1. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions Ruth J. Corbett, MSN, ARNP, CCRC Gastroenterology Advanced Practice Nurse, Specialty Care Department of Veteran Affairs Kansas City, Missouri This program is supported by an educational grant from

2. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep Program Director Emmet B. Keeffe, MD, MACP Professor of Medicine Co-Director, Liver Transplant Program Chief of Hepatology Stanford University School of Medicine Palo Alto, California Faculty Ruth J. Corbett, MSN, ARNP, CCRC, has disclosed that she is a member of the speakers’ bureau for Roche and Schering-Plough. Emmet B. Keeffe, MD, MACP, has disclosed that he has received grants or research support from Roche. He has received consulting fees from Idenix, Roche, and Valeant. He has received fees for non-CME services from Roche and Schering-Plough. Staff Jenny Schulz, PhD, has no significant financial relationships to disclose. Gordon Kelley has no significant financial relationships to disclose. Edward King, MA, has no significant financial relationships to disclose. Faculty and Disclosures Faculty Ruth J. Corbett, MSN, ARNP, CCRC Gastroenterology Advanced Practice Nurse, Specialty Care Department of Veteran Affairs Kansas City, Missouri

3. Goals and Benefits of HCV Therapy

4. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep  Nearly 4 million persons in United States infected –Approximately 35,000 new cases yearly –85% of new cases become chronic  10,000-20,000 HCV-related deaths per year –Number expected to triple in next 10-20 years  Leading cause of –Chronic liver disease –Cirrhosis –Liver cancer –Liver transplantation CDC. MMWR Morb Mortal Wkly Rep. 1998;47;1-39. NIH Consensus Conference Statement. Available at: http://consensus.nih.gov/2002/2002HepatitisC2002116html.htm. Accessed September 25, 2006. Hepatitis C Virus Infection: Magnitude of the Problem

5. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep Lindsay KL. Hepatology. 2002;36(suppl 1):S114-S120. Goals of HCV Therapy  Primary goal of treatment is to eradicate the virus  Additional goals –Slow disease progression –Minimize risk of hepatocellular carcinoma –Improve liver histology –Enhance quality of life –Prevent transmission of virus –Reduce extrahepatic manifestations

6. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep DrugRecommended Dosage Pegylated interferons  Peginterferon alfa-2b  Peginterferon alfa-2a  1.5 µg/kg SQ once weekly combined with RBV; 1.0 µg/kg SQ once weekly monotherapy  180 µg SQ once weekly combined with ribavirin or as monotherapy Interferon alfacon-1  9 µg SQ TIW; 15 µg TIW for nonresponders Ribavirin  800-1400 mg PO daily depending on weight and genotype PEG-IntronTM [package insert]. Kenilworth, NJ: Schering Corporation; 2003. Pegasys [package insert]. Nutley, NJ: Hoffmann-La Roche Inc; 2003. Modified from Strader DB et al. Hepatology 2004;39:1147-1171. Overview of Current FDA-Approved Treatments for HCV

7. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep SVR Rates: Progress in the Treatment of Chronic Hepatitis C McHutchison J, et al. N Engl J Med. 1998;339:1485-1492. Poynard T, et al. Lancet. 1998;352: 1426- 1432. 100 80 60 40 20 0 19 43 6 IFN 24 Weeks IFN 48 Weeks IFN/RBV 48 Weeks SVR Rates With Standard Interferon Patients (%)

8. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep  Peginterferon alfa-2b 1.5 µg/kg/wk + ribavirin 800 mg/d for 48 weeks  Peginterferon alfa-2a 180 µg/wk + weight-based ribavirin (1000 or 1200 mg/d) for 48 weeks SVR Rates: Progress in the Treatment of Chronic Hepatitis C Manns M, et al. Lancet. 2001;358:958-965. Fried MW, et al. N Engl J Med. 2002;347: 975-982. 46 76 56 OverallGenotype 1 Genotype 2/3 n = 298n = 140n = 453 42 82 100 80 60 40 20 0 54 OverallGenotype 1 Genotype 2/3 Sustained Virologic Response (%) n = 348n = 163n = 511

9. Predicting Response to HCV Therapy

10. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep Alberti A, et al. J Hepatol. 1999;31(suppl 1):17-24. Virus Viral load HCV genotype Quasispecies Environment Alcohol or drugs HBV coinfection HIV coinfection Steatosis Iron NASH Factors That May Influence the Outcome of Hepatitis C Host Sex Age Race Genetics Immune response Duration of Infection

11. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep Baseline FactorSustained Virologic Response Rates PegIFN alfa-2a + RBV OR PegIFN alfa-2b + RBV HCV RNA, % [1,2]  < 2 x 10 6 copies/mL  > 2 x 10 6 copies/mL 62-78 42-53 Genotype, % [1,2]  2 or 3  1 76-82 42-46 Genotype 1 and high viral load, %30-41 Liver histology, % [1,2]  Stage 0-2  Stage 3-4 55-57 41-44 Age [1,2] Older age, lower SVR* Weight [1,2] Higher weight, lower SVR* Race, % [3,4]  Black  White 52 19-28 *Logistic regression analysis, P ≤.002. 1. Manns MP, et al. Lancet. 2001;358:958-965. 2. Fried MW, et al. N Engl J Med. 2002;347: 975-982. 3. Muir AJ, et al. N Engl J Med. 2004;350:2265-2271. 4. Conjeevaram HS, et al. 2006;131:470-477. Predictors of Sustained Virologic Response: Fixed Factors

12. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep Pawlotsky JM. Hepatology. 2002;36(suppl 1):S65-S73. Sethi A, et al. Clin Liver Dis. 2005;9:453-471. Virologic Monitoring Markers and Definitions of Response to Treatment Rapid Virologic Response (RVR) HCV RNA undetectable by Week 4 Early Virologic Response (EVR) ≥ 2 log decline in HCV RNA by Week 12 End of Treatment (EOT) Response Undetectable HCV RNA at end of treatment Partial Virologic Response ≥ 2 log decline in HCV RNA by Week 12, but HCV RNA detectable at Week 24 Sustained Virologic Response (SVR) HCV RNA negativity 12-24 weeks after treatment end

13. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep Pawlotsky JM. Hepatology. 2002;36(suppl 1):S65-S73. Sethi A, et al. Clin Liver Dis. 2005;9:453-471. Virologic Monitoring Markers and Definitions of Response to Treatment Null ResponseHCV RNA decline < 2 log 10 IU/mL by Week 12 Nonresponse Failure to achieve HCV RNA undetectability at any time point during therapy Virologic Breakthrough Decline in HCV RNA to undetectable levels followed by return of HCV RNA despite continued treatment Relapse End of treatment response followed by return of HCV RNA after treatment discontinuation Positive Predictive Value (PPV) Given a positive response, what the chance is that an SVR will occur Negative Predictive Value (NPV) Given a negative response, what the chance is that an SVR will not occur

14. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep Days on Treatment Patterns of Response to Initial Antiviral Therapy 1 2 3 4 5 6 7 01237142128 Nonresponder Flat-partial responder Slow-partial responder Rapid responder Second phase First phase Limit of detection HCV RNA

15. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep 0 1 2 3 4 5 6 7 8 -606121824303642485460667278 Weeks HCV RNA (log IU/mL) 2 log decline Limit of detection PegIFN/RBV Relapse Breakthrough Nonresponse Treatment of Chronic HCV Infection: Nonresponse, Breakthrough, Relapse

16. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep  Virologic monitoring to predict response can provide the following benefits to the patient and clinician –Limits unnecessary exposure to therapy –Identifies treatment failure –Justifies early discontinuation in those responding poorly –Limits treatment toxicity –Limits cost for those unlikely to respond –Identifies optimal duration of treatment –Provides incentive to continue therapy Benefits of a Thorough Virologic Monitoring Strategy Sanchez-Tapias JM. AASLD 2004. Abstract 125. Jensen DM, et al. N Engl J Med. 2000;343:1673-1680. Davis GL, et al. Hepatology. 2003;38:645.

17. The Predictive Value of Week 12 and Week 4 HCV RNA

18. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep Davis GL. Hepatology. 2002;36(suppl 1):S145-S151. NIH Consens State Sci Statements. 2002;19:1-46. Fried MW, et al. N Engl J Med. 2002;34:7975-7982. Manns MP, et al. Lancet. 2001;358:958-965. Week 12 Stopping Rule: Patients Without EVR Unlikely to Achieve SVR  Week 12 viral kinetics predictor of SVR –Only 1.6% of patients who fail to meet EVR criteria achieve SVR (NPV: 98.4%) –2 log cutoff at Week 12 optimal for predicting response  Poor PPV of Week 12 EVR (68%) –Week 12 HCV RNA predictor of treatment failure but not predictor of success in achieving SVR  Week 12 stopping rule included in current guidelines –~ 20% of patients can stop early, lowering total treatment costs by 16% and decreasing unnecessary side effects

19. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep PPV of HCV RNA Undetectability Determining SVR 86 80 76 0 20 40 60 80 100 Week 4Week 12Week 24 PPV for SVR (%) Time to Undetectable HCV RNA Davis GL. Hepatology. 2002;36(suppl 1):S145-S151. Fried MW, et al. N Engl J Med. 2002;34:7975-7982. Manns MP, et al. Lancet. 2001;358:958-965.  Pooled data from PegIFN alfa-2b/RBV and PegIFN alfa- 2a/RBV phase III trials Time to Undetectable HCV RNA Identified as Best Predictor of SVR

20. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep End-of-treatment response SVR 91 90 13 91 60 48 2 0 20 40 60 80 100 Week 4 Week 12 Week 24 Negative < 2 log drop Negative < 2 log drop > 2 log drop Negative Any drop Positive Patients (%) Ferenci P, et al. J Hepatol. 2005;43:425-433. Relationship Between SVR and Time to HCV RNA Undetectability  Retrospective analysis of genotype 1 patients receiving 48 weeks of PegIFN alfa-2a + RBV

21. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep 1. Drusano GL, et al. J Infect Dis. 2004;189:964-970. 2. Tang KH, et al. EASL 2005. Abstract 609.  Retrospective analysis of PegIFN alfa-2b/RBV dataset evaluated predictors of SVR in genotype 1 [1] –32 weeks of HCV RNA negative: 80% chance of SVR –36 weeks of HCV RNA negative: 90% chance of SVR  Prospective study of viral kinetics and SVR evaluated in genotype 1 patients on PegIFN alfa-2a/RBV [2] –Minimum time of HCV RNA negativity on therapy to achieve high SVR rates (80%) was 24 weeks Longer Duration of Undetectability on Treatment Increases Chance for SVR

22. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep Wk 4 Wk 0 Wk 12Wk 24Wk 48 (EOT) HCV RNA undetectable for 44 weeks HCV RNA undetectable for 36 weeks HCV RNA undetectable for 24 weeks Time to HCV RNA negativity Rate of Viral Decline Determines Period of HCV RNA Negativity Modified from figure by Michael Fried, MD.

23. Shorter Treatment Duration for Genotype 1 Patients Reaching RVR

24. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep Jensen DM, et al. Hepatology. 2006;43:954-960. 24 weeks48 weeks 97 88 93 91 0 20 40 60 80 100 EOTSVR 70 23 63 44 Outcomes in Patients With RVR According to Treatment Length Patients (%)  Retrospective analysis of multinational, randomized, phase III study: PegIFN alfa-2a + weight-based RBV (N = 740) EOTSVR 0 20 40 60 80 100 Patients (%) Outcomes in Patients Without RVR According to Treatment Length Shorter Treatment Duration in Genotype 1 Patients With RVR

25. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep Ferenci P, et al. EASL 2006. Abstract 8.  Patients with undetectable HCV RNA by Week 4 on PegIFN alfa-2a + RBV treated for total of 24 weeks –SVR rate for Week 4 responders (per-protocol analysis) –Overall: 87% – Genotype 1: 84% – Genotype 4: 100%  Higher baseline, Week 4 viral load predictive of relapse Baseline Viral Load (IU/mL) Relapse Rate Based on Week 4 Viral Load (ITT Analysis) 7 5 15 22 10 38 0 20 40 60 80 100 All Patients< 600,000≥ 600,000 Patients (%) < 10 IU/mL 10-49 IU/mL Week 4 HCV RNA Week 4 Response as a Predictor of SVR

26. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep  24 vs 48 weeks PegIFN alfa-2b + RBV in genotype 1 patients with low viral load (< 600,000 IU/mL) –24-week group received weight-based RBV –48-week group received 800 mg/day RBV (historical controls) 89 25 17 50 85 93 67 71 Week 4Week 12Week 24Total 24 weeks 48 weeks SVR According to Time to First Negative HCV RNA Patients With SVR Treatment Duration Time to First Negative HCV RNA Zeuzem S, et al. J. Hepatol. 2006;44:97-103. 0 20 40 60 80 100 Shorter Treatment for Genotype 1 and Low Baseline Viral Load

27. Extended Treatment Duration for Genotype 1

28. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep 53 54 0 20 40 60 80 100 17 29 P =.04 Patients (%) n = 100 n = 106n = 230 n = 225 Overall SVR SVR Among Patients HCV RNA Positive at Week 12 Week 48Week 72 Berg T, et al. Gastroenterology. 2006;130:1086-1097.  48 vs 72 weeks of PegIFN alfa-2a + RBV 800 mg/day in genotype 1 patients Longer Treatment Duration May Be Beneficial for Slow Responders Week 48Week 72 P = NS 0 20 40 60 80 100

29. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep 32.0 48.0 4.8 45.0 13.0 18.0 0 20 40 60 80 100 SVRRelapseDiscontinuation 48 weeks (n = 161)72 weeks (n = 165) Patients (%) Sanchez-Tapias J, et al. AASLD 2004. Abstract 126.  Patients who failed to achieve RVR randomized to 48 or 72 weeks of PegIFN alfa-2a + RBV 800 mg/day Longer Treatment Duration May Be Beneficial for Slow Responders P =.014 P =.005

30. Evaluating Shorter Treatment Duration in Genotype 2/3 Rapid Responders

31. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep Dalgard O, et al. Hepatology. 2004;40:1260-1265. 90 10 56 26 0 20 40 60 80 100 SVRRelapse RVR, received 14 weeks (n = 95) No RVR, received 24 weeks (n = 27) Patients (%)  PegIFN alfa-2b + weight-based RBV –14 weeks for patients with RVR; 24 weeks for patients without RVR Shorter Treatment in Genotype 2/3 Patients Achieving RVR

32. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep 82 13 80 5 Von Wagner M, et al. Gastroenterology. 2005;129:522-527. 0 20 40 60 80 100 SVRRelapse 16 weeks (n = 71) 24 weeks (n = 71)  Patients with RVR received 16 or 24 weeks PegIFN alfa-2a + weight-based RBV Shorter Treatment in Genotype 2/3 Patients Achieving RVR Patients (%)

33. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep  PegIFN alfa-2b + weight-based RBV –12 weeks for patients with RVR; 24 weeks for patients without RVR No RVR, received 24 weeks (n = 80) 85 10 64 6 Mangia A et al. N Engl J Med. 2005;352:2609-2617. 0 20 40 60 80 100 SVRRelapse RVR, received 12 weeks (n = 133) Shorter Treatment in Genotype 2/3 Patients Achieving RVR Patients (%)

34. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep Shiffman M, et al. EASL 2006. Abstract 734. 82 27 90 49 SVR Rates in Patients With or Without SVR: 16 vs 24 Weeks of Treatment P <.001 P =.0007 0 20 40 60 80 100 Patients With RVRPatients Without RVR 16 weeks (n = 732) 24 weeks (n = 732)  Genotype 2/3 patients treated with PegIFN alfa-2a + RBV 800 mg/day for 16 vs 24 weeks Poorer Responses With 16 vs 24 Weeks in Genotype 2/3 Patients Patients (%)

35. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep Summary of Shortened Treatment Duration for Genotypes 2 and 3  Mixed results on probability of SVR in patients with 24 weeks of therapy vs shorter durations –Higher relapse rate with shorter duration –Largest study suggests need for 24 weeks of therapy  Need more data on how shorter duration affects patients with cirrhosis, high HCV RNA levels at baseline

36. Summary: Using Virologic Monitoring in Your Practice

37. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep Week 4 RVR reached Genotype 1Genotype 2/3 Week 12 EVR not reached Slow response (EVR, not HCV RNA undetectable until Week 24) Reduction to 24 weeks total treatment time may be possible Data mixed: continue through Week 24 if RVR achieved Guidelines recommend treatment be stopped Extension of treatment duration to 72 weeks may improve SVR rates Using Virologic Monitoring in Your Practice

38. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep Summary: Benefits of Virologic Monitoring  In addition to host and environmental predictors of SVR, frequent virologic monitoring has key impact on treatment decisions  By using Week 4 and Week 12 HCV RNA markers, treatment failures can be predicted early  Predictive negative value from Week 4 and Week 12 HCV RNA levels justify early discontinuation  Early virologic monitoring can limit unnecessary exposure, toxicity, and cost from treatment  Early responses can provide incentive to continue therapy

39. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep  Virologic monitoring can identify optimal duration of treatment in genotype 1 and 4 –Week 12 HCV RNA showing a drop of ≤ 2 log 10 now commonly used to identify those unlikely to respond –Emerging data suggest that 24 weeks of therapy may be effective for genotype 1 patients who achieved an RVR –Patients who do not achieve undetectable HCV RNA before Week 24 have ~ 50% chance of relapsing after 48 weeks of therapy –Studies show that these slow responders may benefit from extended treatment Summary: Virologic Monitoring in Genotype 1 and 4 Patients

40. HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions clinicaloptions.com/hep  Virologic monitoring can identify optimal duration of therapy in genotypes 2 and 3 –Mixed results on whether genotype 2/3 patients achieving RVR can reduce treatment duration to < 24 weeks –Largest study to date suggests 24 weeks optimal duration  HCV on-treatment virologic monitoring can have a positive impact on treatment decisions and patient outcomes Summary: Virologic Monitoring in Genotype 2 and 3 Patients

41. Go Online to View More of This HCV Program! Interactive Case Challenges evaluating real-life case scenarios and treatment decisions Interactive Tools for monitoring on-treatment HCV RNA and following HCV treatment guidelines Downloadable Slides of this slideset for your own use! clinicaloptions.com/HCVTools