1. Current Status and Benefits of Therapy for Chronic Hepatitis C Virus (HCV) Fuad AM Hasan Department Of Medicine Faculty of Medicine Kuwait University

4. Current Status and Benefits of Therapy for Chronic Hepatitis C Virus (HCV) Fuad AM Hasan Department Of Medicine Faculty of Medicine Kuwait University

5. Current And Future Treatment of HCV: The Count Down To The Demise of Hepatology Fuad AM Hasan Department Of Medicine Faculty of Medicine Kuwait University

6. True or False Hepatitis C is incurable. Treatment only suppresses the virus Interferon and ribavirin therapy are associated with minor adverse events HCV genotype is a major determinant of response to interferon based therapy. Boceprevir and telaprevir are effective against all genotypes. Sofosbuvir in combination with IFN and ribavirin cures around 90% of HCV infected patients

7. Outline HCV structure and life cycle HCV genotypes Standard treatment of HCV (2001-2011) Standard treatment of HCV genotype 1 (2011- 2013) Current treatment of HCV genotypes 1-6 The future

9. HCV Polyprotein Processing and Viral Protein Function McGovern B, Abu Dayyeh B, and Chung RT. Hepatology. 2008; 48:1700-12

10. HCV Life Cycle and DAA Targets Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000. Receptor binding and endocytosis Fusion and uncoating Transport and release (+) RNA Translation and polyprotein processing RNA replication Virion assembly Membranous web ER lumen LD ER lumen LD NS3/4 protease inhibitors NS5B polymerase inhibitors Nucleoside/nucleotide Nonnucleoside Block replication complex formation, assembly NS5A inhibitors RNA replication

11. HCV Genotypes

12. The Prevalence of HCV Genotype 4 in Kuwait Hasan et al. Hepatogastroenterology 2002 * Eastern province of Syria

13. Seroprevalence of HCV in Kuwait Ameen R et al. Transfusion. 2005 ;45:1973-80. Chehada W et al. J infect Public Health 2011 ;4:200-6 *Al Khalidi J et al. Unpublished data

14. Treatment of HCV 2001-2011 Pegylated Interferon plus Ribavirin combination was the standard treatment of HCV regardless of genotype until 2011

15. Sustained Virologic Responses By Genotype *Hasan F, et al. Am J Gastroenterol 2004;99:1733-1737

16. Interferon Plus Ribavirin Therapy Limitations 20-60 % do not respond Numerous side effects

17. Factors that affect outcome Treatment regimen PEG-IFN Ribavirin DAA Host factors Age, gender, race obesity, co-morbidities Genetic factors (IL28B and ITPA) Disease features Fibrosis, steatosis, co-infection (HBV, HIV) Viral factors Genotype / Subtype Quasispecies / Resistance Viral load Factors That Influence Response to Interferon Based Therapy

18. Most Important Factors that Influence Treatment Outcome HCV Genotype IL 28 B Polymorphism Degree of Fibrosis HCV RNA level

19. Side Effects of PegIFN/Ribavirin “Interferon Man” Fever Myalgias Hair loss Depression Anemia Rash Many others !

20. Was it the Interferon Man ?

21. Contraindications of Pegylated Interferon and Ribavirin De-compensated cirrhosis Coronary artery disease, heart failure, serious dysrythmia Proliferative diabetic retinopathy Kidney transplant patients Renal impairment (ribavirin)

22. 2011: Telaprevir and Boceprevir for HCV Genotype 1

23. Sustained Virologic Response: Telaprevir plus Peg Interferon Plus Ribavirin PR T12/PR 683/903 PR48 166/361 n/N = 74–79* INCIVO (telaprevir) EU SmPC *p<0.0001 T12/PR vs PR48 (79% versus 46%) in ADVANCE SVR, considered virologic cure, was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was used

24. SVR rates with boceprevir plus PR versus PR alone BOC RGT 233/368 BOC44/PR48 242/366 PR48 137/363 n/N = VICTRELIS (boceprevir) EU SmPC * * *p<0.001 for both boceprevir arms versus PR48 SVR was defined as undetectable HCV RNA at the last available value in the period at or after follow-up Week 24. If there was no such value, the follow-up Week value was carried forward

25. Adverse Events with Telapravir and Bocepravir Telaprevir Telaprevir plus P/RP/R Pruritis45-50%28% Nausea40-43%31% Rash56%34% Anemia37-39%19% Diarrhea28-32%17% Anorectal discomfort11%3% Boceprevir Anemia50%30% Dysgeusia35-43%16% Neutropenia25%19% Nausea46%42%

26. Contraindicated Drugs and Other Precautions for Telaprevir *These interactions have been studied; † Impaired renal/hepatic function; ‡ No clinical data are available regarding the treatment of organ transplant patients with TRADENAME in combination with peg-IFN/RBV. Therefore, the use of TRADENAME in organ transplant patients is not recommended; § Normal renal/hepatic function. Important Safety Information

27. December 2013 Simeprevir and Sofosbuvir

28. Efficacy With Simeprevir + P/R in Tx- Naive GT1 Patients: Phase III Trials SMV + P/R for 12 wks followed by 12-36 wks of P/R (placebo control) Jacobson I, et al. EASL 2013. Abstract 1425. 18/ 31 n/N = 5/ 17 188/ 229 60/ 113 82 53 58 29 100 80 60 40 20 0 No CirrhosisCirrhosis n/N = 419/ 521 133/ 264 138/ 165 36/ 83 49/ 84 23/ 44 228/ 267 70/ 133 100 80 60 40 20 0 SVR (%) Simeprevir + P/R Placebo + P/R 80 50 84 43 58 52 85 53 OverallGT1a Without Q80K GT1a With Q80K GT1b

29. Simeprevir Is Well Tolerated BilirubinHemoglobin Mean (µmol/L) Wks  Mild unconjugated hyperbilirubinemia → transporter  No anemia signal beyond P/R  Rash up to 25% (mild) Manns M, et al. EASL 2013. Abstract 1413. SMV + P/R P/R 30 20 10 0 0248121620243648 200 180 120 100 0248121620243648 160 140

30. Efficacy With Sofosbuvir + P/R in Tx-Naive GT1/4/5/6 Patients: Phase III Trials Single-arm study of sofosbuvir + P/R for 12 wks SVR12 (%) 92 80 100 80 60 40 20 0 No Cirrhosis Cirrhosis 252/27343/54 SVR12 According to Fibrosis Level SVR12 (%) 89 96 100 80 60 40 20 0 GT1GT4GT5/6 261/29227/287/7 SVR12 According to GT n/N = Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.

31. Efficacy of Sofosbuvir in GT2 1. Gane E, et al. EASL 2013. Abstract 5. 2. Jacobson I, et al. N Engl J Med. 2013;368:1867-1877. SVR12 (%) No CirrhosisCirrhosis 58/5944/5410/118/13n/N = 100 80 60 40 20 0 98 82 91 62 12 wks of SOF + RBVPegIFN/RBV Treatment Naive [1] 6/1025/267/923/23 No CirrhosisCirrhosis GT2 n/N = 100 80 60 40 20 0 96 60 78 16 wks of SOF + RBV 100 Treatment Experienced [2]

32. FDA Approved Indications for Sofosbuvir TreatmentDuration HCV genotype 1 &4Sofosbuvir+Peg-IFN+RBV12 wks HCV genotype 2Sofosbuvir + RBV12 wks HCV genotype 3Sofosbuvir + RBV24 wks HCV plus HCC Decompensated Cirrhosis Sofosbuvir + RBV48 wks or Tx

33. DO NOT USE TELAPREVIR OR BOCEPREVIR

34. The Future Interferon Free Regimens

35. IFN-Free Therapy for Tx-Naive GT1 HCV 1. Kowdley K, et al. EASL 2013. Abstract 3. 2. Lawitz E, et al. AASLD 2013. Abstract 215. 3. Everson GT, et al. AASLD 2013. Abstract LB-1. 4. Lawitz E, et al. AASLD 2013. Abstract 76. AI443-014 [3] Daclatasvir + Asunaprevir + BMS-791325 for 12 wks 77 100 80 60 40 20 0 100 96 89 25 2713 MK-5172 + MK-8742 20 mg + RBV MK-5172 + MK-8742 50 mg + RBV MK-5172 + MK-8742 50 mg C-WORTHY 12-wk regimens [4] 100 80 60 40 20 0 92 100 80 60 40 20 0 95 100 20 2119 SOF/LDV FDC 8 wks SOF/LDV + RBV 8 wks SOF/LDV FDC 12 wks LONESTAR [2] 100 80 60 40 20 0 96 90 79 80 12 wks AVIATOR [1] ABT-450/RTV + ABT-333 + ABT-267 + RBV SVR12/24 (%) 24 wks n =

36. Is the demise of Hepatology imminent ? HCV cure rate approaching 95% HBV incidence declining rapidly due to vaccination Treatment of HBV and HCV using direct acting antivirals is safe, simple and can be handled by internists. Alcoholic liver disease and NASH can be handled by internists Only end stage liver disease and liver transplant patients need specialty care ?