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HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions

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. Faculty and Disclosures.

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HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions

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  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. Faculty and Disclosures 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 Kelleyhas no significant financial relationships to disclose. Edward King, MA,has no significant financial relationships to disclose. 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. Hepatitis C Virus Infection:Magnitude of the Problem • 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.

  5. 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 Lindsay KL. Hepatology. 2002;36(suppl 1):S114-S120.

  6. Overview of Current FDA-Approved Treatments for HCV 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.

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

  8. 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 100 82 76 80 56 60 Sustained Virologic Response (%) 54 46 42 40 20 n = 453 n = 298 n = 140 n = 511 n = 348 n = 163 0 Overall Genotype 1 Genotype 2/3 Overall Genotype 1 Genotype 2/3 Manns M, et al. Lancet. 2001;358:958-965. Fried MW, et al. N Engl J Med. 2002;347: 975-982.

  9. Predicting Response to HCV Therapy

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

  11. Predictors of Sustained Virologic Response: Fixed Factors *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.

  12. Virologic Monitoring Markers and Definitions of Response to Treatment Pawlotsky JM. Hepatology. 2002;36(suppl 1):S65-S73. Sethi A, et al. Clin Liver Dis. 2005;9:453-471.

  13. Virologic Monitoring Markers and Definitions of Response to Treatment Pawlotsky JM. Hepatology. 2002;36(suppl 1):S65-S73.Sethi A, et al. Clin Liver Dis. 2005;9:453-471.

  14. Patterns of Response to Initial Antiviral Therapy 7 Nonresponder First phase 6 5 Flat-partial responder 4 HCV RNA Second phase Slow-partial responder 3 Limit of detection 2 Rapid responder 1 0 1 2 3 7 14 21 28 Days on Treatment

  15. Treatment of Chronic HCV Infection:Nonresponse, Breakthrough, Relapse 8 PegIFN/RBV 7 Breakthrough Relapse 6 5 Nonresponse HCV RNA (log IU/mL) 4 2 log decline 3 2 Limit of detection 1 0 -6 0 6 12 18 24 30 36 42 48 54 60 66 72 78 Weeks

  16. Benefits of a Thorough Virologic Monitoring Strategy • 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 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. 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 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.

  19. Time to Undetectable HCV RNA Identified as Best Predictor of SVR • Pooled data from PegIFN alfa-2b/RBV and PegIFN alfa-2a/RBV phase III trials PPV of HCV RNA Undetectability Determining SVR 100 86 80 76 80 PPV for SVR (%) 60 40 20 0 Week 4 Week 12 Week 24 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.

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

  21. Longer Duration of Undetectability on Treatment Increases Chance for SVR • 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 1. Drusano GL, et al. J Infect Dis. 2004;189:964-970.2. Tang KH, et al. EASL 2005. Abstract 609.

  22. Rate of Viral Decline DeterminesPeriod of HCV RNA Negativity Wk 0 Wk 4 Wk 12 Wk 24 Wk 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 Modified from figure by Michael Fried, MD.

  23. Shorter Treatment Duration for Genotype 1 Patients Reaching RVR

  24. Shorter Treatment Duration in Genotype 1 Patients With RVR • Retrospective analysis of multinational, randomized, phase III study: PegIFN alfa-2a + weight-based RBV (N = 740) Outcomes in Patients With RVR According to Treatment Length Outcomes in Patients Without RVR According to Treatment Length 24 weeks 48 weeks 97 93 100 100 91 88 80 80 70 63 60 60 Patients (%) 44 Patients (%) 40 40 23 20 20 0 0 EOT SVR EOT SVR Jensen DM, et al. Hepatology. 2006;43:954-960.

  25. Week 4 Response as a Predictor of SVR • 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 Relapse Rate Based on Week 4 Viral Load (ITT Analysis) 100 80 Week 4 HCV RNA 60 Patients (%) 38 < 10 IU/mL 40 22 10-49 IU/mL 15 10 20 7 5 0 All Patients < 600,000 ≥ 600,000 Baseline Viral Load (IU/mL) Ferenci P, et al. EASL 2006. Abstract 8.

  26. Shorter Treatment for Genotype 1 and Low Baseline Viral Load • 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) SVR According to Time to First Negative HCV RNA 93 100 89 85 71 80 Treatment Duration 67 60 50 24 weeks Patients With SVR 40 48 weeks 25 17 20 0 Week 4 Week 12 Week 24 Total Time to First Negative HCV RNA Zeuzem S, et al. J. Hepatol. 2006;44:97-103.

  27. Extended Treatment Duration for Genotype 1

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

  29. Longer Treatment Duration May Be Beneficial for Slow Responders • Patients who failed to achieve RVR randomized to 48 or 72 weeks of PegIFN alfa-2a + RBV 800 mg/day 48 weeks (n = 161) 72 weeks (n = 165) 100 80 P = .014 P = .005 60 48.0 Patients (%) 45.0 40 32.0 18.0 13.0 20 4.8 0 SVR Relapse Discontinuation Sanchez-Tapias J, et al. AASLD 2004. Abstract 126.

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

  31. Shorter Treatment in Genotype 2/3 Patients Achieving RVR • PegIFN alfa-2b + weight-based RBV • 14 weeks for patients with RVR; 24 weeks for patients without RVR 100 RVR, received 14 weeks (n = 95) 90 No RVR, received 24 weeks (n = 27) 80 56 60 Patients (%) 40 26 20 10 0 SVR Relapse Dalgard O, et al. Hepatology. 2004;40:1260-1265.

  32. Shorter Treatment in Genotype 2/3 Patients Achieving RVR • Patients with RVR received 16 or 24 weeks PegIFN alfa-2a + weight-based RBV 100 16 weeks (n = 71) 82 80 24 weeks (n = 71) 80 60 Patients (%) 40 20 13 5 0 SVR Relapse Von Wagner M, et al. Gastroenterology. 2005;129:522-527.

  33. Shorter Treatment in Genotype 2/3 Patients Achieving RVR • PegIFN alfa-2b + weight-based RBV • 12 weeks for patients with RVR; 24 weeks for patients without RVR 100 RVR, received 12 weeks (n = 133) 85 No RVR, received 24 weeks (n = 80) 80 64 60 Patients (%) 40 20 10 6 0 SVR Relapse Mangia A et al. N Engl J Med. 2005;352:2609-2617.

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

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

  38. 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. Summary: Virologic Monitoring in Genotype 1 and 4 Patients • Virologic monitoring can identify optimal duration of treatment in genotype 1 and 4 • Week 12 HCV RNA showing a drop of ≤ 2 log10 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

  40. Summary: Virologic Monitoring in Genotype 2 and 3 Patients • 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

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

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