Towards an End to HCV Epidemic in Egypt New Treatment for HCV G4 Towards an End to HCV Epidemic in Egypt Now let us move on to talk about the epidemiology of hepatitis C.

Several potential innovative drug targets in HCV IFN-lambda A type III interferon with a restricted distribution of receptors contributing to a favourable adverse event profile7 BMS-9141438 Cyclophilin A Host protein involved in HCV replication through interaction with NS5A and the HCV polymerase Alisporivir5,* SCY-6351 c NS2 NS3 NS5A NS5B E1 E2 NS3/4A NS5A NS5B A serine protease, essential for post-translational processing of HCV polyproteins Multifunctional membrane- associated phosphoprotein, essential component of the HCV-RNA replication complex An HCV-specific, RNA-dependent RNA polymerase Boceprevir1 Telaprevir1 ABT-450/r2 Sovaprevir3 Asunaprevir11 Simeprevir9 Faldaprevir12 Danoprevir12 GS-945113 MK-517214 ACH-806/GS-91321 Daclatasvir4 Ledipasvir4 ABT-2672 PPI-6686 AZ-6894 BMS-8243934 PPI-4614 Nucleos(t)ide analogue Sofosbuvir10 Mericitabine15 VX-13520 Non-nucleoside analogue BI-20712716 ABT-3332 ABT-07217 BMS-79132518 Tegobuvir12 Setrobuvir12 VX-22219 Filibuvir12 *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/hcv-treatment/bi-207127. 17. http://www.pipelinereport.org/browse/hcv-treatment/abt-072. 18. http://clinicaltrials.gov/show/NCT01193361. 19. http://www.vrtx.com/research-development/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].

Characteristics of DAA PI 1st generation PI 2nd generation NS5A Inh. 1st generation NS5A Inh. 2nd 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

In different patient types Many studies have looked at different ways of combining these compounds Alfa RBV NS5A In different patient types NS5A Alfa RBV NS3/4A Different genotypes Treatment-naive Null-responders to prior therapy Intolerant to previous therapy RBV Alfa NS3/4A Lambda RBV Lambda RBV NS5A NS5A NS3/4A NS5B (non-nuc inhibitor) NS5B (nuc inhibitor) RBV NS5A NS3/4A NS3/4A Lambda RBV 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 Response Duration Regimen Patients Study SVR 24 Non cirrhotic: 90% Wight based RBV: 68% Low dose RBV: 48% 12 weeks A: 10 non cirrhotic B: 50 All stages of fibrosis: 25 (weight based RBV) 25 (low dose RBV: 600) No: 60 treatment-naive patients genotype 1 with bad predictors: (African-American, high BMI, low frequency of IL28B CC, viral load and advanced fibrosis) Sofosbuvir and Ribavirin for Hepatitis C Genotype 1 in Patients With Unfavorable Treatment Characteristics Osinusi (2013) JAMA 12 weeks SVR12 68% 24 weeks SVR12 93%: Or 24 weeks Sofosbuvir + RBV 60 patients Egyptians G4 Treatment naive and -experienced Sofosbuvir plus ribavirin in the treatment of chronic HCV genotype 4 infection in Egyptian patients Ruane (2013) Hepatology 12 weeks SVR12 77% 24 weeks SVR12 90% G4 100 patients Egyptian study

Sofo+IFN+RBV Response Duration Regimen Patients Study SVR 24 A: 89% C: 87% 12 w 24 weeks 24 weeks (12 +12) 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 316 naïve genotype-1 ATOMIC Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial Kowdley et al (2013) Lancet 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) 12 weeks Sofosbuvir + PegIFN + RBV G1, 4, 5, 6 Naïve n = 327 (G1 79%) NEUTRINO Sofosbuvir for previously untreated chronic hepatitis C infection Lawitz (2013) NEJM

Sofo and other DAA combination trials Study Patients Regimen Duration Response Electron (1) Once daily sofosbuvir/ledipasvir fixed dose combination with or without ribavirin G1 prior null responders with compensated cirrhosis and in naive, noncirrhotic patients Sofosbuvir+ ledipasvir With or without RBV 12 weeks 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 LONESTAR (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 trial G 1 treatment-naive, noncirrhotic 8 weeks 8 weeks with RBV: 100% 8 weeks without RBV: 95% 12 without RBV: 95% 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 Noncirrhotic and cirrhotic, treatment-naıve and prior null responder Sofosbuvir+simeprevir with or without RBV for 12 or 24 weeks 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. Gane (2013), Hepatology 2) Lawitz (2013), Lance, 3) Jacobson (2013), Hepatology

Treatment experienced SOF + RBV: In genotype 4 This study done on 60 Egyptians (G4) living in USA 20% of them are cirrhotics. SVR12 (%) 11/14 14/14 10/17 13/15 21/31 27/29 12 Week SOF + RBV 24 Week SOF + RBV 12 Week SOF + RBV 24 Week SOF + RBV 12 Week SOF + RBV 24 Week SOF + RBV Treatment naïve Treatment experienced All Ruane PJ, et al. EASL 2014. P1243 Ruane PJ, et al. EASL 2014. P1243 Ruane PJ, et al. AASLD 2013. Abstract 1090

Sofosbuvir+ Ribavirin in G4 (Egypt) 100 patients (20% C, 3 centers) Arm 1 (12 wks) Arm 2 (24 wks) (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

SOF STUDIES EGYPTIAN 1. Lawitz et al. DDW 2013. 2. Ruane et al. EAS L2014. Poster 1242. 3. Esmat et al,AASLD. 2014 EGYPTIAN

Non invasive detection of hepatic fibrosis Fib-4 Formula http://gihep.com/calculators/hepatology/fibrosis-4-score/

Non invasive detection of hepatic fibrosis Fibroscan

Non invasive diagnosis of Advanced hepatic fibrosis(>F2) AUC No of patients Best cutoff sensitivity specificity PPV NPV accuracy LR+ LR- *Fib-4 0.71 36841 1.45 0.69 0.63 0.28 0.90 1.9 0.49 ♠Fibroscan 0.82 231 9.5 0.87 0.68 0.93 0.86 6.52 0.20 Fib-4 Fibroscan >1.45 ≤1.45 Wait or Do liver biopsy Do not treat ≤9.5 Treat >9.5 *National Committee for control of viral hepatitis, NNTC data , Jan 2014 ♠ Esmat et al, Arab Journal of Gastroenterology 14 (2013) 109–112

PEARL 1 INTERFERON-FREE REGIMENS OF ABT-450/R + ABT-267 WITH OR WITHOUT RIBAVIRIN In 135 Ch HCV GENOTYPE 4 Patients Treatment-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

ABT-450/r + Ombitasvir +RBV*4 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 SVR (%) 27/28 11/14 10/17 14/14 13/15 29/35 42/42 37/37 12/12 12/12 41/72 SOF/PR1 NEUTRINO SOF/RBV2 12 wk SOF/RBV2 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 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.

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 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) TN: SVR 89% 31/35 Prior Relapsers: SVR 86% 19/22 Non Responders 57% 41/72 Option 3 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) Theoretically effective, few data available SVR 100% in 12/12 COMMAND 1 trial Option 4 IFN intolerant or ineligible C2:R + SOF 24 wks „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 Option 5 B2: SOF+SMV 12 wks Consider 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 6 B2: SOF +DAC (60mg) 12 wks TN or 24wks TE „no data with this combination- it is likely that data can be extrapolated“

COST EFFECTIVENESS CHART 120,000 L.E SVR % COST/PT 12,000 L.E 9600 L.E 12,600 L.E 6600 L.E *NAÏVE, NON CIRRHOTIC, LOW VIREMIA,

Eradication of HCV in Egypt Overcoming the Barriers

Annual mortality assumed at: 50/100,000 Or 5/1000 for HCV positive patients

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

HCV Treatment guidelines (Draft)

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.

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 1.45. 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.

Upper GI endoscopy is mandatory in the following circumstances: a. Histological evidence of cirrhosis by liver biopsy b. Fibroscan > 19.2 K.Pa c. Platelet count < 100,000

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

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 8 Total bilirubin ≤ 3 Albumin ≥ 2.5 Platelet count ≥ 50,000 Prtothrombin concentration ≥ 50% Hemoglobin concentration ≥ 10 mg Otherwise, waiting for new DAAs combination is advised.

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 ≥ 9 Presence 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)

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.

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.

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.

Gamal Esmat