Advances in the Treatment of Chronic Hepatitis C

1. Advances in the Treatment of Chronic Hepatitis C Gregory T Everson, MD Professor of Medicine Director of Hepatology University of Colorado Denver

2. Disclosures Advisory Boards: Roche/Genentech, Merck, Vertex, BMS, GlobeImmune, Abbott, Eisai, Novartis, Pfizer, Gilead, Biotest, Tibotec/Janssen Consulting: Roche-Genentech, Novartis, BMS, Eisai, Kadmon, Vertex, Abbott, Biotest, Tibotec/Janssen DSMB: Centocor Stock/Ownership: Source, HepQuant LLC Management: HepQuantLLC Research Grants: Roche/Genentech, Schering-Plough/Merck, Vertex, GlobeImmune, Gilead, Novartis, BMS, Pfizer, Source, Eisai, GSK, Pharmassett, Ortho Biotech, Tibotec/Janssen, Amgen, Medtronic, Abbott

3. Primer on HCV

4. Worldwide Prevalence of HCV WHO, Wkly Epidemiol Rec, 2000

5. Genotype and Viral Load in US Geno 2 & 3 Geno 1 HVL > 800,000 IU/ml Geno 1 LVL Approximately 2/3 cases of GT1 infection in the US are due to the GT1a subtype.

6. Natural History of HCV Infection Acute HCV Infection 15%-45% 55%-85% Chronic HCV Infection Recovery Chronic Hepatitis C Mild Moderate Severe Cirrhosis End-Stage Liver Disease Hepatocellular Carcinoma Liver Transplantation Death There are an estimated 3 to 5 million cases of chronic hepatitis C in the US.

7. Hepatitis C Testing for Anyone Born During 1945-1965: New CDC Recommendations If you were born during 1945-1965 (baby boomer), talk to your doctor about getting tested for Hepatitis C. The only way to know if you have Hepatitis C is to get tested. Early detection can save lives. Reasons for this recommendation: 1. Baby boomers – represent 75% of cases in US). 2. This one-time testing may prevent more than 120,000 deaths. 3. Most cases are undiagnosed - testing would find 800,000 new cases. 4. There have been recent advances in treatment. Source: CDC. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945–1965. MMWR 2012;61(No. RR–4).

8. Recommendations for the Identification of Chronic Hepatitis C Virus Infection Among Persons Born during 1945–1965* • Adults born during 1945–1965 should receive one-time testing for HCV without prior ascertainment of HCV risk. • All persons with identified HCV infection should receive a brief alcohol screening and intervention as clinically indicated, followed by referral to appropriate care and treatment services for HCV infection and related conditions. Source: CDC. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945–1965. MMWR 2012;61(No. RR–4).

9. Case

10. A baby boomer is screened for HCV and HCV-Ab is positive. You order a polymerase-chain-reaction-based test for HCV RNA quantification. What is the likelihood that the HCV RNA will be positive? 0% ~ 25% ~ 50% ~ 75% 100%

11. A baby boomer is screened for HCV and HCV-Ab is positive. You order a polymerase-chain-reaction-based test for HCV RNA quantification. What is the likelihood that the HCV RNA will be positive? 0% ~ 25% ~ 50% ~ 75% 100%

12. The HCV RNA is positive. Standard laboratory tests are normal except for ALT 85 IU/mL. Further evaluation reveals HCV genotype 1a, advanced fibrosis (F3), and IL28B genotype CT. Given these factors, what would you advise for treatment? None Silymarin (milk thistle) Peginterferon alone Peginterferon + Ribavirin Peginterferon + Ribavirin + DAA

13. The HCV RNA is positive. Standard laboratory tests are normal except for ALT 85 IU/mL. Further evaluation reveals HCV genotype 1a, advanced fibrosis (F3), and IL28B genotype CT. Given these factors, what would you advise for treatment? None Silymarin (milk thistle) Peginterferon alone Peginterferon + Ribavirin Peginterferon + Ribavirin + DAA

14. Treatment

15. Undetectable HCV RNA - 3 months (SVR12) or6 months (SVR24) after TreatmentThe Primary Objective ofTherapy for Chronic Hepatitis C The Goal of Treatment is SVRSustained Virologic Response

16. SVR Equates with CURE Swain MG, et al. Gastroenterology 2010;139:1593-1601.

17. 1. Probably “Cured” of HCV infection – chance for late relapse <1%.2. Halts progression of liver disease.3. Reduces risk for HCC – although patients with bridging fibrosis or cirrhosis may develop HCC after SVR and still need to be screened.4. HCV-related extrahepatic manifestations disappear or are ameliorated5. Health-related (HCV) Quality of Life Improves Established Benefits of SVR

18. Past and Current Treatment for HCV GT2 & 3 % of Patients Achieving SVR 1991 Year of FDA Approval 2002

19. Triple TherapyThe Current Standard-of-CareforHCV Genotype 1 First Generation Protease InhibitorsTelaprevirBoceprevirwith Peginterferon/Ribavirin

20. Past and Current Treatment for HCV GT1 % of Patients Achieving SVR 1991 Year of FDA Approval 2002 2011

21. Predictors of SVR with TT inTreatment Naïve Patients • Interferon Sensitivity • IL28B Polymorphism • HCV RNA decline during Lead-In with PEG/RBV • On-treatment (TT) Response (eRVR) • Stage of Fibrosis

22. IL28b Polymorphism

24. Telaprevir (TPV): Treatment-NaïveSVR by IL28B Polymorphism % SVR ∆ = 18% ∆ = 50% CC CT TT CC CT TT

25. Boceprevir (BOC): Treatment-NaïveSVR by IL28B Polymorphism % SVR ∆ = 9 to 27% ∆ = 50% CC CT TT CC CT TT CC CT TT

26. IL28b Polymorphism inTreatment-Naïve Highly predictive when treatment is peginterferonplus ribavirin (PR) Less predictive when treatment has higher chance of success in CT and TT polymorphisms – less predictive when treatment is triple therapy.

27. Lead-InBoceprevir Trial of Treatment-Naïve(SPRINT-2)

28. Boceprevir (BOC): Treatment-NaïveSVR by Log10 HCV RNA Decline during Lead-In with PR % SVR SPRINT-2 Study. N Engl J Med 2011;364:1195-1206.

29. Lead-In inTreatment-Naïve Predicts likelihood of SVR with Boceprevir-based triple therapy SVR is still greater than 30% in the patients treated with triple therapy who have < 1 Log10 decline in HCV RNA during Lead-in - < 1 Log10 decline is NOT a Stop Guideline

30. Extended Rapid Virologic Response(eRVR)

31. Extended Rapid Virologic ResponseeRVR Identifies the “Super” Responders who can Stop Early • Two components of eRVR • HCV RNA <10 IU/mL at Week 4 of Triple Therapy (RAPID) • HCV RNA <10 IU/mL subsequently (EXTENDED) • Telaprevir (T12/PR24) • HCV RNA <10 IU/mL Weeks 4 through 12 • Stop treatment at Week 24 (58% & 65% of patients1) • ILLUMINATE, randomized trial of eRVR, 24 vs 48 wks PR • Boceprevir (LI PR4, B24/PR24) • HCV RNA <10 IU/mL Weeks 8 through 24 • eRVR – Stop treatment at Week 28 (44% of patients2) • ADVANCE. N Engl J Med 2011;364:2405-2416. ILLUMINATE. N Engl J Med 2011;365:1014-1024. • SPRINT-2. N Engl J Med 2011;364:1195-1206.

32. eRVR and Treatment DurationILLUMINATE study of Telaprevir – 65% Achieved eRVR % SVR ILLUMINATEStudy. N Engl J Med 2011;365:1014-1024.

33. Stage of Fibrosis

34. Impact of Stage of FibrosisTelaprevir and Boceprevir: Treatment-Naive SVR (%) * * Jacobson IM, et al. ADVANCE trial. N Eng J Med 2011;364:2405-2416. Sherman KE, et al. ILLUMINATE trial. N Engl J Med 2011;365:1014-1024. Poordad F, et al. SPRINT-2 trial. N Engl J Med 2011; 364:1195-1206. * Biggest Impact of reducing duration of TPV in ADVANCE, or PR in ILLUMINATE, was in F4 patients.

35. Case

36. The Patient Elects Treatment with Telaprevir-based Triple Therapy. HCV RNA is undetectable from Weeks 1 through 8. HCV RNA (IU/mL) GT1a, F3, IL28b CT No viral variants at baseline Diverticulitis HCV RNAnegative

37. The patient is admitted to the hospital with fever, LLQ abdominal pain, and leucocytosis. CT confirms sigmoid diverticulitis and blood cultures were positive for E. coli. Best management includes antibiotic therapy and: Continuation of TPV, PEG, and RBV Continuation of PEG and RBV only Continuation of PEG only Discontinuation of TPV, PEG, and RBV

38. The patient is admitted to the hospital with fever, LLQ abdominal pain, and leucocytosis. CT confirms sigmoid diverticulitis and blood cultures were positive for E. coli. Best management includes antibiotic therapy and: Continuation of TPV, PEG, and RBV Continuation of PEG and RBV only Continuation of PEG only Discontinuation of TPV, PEG, and RBV

39. Pitfalls of Current DAA Rx • Single DAA – low barrier to resistance • Only indicated for HCV GT1 • Complex treatment algorithms • High pill burden • Rx duration of 24 to 48 weeks • Requires PEG/RBV – SEs, AEs, SAEs • Unique SEs, AEs, SAEs • Drug-Drug Interactions

40. Viral Resistance

41. Case

42. TPV, PEG, and RBV are discontinued and HCV RNA is monitored. HCV RNA Positive 30 IU/mL Stopped all Meds due to Diverticulitis HCV RNAnegative

43. After confirming relapse by repeat testing of HCV RNA, a blood sample is analyzed for variants of HCV resistant to TPV. HCV RNA Positive R155K Detected Stopped all Meds due to Diverticulitis HCV RNAnegative

44. Complex Treatment Algorithms

45. Telaprevir: Treatment-Naïve Patients Triple Therapy with TPV+P+R For 12 weeks Additional 12 weeks of P+R* eRVR HCV RNA negative At Weeks 4 & 12 HCV RNA is quantified at weeks 4, 8, 12 while the patient is taking TPV – to evaluate for viral response and resistance. TPV is stopped if there is evidence of rebound in HCV RNA. Additional 36 weeks of P+R NO eRVR Slow Responder** Treatment is discontinued if HCV RNA is >1000 IU/mL at week 4 or 12 or detectable at week 24 * FDA recommends extending P+R for 36 weeks in patients with cirrhosis. ** Slow responder is RNA positive at week 4 but RNA negative prior to or at week 24.

46. Boceprevir: Treatment-Naïve Patients HCV RNA at Weeks 4, 8, 12, 24 while the patient is taking BOC – to evaluate for viral response and resistance. Lead-In With 4 weeks P+R Triple Therapy with BOC+P+R For additional 24 weeks* No additional Treatment* (28 weeks total) eRVR’ 8 - 24 wk RNA neg The drop in HCV RNA predicts likelihood of responding to subsequent triple therapy with BOC. Patients with <1log10 decrease (Poor response) have SVR ~30%. Additional 8 weeks of BOC+P+R and 12 weeks P+R Treatment* (48 weeks total) NO eRVR’ Slow Responder All treatment is discontinued if either HCV RNA >100 IU/mL at wk 12 or HCV RNA detectable at wk 24 * Cirrhotic patients and Poor Responders are treated for 44 weeks BOC+P+R, regardless of eRVR’. ** Slow responders are RNA positive at week 8 but RNA negative prior to or at week 24.

47. Unique Side Effects

48. Telaprevir and Rash • Can be nasty (DRESS, S-J syndrome)! • Occurs in over 50% of patients, mild in most cases (hydroxyzine, topicals) • Telaprevir discontinued in 5 - 10% due to rash. Systemic steroids may be required. All treatment stopped in 1-2% due to rash.

49. Ribavirin Rash

50. Telaprevir – Mild to Moderate Rash