Putting progress into practice for HCV care in Egypt

Putting progress into practice for HCV care in Egypt Chairs: Maria Buti, Ashraf Abou-Gabal, Sami Abdel Fattah, Ali Farag, Faisal Sanai This session has been funded by Gilead Sciences Europe The content of the programme is at the discretion of the faculty

Session disclaimer This is an independent programme for which Gilead Sciences Europe Ltd. ( Gilead ) provided funding; Gilead has had no input into the content of the materials and/or presentations used during this session This session includes reference to use of unlicensed products or unlicensed indications The presentations express the views and opinions of the presenter which were based on information and data available at the time Any patient cases and treatment options referred to are in the context of contemporary knowledge and medical practice in the field; unlicensed doses and indications are included

Hepatology on the Nile 2 Putting Progress into Practice for HCV Care in Egypt Cairo, 25 September 2014 Welcome Maria Buti Autónoma University, Barcelona; Chief of Internal Medicine and Hepatology, Vall d Hebron University Hospital, Barcelona, Spain

Disclosures Advisor: AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharp & Dohme, Novartis Lecturer: Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharp & Dohme, Novartis Clinical trials: Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharp & Dohme, Novartis, Roche

Programme and faculty revised Time Title Speaker 14.00 Welcome & introduction Maria Buti (Spain) 14.05 HCV co-infection: no longer a special population? Karine Lacombe (France) 14.25 HCV guidelines: from paper to practice Ashley Brown (UK) 14.45 Can we take HCV out of the transplant equation? 15.05 Linking care to cure in difficult-to-reach populations Maria Buti (Spain) Ashley Brown (UK) 15.25 Summary Maria Buti (Spain) 15.30 Close

Global HCV burden and genotype distribution 6 HCV genotypes (GT 1 6) GT 1 and GT 4 predominate in Egypt and Middle East Messina JP, et al. Hepatol 2014; doi: 10.1002/hep.27259 GT: genotype

HCV a uniquely Egyptian epidemic Egypt s HCV burden is at least 4 x greater than that of any other country 1 in 7 sero-positive (global average 1 in 50) But, not only is the Egyptian HCV problem one of size, the prevalent GT 4 is one that is not commonly found in the rest of the world Drug development has primarily focused on GT 1 to date Yahia M, Nature 2011:474:S12 3

The unique Egyptian situation requires a unique approach to HCV management Number of individuals with late-stage liver disease is projected to increase 1 Although Egypt now has the world s largest HCV treatment programme, 2 the current treatment rate and efficacy are not sufficient to manage the disease burden 1 The National Treatment Programme needs to evolve with the availability of new drugs 1. Razavi H, et al. J Viral Hepatitis 2014;21(Suppl 1):34 59; 2. Waked I et al. Arab J Gastro. 2014;15:45 52.

Benefits of second wave anti-hcv DAAs SVR rates 90% Pangenotypic, short treatment courses Better adverse effect profiles

Hepatology on the Nile 2 Putting Progress into Practice for HCV Care in Egypt Cairo, 25 September 2014 Can we take HCV out of the transplant equation? Maria Buti Autónoma University, Barcelona; Chief of Internal Medicine and Hepatology, Vall d Hebron University Hospital, Barcelona, Spain

Disclosures Advisor: AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharp & Dohme, Novartis Lecturer: Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharp & Dohme, Novartis Clinical trials: Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharp & Dohme, Novartis, Roche Note: This presentation includes reference to investigational agents not currently approved for use in HBV by the EMA, FDA and Egyptian MOH

Most liver transplants (LT) in Europe due to cirrhosis are caused by hepatitis viruses European analysis of 55,714 transplants in Europe 1 2% 1% 8% 4% 4% 9% 39% Virus-related Alcoholic Viral and alcoholic Autoimmune Secondary biliary Unknown 33% Primary biliary Others HCV-related cirrhosis accounts for 66% of virus-related LT, therefore approximately 25% of LT are a result of HCV 2 1. European liver transplant registry LTR. ww.eltr.org/spip.php?article162 (accessed September 2014); 2. EASL. The burden of liver disease in Europe. www.easl.eu/assets/application/files/54ae845caec619f_file.pdf (accessed June 2014) Study period January 1998 December 2012

This is also true in Egypt Egyptian analysis of 58 transplant candidates (12 transplanted; 46 control) 48% 43% Virus-related Biliary Schistosomiasis Cryptogenic Mixed 2% 3% 3% Khalaf H, et al. Suez Canal Univ Med J. 2000:3;157 67

Challenges for liver transplantation in Egypt Cadaveric organ donation is illegal in Egypt Many patients travel to America, Europe or China Living donor liver transplantation (LDLT) has provided the only option for patients with ESLD Donor must be the patient s relative, between 20 40 years old and free of any diseases Concerns over organ donation for money In Western countries, the average waiting time for an overseas patient to receive a cadaveric graft is 18 24 months Significant mortality during this waiting period 1. Yosry A, et al. Transplantation Proceedings. 2008:40;1481 4; 2. El-Gazzaz GH and El-Elemi AH, Transplant Research and Risk Management. 2010:2;41 46 ESLD: end-stage liver disease

Decreased survival among HCV-infected liver transplanted recipients: 1991 2000 1.0 0.9 Patient survival (%) 0.8 0.7 0.6 0.5 0.4 0.3 P=0.0001 log-rank test 239 283 HCV- HCV+ Years HCV+ HCV- 1 77% 87% 0.2 3 65% 83% 0.1 5 61% 76% 0.0 1 2 3 4 5 6 7 8 9 7 55% 70% Years post-transplantation Berenguer et al, Hepatology 2002;36:202-210

Reduced liver-related mortality liver graft recipients with recurrent HCV who achieve SVR Probability of survival in patients who did not maintain SVR (n=61) 1 Patient survival since treatment initiation in patients without baseline cirrhosis (n=78) 2 100 90 Sustained virological responders 1.0 Survival Probability (%) 80 70 60 50 40 30 20 10 0 Patients with treatment failure Patient survival (%) 0.8 0.6 0.4 0.2 0.0 SVR Yes No Yes-censored No-censored 0 10 20 30 40 50 60 0.00 365 730 1095 1460 1825 2190 2555 Months Follow-up since treatment initiation (days) 1. Picciotto et al, J. Hepatology 2007; 2. Berenguer, Am. J. of Transplant. 2008 SVR: sustained virologic response; TF: treatment failure

Recurrent HCV treatment with TVR or BOC + PEG- IFN/RBV: Cohort and clinical studies Authors DAA Pts Population GT 1a SVR12 Discontinuation Faisal et al TVR 76 F0-F2 72% 58% 44% BOC Burton et al TVR 125 F3-F4 48% 58% 59% 20% Coilly et al TVR 79 F3-F4, FCH 78% BOC 33% 46% 55% Pungpapong et al TVR 60 F3-F4 50% FCH 8% 68% 50% 20% Predictors : SVR: Ciclosporin, Treatment duration, Infections: FCH, Bilirubin; Anaemia, Thrombocytopenia Faisal et al, Ann of Hepatol 2014;13:525-32; Burton et al, J Hepatol. 2014 Sep;61:508-14; Coilly et al, J Hepatol 2014;60:78-86; Pungpapong et al, Liver Transpl 2013;19:690-700 BOC: boceprevir; ; DAA: direct-acting antiviral FCH: fibrosing cholestatic hepatitis; GT: genotype; PEG-IFN: pegylated interferon; Pts: patients; RBV: ribavirin; TVR: telaprevir

Clinical case 1 Male patient, 52 years old, GT 4 Liver transplant in 2008 Recurrence of HCV FCH; FibroScan = 18.9 kpa; MELD = 26 Bilirubin: 13 mg/dl (223 µmol/l); albumin: 35 g/l (3.5 g/dl) Treated with PEG-IFN + RBV Failed to respond What are his next options? FCH: fibrosing cholestatic hepatitis; MELD: model for end-stage liver disease

EASL: Recommended treatment options: Indication for LT Child-Pugh A with HCC: SOF + RBV until LT SOF + daclatasvir + RBV until LT probably better Finite (12 weeks) SOF + PEG-IFN + RBV also acceptable Patients with decompensated cirrhosis awaiting LT (Child-Pugh B or C) SOF + RBV in experienced centres under close monitoring SOF + daclatasvir + RBV until LT probably better Patients with post-transplant recurrence of HCV infection should be considered for therapy IFN-free treatment is recommended No dose-adjustment is required for tacrolimus or ciclosporin with any of the available combinations EASL Recommendations on Treatment of Hepatitis C 2014. http://files.easl.eu/easl-recommendations-on-treatment-of-hepatitis-c.pdf. Accessed September 2014 HCC: hepatocellular carcinoma; IFN: interferon; SOF: sofosbuvir

Safety and tolerability profiles of newly approved DAAs: Simeprevir and sofosbuvir Simeprevir (2nd wave PI) 1 Once-daily dosing GT 1, 4 Main AEs Rash including (22%) Pruritus (22%) Photosensitivity (5%) Mild hyperbilirubinaemia (27%) Due to OATP1B1/MRP2 transporter inhibition Resistance in treatment failures Sofosbuvir 2 Once daily dosing Pangenotypic Minimal AEs Headache ~20% No resistance detected in treatment failures 1. Janssen. OLYSIO (simeprevir). Summary of Product Characteristics, May 2014; 2. Gilead Sciences Europe. SOVALDI (sofosbuvir), Summary of Product Characteristics, January 2014 AE: adverse event; DAA: direct acting antiviral; OATP: organic anion-transporting peptide; MRP: multidrug resistant protein

SOF + RBV for established recurrent HCV post-lt LT 6 months and 150 months MELD 17 Treatment-naïve and treatment-experienced with recurrent HCV (N=40) SOF 400 mg/d + RBV starting at 400 mg/d with dose escalation SVR12 Study week 0 24 36 No response guided therapy SOF + RBV (N=40) Male, n (%) 31 (78) Median age, y (range) 59 (49 75) Genotype, %: 1a / 1b / 2 /3 / 4 55/28/0/15/3 Metavir-equivalent fibrosis stage, % F0 F2/F3/F4 38/23/40 Prior HCV treatment, % Previous PI failures, % Immunosuppressants (%): tacrolimus/ mycophenolate mofetil/ prednisone/ciclosporin/azathioprine 88 23 70/35/ 28/25/5 63% F3/4 Samuel D, et al. EASL 2014; Poster #1232

SOF + RBV for 24 weeks resulted in high SVR rates HCV RNA <LLOQ (%) 100 80 60 40 100 100 73 70 70 20 0 40/40 40/40 29/40 28/40 28/40 Week 4 EOT SVR4 SVR12 SVR24 Relapse was not influenced by RBV dose or exposure No DDI between SOF and any immunosuppressive agents in this study SOF + RBV in patients with recurrent HCV after LT was well tolerated No deaths, graft losses or episodes of rejection reported Samuel D, et al. EASL 2014; Poster #1232 DDI: drug drug interactions; EOT: end of therapy; LLOQ, lower limit of quantification (25 IU/mL)

Compassionate use of SOF in patients with severe recurrent HCV Including FCH following LT Severe recurrent hepatitis C post-lt likely to have <1 yr life expectancy SOF 400 mg/d for 24-48 weeks plus RBV ± PEG-IFN Severe acute hepatitis/early recurrence (<12 mo from LT with typical biochemical-histological findings), n=48 Post-LT compensated (F4) or decompensated cirrhosis, n=56 Early term due to AE n=7 Liver transplant n=12 Death n=13 SOF Compassionate Use Programme SOF + RBV ± PEG, n=104 Completed 24-48 weeks treatment n=72 Forns X. EASL, London 2014

Results: Baseline characteristics Overall (n=104) Age, years 55 (16 76) Male recipient 76 (73%) HCV RNA, log 10 IU/mL 8.4 (1.3 8.9) GT, 1 / 4 vs 2 / 3 88 / 8 vs 1 / 7 Bilirubin, mg/dl 3.1 (0.4 45) Albumin, g/dl 3.1 (1.3 12.2) INR 1.3 (0.8 4.5) ALT, IU/L 71 (8 1162) MELD 15 (6 43) Time from LT to treatment, months 17 (1 262) Forns X. EASL, London 2014

Overall, 62% of patients achieved SVR 100 4/93 Patients (%) 80 60 40 8/93 15/85 4/85 13/85 HCV RNA >LLOQ Lost to follow up Death HCV RNA <LLOQ 62% SVR 20 0 81/93 53/85 EOT SVR12 Forns X. EASL, London 2014

Over 79% of patients receiving at least 1 dose of SOF improved or were stable All patients who received 1 dose of SOF are included 100 79% improved or stable Patients (%) 80 60 40 58 20 0 21 21 60/104 22/104 22/104 Improved* Stable Worsened/deceased * Significant decrease in hepatic encephalopathy, improvement or disappearance of ascites, or improvement in liver-related laboratory values Forns X. EASL, London 2014

Post-transplant recurrent hepatitis C Patients with post-transplant recurrence of HCV infection should be considered for therapy IFN-free treatment is recommended No dose adjustment is required for tacrolimus or ciclosporin with the available combinations

Clinical case 2 Male patient, 52 years old, GT 4 cirrhotic HCV infection since 2001 Treated with PEG-IFN + RBV Could not tolerate the full dose and only achieved a partial response Platelet count: 60 x 10 3 /µl; albumin: 3.2 g/dl (32 g/l); bilirubin: 4.5 mg/dl (77 µmol/l), mild ascites; MELD=15 HCC diagnosed in November 2013 and on LT waiting list What could be done before a donor liver becomes available? HCC: hepatocellular carcinoma; MELD: model of end-stage liver disease

SOF + RBV pre-lt to prevent HCV recurrence post-lt Open-label, Phase 2, GT 1 6 study of SOF + RBV for the prevention of recurrent HCV infection Undergoing LT for HCC 2 to HCV N=61 Time 0 SOF 400 mg/day + RBV 1000 1200 mg/day No response guided therapy Liver transplant (up to 48 weeks) 12 weeks post-transplant virological response (ptvr) SOF + RBV (N=61) Male, n (%) 49 (80) Median age, y (range) 59 (46 73) BMI < 30 kg/m 2, n (%) 43 (70) Genotype, % 1a/1b/2/3a/4 39/34/13/11/2 IL28B non-cc allele, n (%) 47/60 (78) CPT score, n (%) 5/6/7/8 43/30/23/5 Median MELD score, (range) 8 (6 14) Prior HCV treatment, n (%) 46 (75) Curry MP, et al. ILTS 2014; Oral #137 SOF: sofosbuvir; 2 o :secondary

SOF + RBV suppressed viral load and prevented HCV recurrence post-transplant Post-transplant virological response >30 days TND No Recurrence (n=30) Recurrence (n=10) Viral response rate (%) 100 80 60 40 20 0 93 Transplant 70 43/46* 30/43* ptvr12 No recurrence in 24/25 (96%) of patients who maintained HCV RNA TND >30 days Median days TND No recurrence: 99 Recurrence: 5.5 p <0.001 Of the 61 patients treated, 46 underwent LT 0 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450 480 Days with HCV RNA Continuously TND Prior to Liver Transplant SOF + RBV treatment prior to transplantation prevented HCV recurrence in most patients (70%) who were HCV RNA <LLOQ (TND) at time of LT Curry MP, et al. ILTS 2014; Oral #137 *3 subjects were >LLOQ at transplant; 1 subject has not reached ptvr12; BL: baseline; SD: standard deviation; TND: target not detected

HCV care is progressing and this will also be the case for LT patients Several IFN-free regimens are at an advanced stage of development, including: SOF + daclatasvir Ledipasvir/SOF Paritaprevir/ritonavir/ombitasvir + dasabuvir ± RBV MK-5172/MK-8742 ± RBV Asunaprevir, ledipasvir, paritaprevir/ritonavir, ombitasvir, dasabuvir, MK-5172 and MK-8742 are investigational agents and not approved for use in HCV by the EMA, FDA or Egyptian MOH

Paritaprevir/ritonavir/ombitasvir + dasabuvir + RBV in LT recipients with recurrent GT 1 24 weeks therapy in LT recipients with recurrent GT 1 infection; treatment-naïve; F0 2 (n=34); CNI doses adjusted for paritaprevir/r % HCV RNA undetectable 100 80 60 40 20 0 100 100 97 96 34/34 34/34 32/33 25/26 Week 4 (RVR) Week 24 (EOT) SVR4 SVR12 There were no on-treatment failures One patient experienced relapse (post-treatment Day 3) Clinically relevant DDIs seen between regimen and immunosuppressants Kwo P. EASL 2014; oral #114 Paritaprevir/ritonavir, ombitasvir and dasabuvir are investigational agents and not approved for use in HCV by the EMA, FDA or Egyptian MOH CNI: calcineurin inhibitor; EOT: end of therapy; RVR: rapid virological response

Ongoing clinical trials including HCV transplant recipients Identifier Regimen Treatment Duration Genotype Child Pugh class Trial Phase NCT01938430 LDV/SOF + RBV 12 24 wk 1, 4 Pre-LT: B, C Post-LT: A, B, C 2 NCT02032875 DCV/SOF + RBV 12 wk 1 6 Pre- and Post-LT: A 3 NCT01938625 DCV + SMV + RBV 24 wk 1b Post LT Metavir F1 F4 (Child A) 2 NCT01782495 Paritaprevir/r/ Ombitasvir + Dasabuvir ± RBV 12 wk 1 Post LT Metavir F1 F3 (no cirrhotics allowed) 2 Forns et al, Digestive and Liver Disease in press; www.clinicaltrials.gov Paritaprevir/ritonavir, ombitasvir and dasabuvir are investigational gents and not approved for use in HCV by the EMA, FDA or Egyptian MOH; DCV: daclatasvir; LDV: ledipasvir; r: ritonavir; Wk: week

Drug drug interactions between DAAs and calcineurin inhibitors DAA Ciclosporin Tacrolimus Healthy volunteers Dose adjustment Healthy volunteers Dose adjustment Boceprevir 1,2 * AUC 2.7 fold 2 fold AUC 17 fold 5 fold Telaprevir 2,3 ** AUC 4.6 fold 4 fold AUC 70 fold 35 fold Paritaprevir/r 4 AUC 5.8 fold 5 fold AUC 58 fold 100 fold Simeprevir 5 AUC 19% Under investigation. Not recommended AUC 17% Not necessary Sofosbuvir 6 No change Not necessary No change Not necessary Daclatasvir 7 No change Not necessary No change Not necessary *AUC Inf is given **AUC Last is given Adapted from Forns et al, Digestive and Liver Disease in press Paritaprevir is not approved for use in HCV by EMA, FDA or Egyptian MOH 1.Hulskotte et al. Hepatology 2012;56:1622-1630. 2.Coilly et al. Antimicrob Agents Chemother 2012;56:5728-5734. 3.Coilly et al. Liver Int 2013;33 Suppl 1:56-62. 4.Kwo P et al. J Hepatol 2014;60(Suppl 1):S47. 5.Ouwerkerk-Mahadevan et al. J Hepatol 2013;58(S1):S365. 6.Mathias et al. Hepatology 2012;56(Suppl 1): 1063A-1064A. 7.Fontana et al. Liver Transpl 2012;18:1053-1059

Summary taking HCV out of the transplant equation The future is more optimistic for patients with HCV-related ESLD Clear evidence that re-infection post-lt can be prevented by treating HCV before the procedure and cured afterwards with effective DAA treatment, even in those with the severest form of disease SOF + RBV data show promise high efficacy and no DDIs with common immunosuppressant agents To put progress into practice in Egypt, a transformation in management approach is required so that patients are cured of HCV before they require a transplant

Q&A

Hepatology on the Nile 2 Putting Progress into Practice for HCV Care in Egypt Cairo, 25 September 2014 Meeting Close Maria Buti Autónoma University, Barcelona; Chief of Internal Medicine and Hepatology, Vall d Hebron University Hospital, Barcelona, Spain

Vision for future treatment of chronic HCV: Putting progress into practice ALL PATIENTS ALL HCV GTs 1 6 including BOC/TVR failures including decompensated cirrhosis Including HIV/HCV co-infection 1 Pill/day for 8 12 wks Simple prescribing Treatment uptake Health burden

Putting progress into practice for HCV care in Egypt: Summary Recent advances, once accessible, have the potential to transform and simplify patient management New potent, pangenotypic, well tolerated IFN-limiting and IFN-free treatment options of short duration are emerging Need to prioritise and treat now those patients with greatest need Need to preventing the currently high rates of reinfection through appropriate hygiene manoeuvers

THANK YOU FOR YOUR ATTENTION

Putting progress into practice for HCV care in Egypt Chairs: Maria Buti, Ashraf Abou-Gabal, Sami Abdel Fattah, Ali Farag, Faisal Sanai This session has been funded by Gilead Sciences Europe The content of the programme is at the discretion of the faculty