1. Antiviral HCV-Therapy - A Revolution - Dr. Jurriën G.P. Reijnders, MDL arts j.reijnders@hagaziekenhuis.nl Afdeling Maag-, Darm-, en Leverziekten, HagaZiekenhuis, Den Haag

2. Clearance of Chronic HCV Infection –HCV RNA negativity in the circulation 12-24 weeks following antiviral therapy –Long-term durability 1 –The marker of successful antiviral therapy 1 Swain Gastroenterology 2010 Antiviral therapy has the potential to result in a Sustained Virological Response (SVR)

3. SVR and Improvements of Clinical Complications What is the clinical relevance of SVR?

4. Largest histological study: –n=679 with ≥METAVIR F2 –2 nd liver biopsy 24 weeks post treatment Most striking result: –75 of 153 (49%) patients with cirrhosis scored ≤METAVIR F3 after therapy Regression of Hepatic Fibrosis Poynard Gastroenterology 2002

5. Cohort study among 96 patients with chronic HCV-infection and METAVIR F4 –Median time to post-treatment liver biopsy: 17 months –Fibrosis regression: F4  ≤F2 Regression of Fibrosis Linked to Clinical Outcome Mallet Ann Int Med 2008 Median follow-up –9.8 years Less cirrhosis-related events in case of fibrosis regression Non-reversers Reversers p = 0.01 Cirrhosis-related Events (%)

6. Follow-up study among all consecutive patients with chronic HCV infection –Histological proof of advanced hepatic fibrosis (Ishak F4-6) –Initiated interferon-based therapy (1990-2003) SVR and Clinical Endpoints..... Toronto Rotterdam Bern Hannover Homburg

7. Liver Failure (%) Hepatocellular Carcinoma (%) 5-year occurrence With SVR: 0% Without SVR: 13% (8-18%) 5-year occurrence With SVR: 4% (0-20%) Without SVR: 13% (8-19%) Without SVR SV R Without SVR SV R p<0.001p=0.19 Veldt Ann Int Med 2007 Cirrhosis-Related Complications and SVR N = 479 Median follow-up of 2.1 years

8. Liver-Related Survival (%) Time - years 876543210 100 95 90 85 80 0 Without SVR With SVR p=0.024 Veldt Ann Int Med 2007 SVR was Associated with Reduced Liver-Related Mortality

9. Reduced Incidence of HCC p<0.001 Bruno Hepatology 2007 –883 cirrhotic patients from Italy –Median follow-up 8.0 years Cardoso J Hepatol 2010 –307 cirrhotic patients from France –Median follow-up 3.5 years

10. Morgan Ann Int Med 2013

11. Clinical Benefit Beyond the Liver Hsu et al. Gut 2015 Acute Coronary Syndrome p=0.027 End-Stage Renal Disease p<0.001 Ischemic Stroke p=0.001 Nationwide Taiwanese cohort study –12,384 treated patients –24,768 propensity score- matched untreated controls –Median follow-up: 3.3 years

12. Extrahepatic Mortality Innes Hepatology 2015 Nationwide cohort study n = 3,385 –Expected to include over 80% of the HCV-infected population in Scotland Various stages of fibrosis Median follow-up: 5.3 years 0.05.1.15.2 Cumulative Incidence 02.557.5 Time - years Adjusted HR = 0.68 p = 0.026 Without SVR With SVR Liver-unrelated deaths

13. All-Cause Mortality According to Response p<0.001 Time - years Cumulative mortality (%) Without SVR With SVR 30 8.9% (95%CI 3.3-14.5) 26.0% (95%CI 20.2-28.4) Van der Meer JAMA 2012 530 patients with Ishak F4-6 Median Follow-up: 8.4 years

14. Van der Meer JAMA 2014 100 90 80 70 60 2345678910 1 0 Time - Years Cumulative survival (%) Compared to the General Population Matched Dutch Population With SVR 91% (95%CI 86-97) p=0.571 Without SVR p<0.001 74% (95%CI 72-80)

15. Antiviral HCV-Therapy - A Revolution -

16. 1991 2001 0 20 40 60 80 100 SVR (%) 1995 1998 IFN (longer treatment duration ) INF RBV PegIFN RBV 2012 PegIFN RBV + DAA 2015 IFN (RBV) + Multiple DAAs SVR in Almost All Patients All patients Cirrhosis

17. CoreE1E2 P7P7 NS2NS3 NS4 A NS4BNS5ANS5B Direct Acting Antivirals (DAAs) NS3-4A protease Inhibitors ~previr Telaprevir Boceprevir Simeprevir Paritaprevir NS5A Inhibitors ~asvir Daclatasvir Ledipasvir Ombitasvir NS5B polymerase Inhibitors ~buvir Sofosbuvir Dasabuvir 2013-2015: >20 clinical trials on HCV in NEJM only…!

18. Harvoni (sofosbuvir/ ledipasvir) Viekirax (ombitasvir/ paritaprevir/ ritonavir) Exviera (dasabuvir) Available IFN-free Regimens in The Netherlands Sovaldi (sofosbuvir) RIBAVIRIN Sovaldi (sofosbuvir) Daklinza (daclatasvir) Olysio (simeprevir) NO MORE RESTRICTIONS!!

19. Treatment of HCV genotype 1 45 year old man Former intravenous drug user HCV genotype genotype 1a HCV RNA 10 7 IU/mL No evidence for cirrhosis

20. Standard-Dose Peginterferon alfa-2b + Ribavirin -------------------------------------------------------------------- Peginterferon alfa-2b: 1.5 µg/kg 1x/week + Ribavirin: 800-1400 mg/d (by weight) Peginterferon alfa-2a + Ribavirin -------------------------------------------------------------------- Peginterferon alfa-2a: 180 µg 1x/week + Ribavirin: 1000-1200 mg/d (by weight) Low-Dose Peginterferon alfa-2b + Ribavirin -------------------------------------------------------------------- Peginterferon alfa-2b: 1.0 µg/kg 1x/week + Ribavirin: 800-1400 mg/d (by weight) Source: McHutchison JG, et. al. N Engl J Med. 2009;361:580-93. Peginterferon alfa-2b + Ribavirin vs Peginterferon alfa-2a + Ribavirin IDEAL Study: Design 48720Week SVR24 N = 1016 N = 1019 N = 1035

21. Peginterferon alfa-2b + Ribavirin vs Peginterferon alfa-2a + Ribavirin IDEAL Study: Results IDEAL Study: Virologic Responses by Treatment Regimen Source: McHutchison JG, et. al. N Engl J Med. 2009;361:580-93. 542/1019500/1016667/1035406/1019386/1016423/1035

22. Peginterferon and ribavirin: side effects and contraindications Side effects Treatment of chronic hepatitis C virus infection – Dutch national guidelines 2009 Presence of Child-Pugh-class B or C cirrhosis Significant comorbidity (severe cardiac disease, COPD, SLE, other autoimmune diseases or severe psychiatric disorders). Relative contraindications are age of 70 years or above, mild comorbidity and various social factors. In patients with pre-existing comorbidity such as depression, COPD, psoriasis, diabetes mellitus, one should be alert for exacerbations of these diseases Contraindications About 10% of patients has to discontinue antiviral therapy prematurely because of adverse events

23. Source: Afdhal N, et al. N Engl J Med. 2014;370:1889-98. Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Naïve HCV GT 1 ION-1 Study: Features

24. Source: Afdhal N, et al. N Engl J Med. 2014;370:1889-98. Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Naïve HCV GT 1 ION-1 Study: Study Design LDV-SOF SVR12 GT-1 Naive n = 214 LDV-SOF SVR12 LDV-SOF + RBV SVR12 LDV-SOF + RBV SVR12 GT-1 Naive n = 217 Week 0361224 Abbreviations: LDV-SOF= ledipasvir-sofosbuvir; RBV = ribavirin Drug Dosing Ledipasvir-sofosbuvir (90/400 mg): fixed dose combination; one pill once daily Ribavirin (weight-based and divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg

25. Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Naïve HCV GT 1 ION-1 Study: Results ION-1: SVR 12* by Treatment Duration and Regimen Source: Afdhal N, et al. N Engl J Med. 2014;370:1889-98. 211/214 12-Week Regimen 211/217212/217215/217 Abbreviations: LDV-SOF= ledipasvir-sofosbuvir; RBV = ribavirin *Primary end-point by intention-to-treat analysis 24-Week Regimen

26. Ledipasvir-Sofosbuvir (Harvoni) Adverse Effects Adverse Effects with Ledipasvir-Sofosbuvir Reported in ≥5% of Subjects Ledipasvir-Sofosbuvir 8 Weeks12 Weeks 24 Weeks N=215N=539 N=326 Fatigue16%13% 18% Headache11%14% 17% Nausea6%7% 9%9% Diarrhea4%3% 7%7% Insomnia3%5% 6% Source: Harvoni Prescribing Information. Gilead Sciences

27. HCV-TARGET Study: Real-World data form North America HCV-TARGET  Real-World registry Consortium of academic (n=39) and community (n=15) centers that provide medical care and antiviral treatment to HCV-infected patients Design: longitudinal, prospective observational cohort study Start of the study: 2011 Included: patients prescribed anti-HCV treatment as part of routine clinical practice No randomization

28. HCV-TARGET: Sofosbuvir/Ledipasvir for HCV genotype 1

29. 97% 95% 97% 92% N=154 N=624 N=161 N=89N=13

30. Treatment of hepatitis C - Summary Peginterferon Ribavirin (old treatment regimen) Low efficacy (SVR 50-70%) Many adverse events (Discontinuation rate > 10%) Low costs (PR 48 weeks): 8.795 euro Direct antiviral agents (new treatment options) High efficacy (SVR > 95%) Almost no adverse events (Discontinuation rate < 1%) High costs (SOF-LDV 12 weeks): 48.759 euro

31. HCV-Clearance and Improvements of Clinical Complications Even the best antiviral treatment regimens need to be given in order to have an effect

32. Treatment Rates Remain Poor In Europe up to 90% is unaware they have chronic viral hepatitis 1 Razavi EASL 2013 1 Blachier J Hepatol 2013

33. Increased treatment rate in Germany Next to the increase in treatment efficacy, a ~2-fold increase in treatment rate would lower the number with liver-related death by 75% in 2030 1 Wedemeyer J Viral Hep 2014 Continue with current situation Increase SVR rate Increase SVR rate AND treatment rate -75% -40%

34. IFN Slides with courtosy of Prof. H. Wedemeyer Where We Were! HCV-infected Patients Diagnosed Patients SVR

35. DAA Slides with courtosy of Prof. H. Wedemeyer Where We Could Be! Diagnosed Patients HCV-infected Patients

36. SVRDAA Slides with courtosy of Prof. H. Wedemeyer Where We Should Go! Diagnosed patients HCV-infected patients Diagnosed Patients DAASVR

37. Clearance of chronic HCV infection is associated with a reduced occurrence of: –Liver failure –Hepatocellular carcinoma –Diabetes mellitus –End-stage renal disease –Cardiovascular complications We need to treat! Increasing the treatment rate is needed to make a real impact on HCV-related morbidity and mortality We need to diagnose! Take Home Messages Liver-related mortality Liver-unrelated mortality Overall mortality