22

SVR (%) SVR 20

0 24 48 78 DAA IFN monotherapy (weeks) IFN + ribavirin PegIFN PegIFN +PegIFN ribavirin + ribavirinSMV + BOC/TVR or SOF SOF+ + comb PegIFN + RBVRBV os

Davis GL, et al. N Engl J Med 1989; 321:1501–1506; Poynard T, et al. N Engl J Med 1995; 332:1457–1462; McHutchison JG, et al. N Engl J Med 1998; 339:1485–1492; Poynard T, et al. Lancet 1998; 352: 1426–1432; Zeuzem S, et al. N Engl J Med 2000; 343:1666–1672; Linsay KL, et al. Hepatology 2001; 34:395–403; Pockros PJ, et al. Am J Gastroenterol 2004; 99:1298–1305; Manns MP, et al. Lancet 2001; 358:958–965; Fried MW, et al. N Engl J Med 2002; 347:975–982; Poordad F, et al. N Engl J Med 2011; 364:1195–1206; Jacobson IM, et al. N Engl J Med 2011; 364:2405–2416; Simeprevir prescribing information, November 2013; Lawitz E, et al. N Engl J Med 2013; 368:1878–1887; Zeuzem S, et al. Hepatology 2013; 58(Suppl 1):733A; AbbVie press release 2014 [Accessed 25-02-14]; Gilead press release 2013 [Accessed 25-02-14]; Sulkowski MS, et al. N Engl J Med 2014; 370:211–221. We now have highly efficacious DAAs that target different stages in the HCV lifecycle

Summary of New England Journal of Medicine studies on IFN-free therapy Receptor binding in GT 1 patients published in 2014 and endocytosis Transport 96% and release

Fusion and uncoating Virion assembly

(+) RNA ER lumen Translation and LD NS5A inhibitors polyprotein LD processing

LD Membranous web RNA replication ER lumen

Non-NA NS5B inhibitors 3680/ NS3 protease NA NS5B inhibitors 3826 inhibitors SVR DAA: direct-acting antiviral agent; ER: endoplasmic reticulum; Lindenbach BD, Rice CM. Nature 2005;436(Suppl):933–8; GT: genotype; IFN: interferon; LD: luminal domain; NA: nucleos(t)ide analogue; Liang J, Ghany MG. N Engl J Med 2014;370:2043–7. NS: non-structural protein; SVR: sustained virological response Characteristics of DAA

DAA

PI 1st PI 2nd NS5A Inh. 1st NS5A Inh. 2nd NS5B NS5B non generation generation generation generation nucleos(t)ide nucleos(t)ide inh. 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 IFN-free regimens available in 2016

Paritaprevir/r Ombitasvir +/-Dasabuvir NS5A Grazoprevir Elbasvir inhibitors ‘…asvirs’

Sofosbuvir Daclatasvir Protease inhibitors Sofosbuvir Ledipasvir ‘…previrs’ Polymerase Simeprevir Sofosbuvir inhibitors ‘…buvirs’ Non-Nucs Nucleos(t)ide

Sofosbuvir + RBV

EASL Recommendations 2015, DOI: http://dx.doi.org/10.1016/j.jhep.2015.03.025. Accessed April 2015. HCV G4 the Egyptian Clinical Trials in AASLD meeting SF 2015

. Sof + RBV . Sof + PI (Simeprevir) . Sof + NS5A (Ravidasavir) . PI(Paritaprevir) + NS5A(Ombitasvir) HCV G4 the Egyptian Clinical Trials in AASLD meeting SF 2015

. Sof + RBV . Sof + PI (Simeprevir) . Sof + NS5A (Ravidasavir) . PI(Paritaprevir) + NS5A(Ombitasvir) Abstract ID: 1076 Day / Time: Sunday, Nov 15, 8:00 AM – 5:30 PM

Sofosbuvir plus Ribavirin in the Treatment of Egyptian Patients with Chronic Genotype 4 HCV Infection

W.H. Doss, M. Hassany, R. Hammad, National Hepatology and Tropical Medicine Research Institute, Cairo, EGYPT; P.J. Ruane, D. Ain, J. Riad, R. Meshrekey, Ruane Medical and Liver Health Institute, Los Angeles, California, UNITED STATES; , R. Soliman, W. Samir,G.Shiha Egyptian Liver Research Institute and Hospital, Mansoura, EGYPT; M. Khairy, R.F. Omar, M. Gamil, G.E. Esmat, University of Cairo, Cairo, EGYPT; D. Jiang, B. Massetto, S.J. Knox, K. Kersey, J.G. McHutchison, Gilead Sciences, Inc., Foster City, California, UNITED STATES Sofosbuvir + Ribavirin in GT 4 HCV G4 the Egyptian Clinical Trials in AASLD meeting SF 2015

. Sof + RBV . Sof + PI (Simeprevir) . Sof + NS5A (Ravidasavir) . PI(Paritaprevir) + NS5A(Ombitasvir) Abstract ID: 1163 Day / Time: Sunday, Nov 15, 8:00 AM – 5:30 PM

Treatment of Hepatitis C Genotype 4 patients with Simeprevir and Sofosbuvir: Preliminary Results from a Phase IIa, Partially Randomised, Open-label Trial conducted in Egypt (OSIRIS)

. M. El Raziky G. Van Dooren, Janssen Infectious Diseases BVBA, Beerse, BELGIUM; M. Gamil, M. Khairy, A. Elsharkawy, Cairo University, Cairo , EGYPT; R. Hammad, M. Hassany, W.H. Doss, National Hepatology and Tropical Medicine Research Institute, Cairo, EGYPT; M. El Raziky, Cairo University, Cairo , EGYPT; M. Saad Hashem, A. Gomaa, I. Waked, National Liver Institute, Menoufiya, EGYPT; S. Keim, Janssen-Cilag Portugal, Lisbon, PORTUGAL; R. Ryan, R. DeMasi, Janssen Research & Development LLC, Titusville, New Jersey, UNITED STATES; I. Londjon- Domanec, Janssen-Cilag, Paris, FRANCE COSMOS: SVR12 (ITT) in prior null responders, F0–F2

SVR12 Non-VF Relapse

24 weeks 12 weeks

4 7 4 7 (1/24) (1/15) (1/27) (1/14) 100 100 96 17 93 93 (26/27) (4/24) (13/14) 80 (14/15) 80 79 (19/24) 60 60

40 40 Patients (%) Patients

20 20

0 0 SMV + SOF + RBV SMV + SOF SMV + SOF + RBV SMV + SOF Intent-to-treat population; Non-VF, Non-virologic failure, patients who did not achieve SVR12 for reasons other than virologic failure Sulkowski M, et al. EASL 2014 O7 Lawitz E., et al. Lancet 2014. Published Online July 28, 2014. http://dx.doi.org/10.1016/S0140-6736(14)61036-9 OSIRIS: SMV + SOF in genotype 4 HCV infection in treatment-naïve and treatment-experienced patients (N=60)

. Phase 2, partly randomized, open-label, multicentre study (Egypt) . SVR4 will be available by the end of this month.

SMV + SOF F0–F3 n=40 SMV + SOF Primary endpoint: SVR12

F4 SMV + SOF n=20

0 8 12

NCT02278419 Sofosbuvir +Simeprevir in GT4 HCV G4 the Egyptian Clinical Trials in AASLD meeting SF 2015

. Sof + RBV . Sof + PI (Simeprevir) . Sof + NS5A (Ravidasavir) . PI(Paritaprevir) + NS5A(Ombitasvir) Abstract ID: 708 Day / Time: Saturday, Nov 14, 2:00 PM – 7:30 PM

Efficacy and Safety of Co-Formulated Ombitasvir/Paritaprevir/Ritonavir with Ribavirin in Adults with Chronic HCV Genotype 4 Infection in Egypt (AGATE-II)

. Gamal Esmat1, Wahid Doss2, Roula B Qaqish3, Imam Waked4, Gamal Shiha5, Ayman Yosry2, Mohamed Hassany2, Jennifer King3, Carolyn Setze3, Rebecca Redman3, Niloufar Mobashery3 . . Affiliation(s): 1Cairo University, Cairo, Egypt; 2National Hepatology & Tropical Medicine Research Institute, Cairo, Egypt; 3AbbVie Inc, North Chicago, Illinois, United States; 4National Liver Institute, Menoufiya, Egypt; 5Egyptian Liver Research Institute And Hospital (ELRIAH), Dakahliah, Egypt Efficacy and Safety of Co-Formulated Ombitasvir/Paritaprevir/Ritonavir with Ribavirin in Adults with Chronic HCV Genotype 4 Infection in Egypt

Esmat,et al-AASLD,,2015,Ab:a HCV G4 the Egyptian Clinical Trials in AASLD meeting SF 2015

. Sof + RBV . Sof + PI (Simeprevir) . Sof + NS5A (Ravidasavir) . PI(Paritaprevir) + NS5A(Ombitasvir) Abstract ID: LB-4 Day / Time: Monday, Nov 16, 3:45 PM – 4:00 PM Oral presentation

High Virologic Response Rate in Egyptian HCV-Genotype 4 Patients Treated with Ravidasvir (PPI-668) and Sofosbuvir: Results of a Large Multicenter Phase 3 Registrational Trial . G. Esmat, M. El Raziky, T. Elbaz, M.M. Abouelkhair, H. Gamal El Deen, M.K. Ashour, Cairo University, Cairo, EGYPT; M. El Raziky, M.M. Abouelkhair, M.K. Ashour, Cairo Fatemic Hospital, Cairo, EGYPT; A. Gomaa, A. Sabry, I. Waked, National Liver Institute, Cairo, EGYPT; M. Abdel-Hamid, Minia Universtiy, Cairo, EGYPT; O. Nada, Ain Shams University, Cairo, EGYPT; S. Helmy, H. Abdel-Maguid, Pharco Pharmaceuticals, Alexandria, EGYPT; R. Colonno, N. Brown, E. Ruby, P. Vig, Presidio Pharmaceuticals, San Francisco, California, UNITED Study Design

Non-Cirrhotic Treatment Follow-up IFN Naïve RDV+SOF n=45 SVR4 SVR12 SVR24 Group 1a n=90 RDV+SOF+RBV n=45 SVR4 SVR12 SVR24

IFN- RDV+SOF n=40 SVR4 SVR12 SVR24 Group 2 Experienced n=80 RDV+SOF+RBV n=40 SVR4 SVR12 SVR24 Cirrhotic Treatment Follow-up

IFN Naïve RDV+SOF n=31 SVR4 SVR12 SVR24 Group 1b n=60 RDV+SOF+RBV n=29 SVR4 SVR12 SVR24

IFN- RDV+SOF+RBV n=35 SVR4 SVR12 SVR24 Group 3 Experienced n=70 RDV+SOF+RBV n=35 SVR4 SVR12 SVR24

Time (weeks) 0 12 16 20 24 28 36 40

 Total patients enrolled = 300, all patients completed treatment evaluations as of the data cutoff for this report  High percentage of cirrhotic patients: 130/300 (43.3%) SVR12 Outcomes in Non-Cirrhotic Patients (ITT) 100% 100% 100 98% 95%

60 Group 1a Group 2

40 Percent of Patients of Percent

. %

% % % %

2 0

0 0 0 0 0 Treatment Naive IFN Experienced RDV+SOF RDV+SOF+RBV RDV+SOF RDV+SOF+RBV SVR12 Discontinuation Relapse

 Among the 170 non-cirrhotic patients enrolled, there were three early discontinuations unrelated to safety or efficacy failure, WITH NO RELAPSES  100% SVR12 in non-cirrhotic patients , excluding discontinuations SVR12 Outcomes in Cirrhotic Patients (ITT) 100 100% 93% 92% 86% 80

60 Group 1b Group 3

Percent of Patients of Percent

5 .

20 %

% %

4 4

% % %

0 0 0 0 Treatment Naive IFN Experienced RDV+SOF RDV+SOF+RBV RDV+SOF+RBV 12 Wk RDV+SOF+RBV 16 Wk SVR12 Discontinuation Relapse  Among the 130 cirrhotic patients enrolled, there were two premature discontinuations (one safety related) and 6 virologic relapses  No relapses to date in the cirrhotic 16 week treatment cohort  Per protocol evaluation results in 94% SVR12 in cirrhotic patients What Happens Without Therapy?

4 years follow up of 2120 patients

F2 F3 F4

Decompensation 3.6% Decompensation 10.1% Decompensation 27.7% HCC 1% HCC 2.7% HCC 8.3% Death 4.9% Death 10.4% Death 23.7%

Fried M, AASLD 2014 Saleem M AASLD 2014 SVR is Associated with Lower Incidence of ESLD, HCC or Death

Results from the HALT-C Trial 526 Patients, 7.5 years FU

ESLD HCC 20.7 Liver death or transplant 15.9 Death 13.9

9.1 6.5 6.5 5.2 5.2 2.9 1.4 1.4 1.4

SVR Relapse Non-response

Morgan TR et al. Hepatology 2010;52:833-844 Opening of 23 national treatment centres, 2007-2013

Total number of patients treated with PEG-IFN (2007-2013): 350,000 Annual number of new patients treated: 45,000 Annual budget from the Ministry of Health: 90 million $ National Plan of Action: conclusions

. Increase policymakers’ commitment to supporting the policy change necessary to prevent viral hepatitis transmission. . Educate healthcare workers to prevent transmission of viral hepatitis in Egypt. . Increase public awareness of viral hepatitis prevention. . Promote safe injection practices in the community. . Annual treatment of 200- 350.000patients by DAA.

Egyptian National Plan of Action for the Preventton , Care & Treatment of Viral Hepatitis 2014–2018 Chronology of Treatment Protocols Implemented by the National Program

Date Implmented Protocol Inclusion criteria 2007-2014 PegIFN-RBV F1-F3 patients October 2014-May 2015 Sofosbuvir-PegIFN-RBV F3,F4 IFN tolerant Sofosbuvir-RBV F3,F4 IFN intolerant up to Child B 8 (down to 7)

May 2015-November 2015 Sofosbuvir-PegIFN-RBV F0-F4, normal synthetic function Sofosbuvir-Simeprevir F0-F4, impaired synthetic function up to Child A6 November 2015 IFN-free regimen. Two F0-F4, impaired synthetic DAAs ± RBV function up to B7. Higher Child in special centers Before DAAs Era IFN therapy (IFN/RBV) Non Cirrhotics

Week 48 Week 72 PCR results ETR PCR results SVR

71% 62% Positive PCR 949 NR 949 NR 949 Week 48

N=3235 Negative PCR Negative PCR 2286 2016 SVR 2016 RS 2286

Positive PCR 270 Relapser 270 till Nov 2015 Triple therapy (IFN/SOF/RBV) 35%Cirrhotics

Week 12 Week 24 PCR results ETR PCR results SVR

96% 92% Positive PCR 188 NR 188 NR 188 Week 12

N=4582 Negative PCR Negative PCR 4394 4197 SVR 4197 RS 4394

Positive PCR 197 Relapser 197 till November 2015 Dual therapy (SOF/RBV) 70% Cirrhotics

Week 24 Week 36 PCR results ETR PCR results SVR 98% 72%

Positive PCR 43 NR 43 NR 43

2627 Negative PCR 1888 SVR 1888 Negative PCR 2584 RS 2584 Positive PCR 696 Relapser 696 till Feb 2016 (SOF/SIM) 90% Cirrhotics Week 12 Week 24 PCR results ETR PCR results SVR

99% 95%

DC 16 DC 16 NR 16 Week 12

N=1169 Negative PCR Negative PCR 1153 1111 SVR 1111 RS 1153

Positive PCR 42 Relapser 42 Real world experience in the Target cohort: Treatment status by regimen

Total consented in HCV-TARGET 2.0 N=2185

N=2140* ITT ITT ITT ITT SOF + PR SOF + RBV SMV + SOF SMV + SOF + RBV N=391 N=692 N=831 N=226 Started treatment N=1913 Started Started Started Started SOF + PR SOF + RBV SMV + SOF SMV + SOF + RBV N=366 N=645 N=697 N=205

Early termination Early termination Early termination Early termination SOF + PR SOF + RBV SMV + SOF SMV + SOF + RBV N=7 N=16 N=11 N=3

Based on available data as of 10th September 2014 *N=45 Data in processing ITT= intent-to-treat 11 patients have started other regimens: 1 TVR + PR; 1 BOC + PR; 1 SMV + PR; 1 SOF + PR; 4 PR; 3 DCV + SOF + RBV Nelson D et al. AASLD/EASL 2014. Oral presentation Cohorte ANRS CO22 HEPATHER ATU / AMM project 2014 - 07/12/15 (patients treated with AAD) 4 978 patients treated with DAA (patients treated in therapeutic trials excluded) • Combinaisons thérapeutiques Combination Effective Patients 12 weeks after Patients 24 weeks after the DAA initiation the DAA initiation W12 or EOT SVR12 or EOT

SOF + RBV 463 453 427 SOF + PegIFN + RBV 270 270 268

SOF + DCV 1 487 1 438 1 412 SOF + DCV + RBV 495 472 446 SOF + SMV 793 788 780 SOF + SMV + RBV 88 85 82 SOF + LDV 958 837 711 SOF + LDV + RBV 410 376 319 OBV + PTV+ RTV 123 84 56 OBV + PTV+ RTV + RBV 82 70 55

41 SOF + DCV +/- RBV in Genotype 1 patients : HEPATHER ANRS CO-22 cohort

SVR according to treatment duration and use of ribavirin

SOF + DCV SOF + DCV + RBV (n = 317) (n = 92) 12 weeks 24 weeks 12 weeks 24 weeks SVR 4 46/54 250/263 12/12 79/80 N % 85,2 95,1 100 98,7 SVR 12 45/53 172/184 11/11 61/62 N % 84,9 93,4 100 98,4 SVR 4 in cirrhotic patients 26/34 203/216 9/9 59/60 N % 76,5 94,0 100 98,3 SVR 4 in non cirrhotic patients 20/20 47/47 3/3 18/18 N % 100 100 100 100 SVR 4 in naïve patients 27/31 47/53 4/4 14/14 N % 87,1 88,7 100 100 SVR 4 in treatment-experienced patients 19/23 203/210 8/8 65/66 N % 82,6 96,7 100 98,5 SVR 4 in PI failure 4/5 128/132 4/4 32/32 N % 80,0 97,0 100 100 SVR 4 in PR failure 15/18 75/78 4/4 33/34 N % 83,3 96,1 100 97,1

Pol S et al. EASL 2015, Abs. LO3 Efficacy of the oral Sofosbuvir-based combination in HCV genotype 4-mono- infected patients from the French observational cohort ANRS CO22 HEPATHER

Hélène FONTAINE, Christophe HEZODE, Fabien ZOULIM, Didier SAMUEL, Marc BOURLIERE, Georges HAOUR, Céline DORIVAL, Jean-Pierre ZARSKI, Victor DE LEDINGHEN, Sandy LUCIER , Dominique LARREY, Albert TRAN, Sophie METIVIER, Yves BENHAMOU, Paul CALES, François HABERSETZER, Patrick MARCELLIN, Philippe MATHURIN, Laurent ALRIC, Jean-Pierre BRONOWICKI, Dominique GUYADER, Véronique LOUSTAUD-RATTI, Anne MINELLO, Ghassan RIACHI, Isabelle ROSA, Mélanie SIMONY, Alpha DIALLO, Fabrice CARRAT, Stanislas POL and the ANRS/AFEF HEPATHER Study group.

43 Initial characteristics

SOF + DCV + SOF + SMV + Characteristics SOF + DCV SOF + SMV Total RBV RBV N 33 15 27 7 82 Age, mean. (DS) 54,4 (8,5) 55,2 (6,8) 52,7 (8,9) 52.6 (7,2) 53,8 (8,1) Male, n (%) 22 (66,7) 11 (73,3) 16 (59,3) 7 (100) 56 (68,3) BMI, mean. (DS) 26 (3,52) 27,4 (6,6) 25,8 (5,1) 27,7 (4,8) 26,3 (4,8) European origin, n (%) 20 (60,6) 6 (40,0) 17 (63,0) 5 (71,4) 38 (46,3) Naive patients (%) 6 (27,3) 2 (33,3) 8 (26,9) 3 (28,6) 19 (28,4) Cirrhosis, n (%) 26 (78,8) 13 (86,7) 21 (80,8) 7 (100) 67 (82,7) Decompensated cirrhosis, 5 (15,2) 1 (6,7) 0 (0) 1 (14,3) 7 (8,7) n (%) Oesophageal varices, n 8 (24,2) 6 (40) 6 (23,1) 4 (57,1) 24 (29,6) (%) Child B or C, n (%) 3 (9,1) 3 (20) 1 (3,7) 3 (42,8) 10 (12,2) MELD score, mean. (DS) 9,8 (4,9) 11,9 (6,2) 7,6 (2.2) 13 (3,3) 9,8 (4,8) 44 Fontaine H, Paris, EASL 2015, Abs. LP28 actualisé Results (2) : SVR12

12 weeks 24 weeks 100 100 100 100 100 100 100 88.9 100 90.9

60 RVS12 40

20 % ARN VHC indétectable VHC ARN % 80 0 SOF/DCV SOF/DCV/RBV SOF/SMV SOF/SMV/RBV SOF/DCV SOF/DCV/RBV SOF/SMV SOF/SMV/RBV 100 100 100 100 100 100 100 100 100 100 100100100 100100 100 100100 100 100 100 100 100 100 91.7 90 88.9 83.3 83.3 80 80

60 60

40 40

20 20

0 0 0 0 0 % ARN VHC indétectable VHC ARN % 0 0 Cirrhotique Non cirrhotique Naïf Antérieurement traité Cirrhotique Non cirrhotique Naïf Antérieurement traité

45 SOF + DCV SOF + DCV + RBV SOF + SMV + RBV SOF + SMV Fontaine H, Paris, EASL 2015, Abs. LP28 actualisé IFN free DAA have expanded the pool of treatable patients

Mild Severe Decomp HCV chronic disease spectrum Currently treated

- By enrolling new patients at the extreme of the spectrum - By enforcing need for mass screening for HCV AASLD 2015

. Patients with HCV who have decompensated cirrhosis (moderate or severe hepatic impairment; Child Turcotte Pugh [CTP] class B or C) should be referred to a medical practitioner who is highly experienced in the management of advanced liver disease and HCV treatment (ideally in a liver transplant center). Unique Patient Populations Decompensated Cirrhosis Genotype Recommended Rating DCV + SOF + RBV** x 12 weeks Class II, Level A 1 and 4 OR Class IIb, Level C SOF/LDV + RBV** x 12 weeks DCV + SOF + RBV** x 12 weeks Class II, Level A 2 and 3 OR Class IIb, Level B SOF + RBV x up to 48 weeks

RBV intolerant/ineligible

1 and 4 DCV + SOF x 24 weeks Class IIb, Level C Prior SOF-based regimen failure

1 and 4 SOF/LDV + RBV** x 24 weeks Class IIb, Level C

* Decompensated cirrhosis (moderate or severe hepatic impairment; CTP class B or C) who may or may not be candidates for liver transplantation, including those with hepatocellular carcinoma **initial RBV dose of 600 mg, increased as tolerated PEG: Pegylated interferon, RBV: Ribavirin, SMV: Simeprevir, SOF: Sofosbuvir, LDV: Ledipasvir, DCV: Daclatasvir, PrOD: Paritaprevir + Ritonavir + Ombitasvir, + Dasabuvir

AASLD Recommendations Recommendations for forTesting, Testing, Managing, Managing, and Treating and Treating Hepatitis Hepatitis C. Available C. Available at: http://www.hcvguidelines.org. at: http://www.hcvguidelines.org. Last accessed Last: Aug acces 8, 2015sed.: Aug 8, 2015. ALLY-1 (AI444-215): Phase 3, Open-label Study of DCV + SOF in Patients With Cirrhosis or Post-liver Transplant

DCV 60 mg QD + Cirrhotic SOF 400 mg QD + RBV Follow-up Post-liver DCV 60 mg QD + transplant SOF 400 mg QD + RBV

Week 0 Week 12 Week 24 Week 36 Primary endpoint: SVR12 • Cirrhotic patients who undergo transplantation while on study treatment may enter a treatment extension period ≥ 3 months posttransplantation with DCV + SOF + RBV for 12 weeks • Patients who relapse posttreatment may be eligible for an additional relapse retreatment period

Patients Regimen Countries Estimated enrollment: 110 • DCV 60 mg QD + SOF 400 mg QD + USA RBV • Treatment-naive or experienced • 12 weeks of treatment with GT 1–6 Status: • Two cohorts Ongoing – Compensated or decompensated cirrhosis – Post-liver transplant HCV recurrence

SOF, sofosbuvir. www.clinicaltrials.gov NCT02032875. ALLY-1: SVR12 by HCV Genotype

Advanced cirrhosis cohort Post-transplant cohort N = 60 N = 53 94 100 100 97 92 100 100 90 91 76 80 83 80 56

, % , 12

SVR 40

11/12 30/ 9/ 20 32 16

0 1a 1b 2 3 4 6 1a 1bA 2 B 3 C4 6

Genotype Child-Pugh Class . In subgroup analysis of pts in the advanced cirrhosis cohort, those who were Child-Pugh class C (n = 16) or had albumin < 2.8 g/dL (n = 18) had SVR12 rates of 56% SOLAR1: LDV-SOF in Decompensated Cirrhosis

 108 patients randomized 12 vs 24 weeks  Rbv: escalating dose staring at 600 mg/day  Deaths (n=3), D/S for AE (n=3), OLT (n=4)

LDV/SOF+RBV 12 weeks LDV/SOF+RBV 24 weeks

100 87 89 87 89 86 90 80 1 relapses 60 1 death 1 relapses

1 LFU 1 death (%)

12 12 40 3 relapses 1 relapses 1 death 2 deaths SVR SVR 20

0 45/52 42/47 26/30 24/27 19/22 18/20 Overall Child Pugh B Child Pugh C

6 patients were transplanted and excluded from analysis 3 patients did not reach SVR12

Flam et al., AASLD 2014 Sofosbuvir + ledipasvir FDC: LONESTAR SVR24 rates

100

80 1 relapse 1 lost to 1 relapse follow up 60 after SVR8

40 Patients (%) Patients

20 19/20 21/21 18/19 18/19 21/21 0 RBV – + – – + Duration 8 8 12 12 12 (weeks) Treatment naïve (no cirrhosis) PI failures (50% cirrhosis)

S282T mutation (NS5B inhibitor RAV) and multiple NS5A RAVs were detected in the patient who relapsed after 8 weeks’ SOF/LDV; retreatment was successful with 24 weeks’ SOF/LDV

RAV: resistance-associated variant Lawitz E, et al. Lancet 2014;383:515–23 ALLY-1 (AI444-215): Phase 3, Open-label Study of DCV + SOF in Patients With Cirrhosis or Post-liver Transplant

DCV 60 mg QD + Cirrhotic SOF 400 mg QD + RBV Follow-up Post-liver DCV 60 mg QD + transplant SOF 400 mg QD + RBV

SOF, sofosbuvir. www.clinicaltrials.gov NCT02032875. SOLAR1: LDV-SOF in Decompensated Cirrhosis

 108 patients randomized 12 vs 24 weeks  Rbv: escalating dose staring at 600 mg/day  Deaths (n=3), D/S for AE (n=3), OLT (n=4)

LDV/SOF+RBV 12 weeks LDV/SOF+RBV 24 weeks

100 87 89 87 89 86 90 80 1 relapses 60 1 death 1 relapses

1 LFU 1 death (%)

12 12 40 3 relapses 1 relapses 1 death 2 deaths SVR SVR 20

0 45/52 42/47 26/30 24/27 19/22 18/20 Overall Child Pugh B Child Pugh C

6 patients were transplanted and excluded from analysis 3 patients did not reach SVR12

Flam et al., AASLD 2014 Unique Patient Populations Renal Impairment

eGFR/ CrCl Renal (ml/mi Impairment n) SOF LDV DCV OBV PTV SMV Mild 50-80 Standard Standard Standard Standard Standard Standard

Moderate 30-50 Standard Standard Standard Standard Standard Standard

Severe <30 Limited Data not Limited Standard Standard Standard data available data available available

ESRD/HD Limited Data not Limited Limited Limited Limited data available data data data data available available available available available

Abbreviations: CrCl, creatinine clearance; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; HD, hemodialysis. PEG: Pegylated interferon, RBV: Ribavirin, SMV: Simeprevir, SOF: Sofosbuvir, LDV: Ledipasvir, PTV: Paritaprevir, OBV: Ombitasvir, DSV: Dasabuvir;

AASLD Recommendations for Testing, Managing, and Treating Hepatitis C. Available at: http://www.hcvguidelines.org. Last accessed: Aug 8, 2015. Currently approved IFN-free treatment choices in the International label for patients with HCV GT-4 Duration (weeks) + RBV ? 12 24 SIM + SOF1,2 ±   DCV + SOF1,2 ±   SOF/LDV (FDC)3 ±   SOF2  -  SOF/PEG/RBV   - PARr/OMB   - Graz/Elba ±  - *Consideration should be given to potentially extending treatment duration, up to 24 weeks, especially for those subgroups with one or more factors historically associated with lower response rates to IFN-based therapies. 1. Daklinza (Daclatasvir) SmPC, Bristol-Myers Squibb Pharmaceutical Limited, October 2014. 2. Sovaldi (Sofosbuvir) SmPC, Gilead Sciences Ltd, March 2015. 3. Harvoni (LDV/SOF FDC) SmPC, Gilead Sciences Ltd, November 2014. Guidelines of the National Treatment Program in Egypt • Easy to treat group: – Treatment naïve – Total serum bilirubin ≤ 1.2 mg/dl. – Serum albumin ≥ 3.5 g/dl. – INR≤ 1.2. – Platelet count≥ 150.000/mm3. • Easy to treat group are eligible to be treated by any of the following regimens for 12 weeks: – Sofosbuvir + daclatasvir – Sofosbuvir + simeprevir – Sofosbuvir + ledipasvir – Paritaprevir-r/ombitasvir +ribavirin Guidelines of the National Treatment Program in Egypt • Difficult to treat group: – Peg-IFN treatment experienced – Total serum bilirubin ≥1.2 mg/dl. – Serum albumin ≤3.5 g/dl. – INR≥1.2. – Platelet count <150.000/mm3. • Difficult to treat group are eligible to be treated by any of the following regimens for 12 weeks: – Sofosbuvir +daclatasvir +ribavirin – Sofosbuvir + simeprevir – Sofosbuvir + ledipasvir +ribavirin – Paritaprevir-r/Ombitasvir +ribavirin • *The dose of ribavirin is 600 mg/day. A trial should be done to reach a dose of 1000 mg/day based on the patient tolerability. • *Neither paritaprevir-r/ombitasvir or sofosbuvir-simeprevir is given to patients with Child B or C cirrhosis. Guidelines of the National Treatment Program in Egypt • Patients with advanced liver disease: • Treatment only in one of several assigned specialized centers. – One of the following regimens is used for 12 weeks : – Sofosbuvir + Daclatasvir + Ribavirin – Sofosbuvir + Ledipasvir + Ribavirin – The dose of ribavirin is 600 mg/day. A trial should be done to reach a dose of 1000 mg/day based on the patient tolerability • Treatment of patients with post organ transplantation: – Treatment will be with Sofosbuvir + Daclatasvir for 24 weeks Guidelines of the National Treatment Program in Egypt

• Patients who failed previous Sofosbuvir containing regimen • Treatment will be with Sofosbuvir + Daclatasvir + Ribavirin Or Sofosbuvir + ledipasvir +ribavirin

• for 24 weeks. • The dose of ribavirin is 600 mg/day. A trial should be done to reach a dose of 1000 mg/day based on the patient tolerability Guidelines of the National Treatment Program in Egypt

• Patients with chronic kidney disease (CKD): • In patients having a serum creatinine exceeding the upper normal level, eGFR is calculated, and, accordingly, • Patients with CKD stage I-II (eGFR> 30 ml/min) are treated by the usual treatment regimens. • Patients with CKD stage III-V (eGFR≤ 30 ml/min) are treated by Paritaprevir-r/Ombitasvir+ribavirin, provided the following are fulfilled • Patients have compensated liver (Child A cirrhosis or no cirrhosis) • Hb level is at least 10 g/dL • The patient has no associated uncontrolled co-morbidity (Cardiac, neuro- psychic,..) • A nephrologist consultation is done. A report determining the treatment eligibility and necessity, and the exact ribavirin recommended dose (and time of administration in relation to dialysis). • In case of dialysis, the patient should be aware of the high risk of re- infection by signing a consent form. C-EDGE TN: Efficacy Results

SVR12 With 12 Wks of Grazoprevir/Elbasvir According to Genotype 95 92 99 100 100 80

80 (%)

60 12 12 40 SVR 20 299/ 144/ 129/ 18/ 8/ n/N = 316 157 131 18 10 0 All Pts GT1a GT1b GT4 GT6 Non-virologic failure 4 3 1 0 0 Breakthrough 1 1 0 0 0 Relapse 12 9 1 0 2 . Subgroup analysis: significantly lower SVR12 rates in pts with baseline HCV RNA > ‒ No differences according to race, IL28B status, presence of cirrhosis

Zeuzem Z, et al. EASL 2015. Abstract G07. Global Burde n of HCV Age 10 20 30 40 50 60 0

Acute Chronic Cirrhosis hepatitis HCV hepatitis latoxin 80% Transmission 10-20% Hepatoma

HBV 1-2% Schistosomiasis Obesity pollution Aflatoxin Smoking Pesticide Genetic Clinical course and evolution of disease after HCV infection& synergistic cofactors for disease progression AlKahera ElGadedh Hospital HCV treatment Unit . They treated 4000 chronic HCV patients during last year. . Cirrhotic patients F3 and F4 represent 90% of them about 3600 patients. . They reported 9 cases of newly developed HCC during the follow up period. . 9/3600 = 0.25% in comparison to the 1-2% (natural history) World Hepatitis Day in Egypt 28July 2015

. Egypt was chosen to host World Hepatitis Day 2015 as the country has demonstrated a high level of commitment by tackling hepatitis comprehensively in their plan of action for prevention, care and treatment. . The Ministry of Health has set up 32 specialized centres and introduced a new hepatitis C drug last year, which is the first highly- effective and approved direct-acting antiviral drug for the nationwide treatment of hepatitis C infection. This medication is safer than previous medications and has been shown to cure more than 90% of those completing treatment, in combination with other drugs. In a global first, the drug has been made available to Egyptian patients for US$ 900, which is 1% of its international price. So far, 128 000 people have started the new treatment. Conclusion

. PegIFN no longer recommended for first-line therapy of any patient. . 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. THANK YOU please visit

www.gamalesmat.com

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