Introduction

2. Introduction Ira M. Jacobson, MD Vincent Astor Professor of MedicineChief, Division of Gastroenterology and HepatologyMedical Director of the Center for the Studyof Hepatitis CWeill Cornell Medical CollegeNew York, New York

3. Phases in the Evolution of Anti-HCV Therapy The Final Phase— Small Molecule Combinations ??? The Empiric Phase The Phase of Specifically Targeted Antiviral Therapy for HCV (STAT-C) The Refinement Phase • Optimal dosing • Viral kinetics • Challengingpopulations • Nonresponders Weisberg IW, et al. Current Hepatitis Reports. 2007;6:75-82. Graphic courtesy of Dr. Ira Jacobson.

4. The Refinement Phase of Anti-HCV TherapyReflections on the Past Decade IFN dosing and formulation RBV dose The Refinement Phase Response-guided therapy • Optimal dosing • Viral kinetics • Challengingpopulations • Nonresponders African Americans, HIV, dialysis,decompensated, posttransplant Strategies for nonresponders and relapsers Graphic courtesy of Dr. Ira Jacobson.

5. Viral Kinetics Negative Predictive Value: 12 Weeks Positive Predictive Value: 4 Weeks Graphic courtesy of Dr. Ira Jacobson.

6. The “Accordion” Effect in Anti-HCV TherapyThe Earlier HCV RNA Clears, the Shorter the Treatment Required1-8 Start 4 8 12 16 24 48 72 (wk) Time to First RNA Neg End of Treatment 12–16 wk: Gt 2/3 with RVR • 24 wk: Gt 1 LVL with RVR • 48 wk: Gt 1 standard 72 wk: Gt 1 slow responders Abbreviations: Gt, genotype; LVL, low viral load; RVR, rapid viral response. 1. Berg T, et al. Gastroenterology. 2006;130:1086-1097. 2. Dalgard O, et al. Hepatology. 2008;47:35-42. 3. Jensen DM, et al. Hepatology. 2006;43:954-960. 4. Mangia A, et al. N Engl J Med. 2005;352:2609-2617. 5. Mangia A, et al. Hepatology. 2008;47:43-50. 6. Sanchez-Tapias JM, et al. Gastroenterology. 2006;131:451-460. 7. von Wagner MV, et al. Gastroenterology. 2005;129:522-527. 8. Zeuzem S, et al. J Hepatology. 2006;44:97-103. Graphic courtesy of Dr. Ira Jacobson.

7. Treatment of Nonresponders to PEG IFN and RBV Retreatment with same or different PEG IFN yields SVR rates of 2% to 16%1-3 Induction therapy does not improve SVR1 Extended treatment duration to 72 weeks doubles SVR rates1 CIFN (9 to 15 µg/d) + RBV yields SVR in 7% to 11%4 Better in noncirrhotics with good response to prior therapy Maintenance therapy studies have been negative5 Abbreviations: CIFN, consensus interferon; PEG IFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response.1. Jensen DM, et al. Ann Intern Med. 2009;150:528-540. 2. Poynard T, et al. Gastroenterology. 2009;136:1618-1628. 3. Schiff E, et al. J Hepatol. 2008;48:S46. 4. Bacon BR, et al. Hepatology. 2009;49:1838-1846. 5. Di Bisceglie AM, et al. N Engl J Med.. 2008;359:2429-2441.

8. Genotype Histologic stage Duration of infection To Treat or not to Treat: A Constellation of Considerations Personal plans (marriage, pregnancy) Age Family and other support Patient "mindset" ALT Occupation Extrahepatic Features (Fatigue, EMC, PCT) HIV coinfection Contraindications & comorbidities

9. Management of Viral Hepatitis—Huge Unmet Needs Efficacy in Clinical Trials and Research Centers Effectiveness in Community Practice Efficacy x Access x Correct Diagnosis x Recommendation x Acceptance x Adherence El-Serag HB. Gastroenterology. 2007;132:8-10.

10. Real World Pressures in an Already Labor-Intensive Specialty Electronic Records Declining Reimbursements PQRI (Physician Quality Reporting Initiative) MedicolegalIssues & Costs Coding and Billing Compliance Ambulatory Surgery Centers Increasingly Complicated Regimens Drug Costs & Potential Insurance Constraints E-prescribing Graphic courtesy of Dr. Ira Jacobson.

12. A Day in the Life of a Hepatology Practice…in the Future Rosemarie Nelson, MS PrincipalMGMA Health Care Consulting GroupEnglewood, Colorado

13. Agenda State of the industry The American Recovery and Reinvestment Act of 2009 (ARRA) = “stimulus package” The Health Information Technology for Economic and Clinical Health (HITECH) Act Encourage adoption of electronic health record Reimbursement shifts Operational questions and technologic answers What does it mean for your patients? 13

14. Top 10 Challenges of Practice ManagementPercent Respondentsa Who Rated Issues as “Considerable” or “Extreme” Challenges 69.9% Maintaining physician compensation with declining reimbursement 68.0% Dealing with operating costs rising more rapidly than revenues 67.8% Selecting and implementing a new electronic health record system 61.4% Recruiting physicians 56.9% Managing finances with uncertain Medicare reimbursement rates 54.4% Negotiating contracts with payers 53.3% Modifying physician compensation methodology 50.3% Hiring and retaining quality staff 50.1% Collecting from self-pay, high deductible, and/or HSA patients 50.1% Participating in Medicare Physician Quality Reporting Initiative 0 10 20 30 40 50 60 70 aSurvey of Medical Group Management Association members.Abbreviation: HSA, health savings account.With permission from Pope C, et al. MGMA Connexion. July 2008;18-23.

15. Commitments of Surveyed Hepatologists • Providing standard of care • Giving more informed advice to patients • Screening for hepatitis C virus Projects In Knowledge, Inc. Internal proprietary survey. 2009.

16. Lower Reimbursement Drop in payments from commercial payersa 2005 to 2006: 10% drop1 2006 to 2007: 6.5% drop2 Average Reimbursement, 992131b$47 Average Price of a Haircut3$45 aEvaluation and management codes; blevel 3 office visit, 2007 overall regional average.1. Moore, P. The 2006 Fee Schedule Survey. Physician’s Practice website. January 2007. Available at: http://www.physicianspractice.com/index/fuseaction/articles.details/articleID/933.htm. Accessed on October 3, 2009. 2. Grace S. Physician's Practice. January 2008; 22-35. 3. Nelson R. Phone interview with Professional Beauty Association, November 2008. 16

17. Patients’ Share of Medical Bills to Skyrocket Hewitt Associates. Survey findings: challenges for health care in uncertain times. Lincolnshire, Ill; 2009. Available at: http://www.hewittassociates.com. Accessed on: October 14, 2009. Graphic courtesy of Rosemarie Nelson, MS.

18. Provider Total Revenues Attributable to Patient Receivables Celent. Press release: The "retailish" future of patient collections. San Francisco, Calif: February 18, 2009.Available at: http://reports.celent.com/PressReleases/20090217/Retailish.asp. Accessed on: October 14, 2009.

19. Annoyances Up aCost per full-time equivalent (FTE) assuming a 10-FTE practice. Medical Group Management Association Center for Research. Analyzing the cost of administrative complexity. September 2004. Available at: http://www.mgma.com/about/default.aspx?id=280. Accessed on: October 2, 2009. Graphic courtesy of Rosemarie Nelson, MS.

20. Administrative Burden Average physician in a solo or 2-physician practice spends 3.5 hours weekly interacting with health plans 4.3 hours for primary care physicians Physicians in practices with 10 or more physicians spend 2.6 hours weekly Casalino LP, et al. Health Affairs. 2009;28:533-543.

21. Mean Dollar Value of Hours Spent per 
Physician per Year for All Health Plan Interactions With permission from Casalino LP, et al. Health Affairs. 2009;28:533-543.

22. Better-Performing Practices Over 62% of better-performing practices employ nonphysician providers to increase physician productivity performance levels1 vs 50% of other practices Improved access for patients Maximize physician time 1. Medical Group Management Association (MGMA). Performance and Practices of Successful Medical Groups 2008 Report Based on 2007 Data. Englewood, Co: MGMA; 2008.

23. Conversion to ICD-10 Code Set Deadline for compliance October 1, 20131 ICD-9(up to 5 characters) ICD-10(up to 7 characters) • Same group: $99,000 to move to EHR3 aSmall practice defined as 3 physicians and 2 administrative staff. 1. US HSS. Press release. January 15, 2009. Available at: http://www.hhs.gov/news/press/2009pres/01/20090115f.html. Accessed on: October 3, 2009. 2. (Bottom graphic) With permission from Nachimson Advisors, LLC. The impact of implementing ICD‐10 on physician practices and clinical laboratories: a report to the ICD­10 coalition. October 8, 2008.3. Nelson R. Unpublished data.

24. Centers for Medicare and Medicaid Services E-Prescribing Incentive Program • Medicare Improvements for Patients and Providers Act of 2008 (MIPPA) • Bonus of 2% of Medicare allowed charges for 2009 • Bonus 1% in 2012 and to 0.5% in 2013 • Bonus eliminated in 2014 • Simple reporting - only 3 G-codes US Health and Human Services. Centers for Medicare and Medicaid Services. Medicare's practical guide to the e-prescribing incentive program. November 2008. Available at: http://www.cms.hhs.gov/partnerships/downloads/11399.pdf. Accessed on: October 3, 2009.

25. The Bonus Isn’t the Only Payoff! Reduced chart pulls for phone calls Average cost of a chart pull is $5–$12 each1 Average hepatology practice gets 12–15 calls per day regarding prescription issues1 Get half that number? Save >$60 per day per physician!1 Patient safety and quality of care Handwriting legibility Oral miscommunications Applications provide warnings and alerts at point of prescribing vs 4 hours later with interrupting phone call from pharmacy And where is the chart then?? 1. Nelson R. Unpublished data.

26. E-Prescribing Reduces Overhead and Management Headaches Bonus money now, penalty reduction later Operational efficiency drives reduced costs Transition and implementation is manageable Address patient safety and quality of care Gain experience to carry over to electronic health record implementation

27. The Stimulus Bill (ARRA, HITECH) Starting in 2011, “meaningful” electronic health record (EHR) users are eligible to earn up to $44,000 in Medicare incentive payments over 5 years and up to $63,750 under the Medicaid plan over 6 years1,2 Still to be determined “Certified” technology that includes e-prescribing Electronic exchange of health information Submit info on clinical quality measures Physicians who do not adopt EHR by 2015 will be penalized through % decreases in Medicare reimbursement rates1 1. US DHHS. Centers for Medicare and Medicaid Services. Available at: http://tinyurl.com/mavrbs.Accessed on: October 5, 2009. 2. Finnegan B, et al. Boosting health information technology in Medicaid: the potential effect of the American Recovery and Reinvestment Act. Policy Research Brief No. 9. Available at: http://tinyurl.com/yfpqs5c. Accessed on: October 8, 2009.

28. Reporting quality initiatives Health maintenance alerts Exchange of information Results Engage the patient Portal services E-prescribing Optimize to Get to “Meaningful Use”

29. Gather information (past medical, social, and family history) Manage requests Appointments Prescription re-issues “Old” telephone triage questions Deliver lab/test results Generate revenue by recall Follow-up and health maintenance reminders Get nurses off the phones with FAQs Business of Medicine Is Communications–Patient Portal

30. Incremental Approach to EHR E-prescribing Patient portal Document image management system Results reporting and messaging “Dealbreaker” – importance of labs in hepatology (to patient too!) Online clinical documentation Transcribed reports Result reports

31. EHR Deliverables and Goals Benefits of EHR to the hepatology practice Increased quality of care through information access Standards-of-care guidelines Lab flow sheets and graphs Improved patient care experience by increasing practice efficiency What is your vision for the future? Access to data Work with data (retrieve, annotate, assign) Document and improve workflow Decision support – clinical guidelines, evidence-based medical protocols

32. No Excuse to Wait Survey findings:Net medical revenue was consistently greater across single-specialty and multispecialty groups using a clinical information solution compared with peers not using similar technologies1 Technology? Or improved operational efficiency? 1. Gans N. MGMA Connexion. July 2005;22-23.

33. Status Quo If we keep doing what we’ve always done, we’ll keep getting what we always got

34. Conclusions EHR is a significant undertaking Tool to improve effectiveness in delivery of care to patients Approach incrementally Start e-prescribing this month Reimbursement environment requires increased efficiency Models of better-performing practices are available to study and follow

36. Good, Better, and Best
Practices in HCV Management Today Bruce R. Bacon, MD James F. King MD Endowed Chair in GastroenterologyProfessor of Internal MedicineDirector, Division of Gastroenterology and HepatologySaint Louis University School of MedicineSt. Louis, Missouri

37. Why Treat Chronic Hepatitis C? • The disease • Common, chronic, and potentially progressive • Complications are becoming more common • Liver failure • Hepatocellular carcinoma (HCC) • The treatment • Viral cure, or sustained virologic response (SVR), is achievable • SVR associated with histologic improvement and gradual regression of fibrosis1 • SVR leads to lower risk for liver failure and HCC, and improved survival2,3 1. Poynard T, et al. Gastroenterology. 2002;122:1303-1313. 2. Craxi A, et al. Clin Liver Dis. 2005;9:329-346. 3. Shiratori Y, et al. Ann Intern Med. 2005;142:105-114.

38. Histologic Improvement After Successful Anti-HCV Therapy Pretreatment biopsy: Trichrome stain with Ishak stage 3 fibrosis (portal-to-portal bridging) Long-term, follow-up biopsy obtained from the same patient57 months after end of treatment: Trichrome stain with Ishak stage 1 fibrosis With permission from George S, et al. Hepatology. 2009;49:729-738.

39. The Problem–Who Gets Treated?Factors Associated with Treatment in a Retrospective Analysis of California Medicaid Dataa Untreated Age >65 years Fibrosis Severe diabetes Renal disease High hospital or ER utilization Alcohol use Treated Age 45–64 years Male gender Mild disease Liver biopsyAntidepressant use“Other” race/ethnicity a529 cases and 1058 control patients.Markowitz JS, et al. J Viral Hepat. 2005;12:176-185.

40. Treatment of Chronic Hepatitis C2001–2009 Combination of peginterferon (PEG IFN) and ribavirin (RBV) PEG IFN -2b and RBV PEG IFN -2a and RBV Genotype-specific duration and response 6–12 months Overall sustained virologic response ~55%1,2 1. Manns M, et al. Lancet. 2001;358:958-965. 2. Fried M, et al. N Engl J Med. 2002;347:975-982.

41. IDEAL—PEG IFN -2a vs -2b + RBVStudy Design PEG IFN -2b1.5 μg/kg/wk + RBV 800–1400 mg/dn = 1019 Follow-up PEG IFN -2b1.0 μg/kg/wk + RBV 800–1400 mg/dn = 1016 Treatment-Naive Patients, Genotype 1 Follow-up PEG IFN -2a180 μg/wk + RBV 1000–1200 mg/dn = 1035 Follow-up Wk 24a Wk 72 Start Tx Wk 48 Wk 36 Wk 12a aStandard response criteria were applied at treatment weeks 12 (no early virologic response) and 24 (HCV RNA +). McHutchison JG, et al. N Engl J Med. 2009;361:580-593.

42. IDEAL—ETR, SVR, and Relapse RatesGenotype 1 Patients, Intent to Treat Analysis PEG IFN -2b 1.5 µg/kg/wk + RBV 800–1400 mg/d PEG IFN -2b 1.0 µg/kg/wk + RBV 800–1400 mg/d P = .57a P = .20b PEG IFN -2a 180 µg/wk + RBV 1000–1200 mg/d a95% CI -13.2% to -2.8%. b95% CI -1.6% to 8.6%. Abbreviations: ETR, end-of-treatment response; SVR, sustained virologic response.McHutchison JG, et al. N Engl J Med. 2009;361:580-593.

43. IDEAL—Adverse Events, Dose Modification, and Treatment Discontinuation With permission from McHutchison JG, et al. N Engl J Med. 2009;361:580-593.

44. Maximizing Response to PEG IFN/RBV in HCV Genotype 1-Infected Patients • Evaluate and correct modifiable factors prior to therapy • Insulin resistance and obesity • Depression • Deliver expert treatment • Adequate RBV dose >13 mg/kg/day1 • Consider extension of therapy in “slow” responders • Aggressively manage side effects 1. McHutchison JG, et al. N Engl J Med. 2009;361:580-593.

45. Maximizing Response to PEG IFN/RBV in HCV Genotype 1-Infected Patients • Treatment response at weeks 4 and 12 are more predictive than baseline factors1-3 • May help tailor treatment to improve response or curtail therapy when it is futile • Rapid virologic response is not a stopping rule 1. Fried MW, et al. J Hepatol. 2008;48:S5. 2. Ferenci P, et al. JHepatol. 2005;43:425-433. 3. Davis GL, et al. Hepatology. 2003;38:645-652.

46. 91 72 60 48 43 Rates of Viral Clearance Predict SVR with PEG IFN/RBV 100 PEG IFN -2a 180 µg/wk + RBV 1000–1200 mg HCV RNAWk 4: Neg 80 HCV RNA|Wk 4: ≥2-log  Wk 12: Neg 60 Patients with SVR (%) HCV RNA|Wk 4: <2-log  Wk 12: Neg HCV RNA|Wk 4: ≥2-log  Wk 12: ≥2-log WK 24: Neg 40 HCV RNA|Wk 4: <2-log  Wk 12: ≥2-log WK 24: Neg The later a patient becomes HCV RNA undetectable, regardless of EVR, the lower the chance for SVR. 20 0 n = 33 93 20 21 30 Ferenci P, et al. JHepatol. 2005;43:425-433.

47. Response-Guided Therapy • HCV RNA determination is essential at week 4 (RVR) and week 12 (EVR) • Shortened therapy vs standard therapy vs extended therapy • Genotype • RVR or EVR • Viral load • Response-guided therapy will be a prominent theme with the advent of novel therapies

48. 100 80 60 40 20 SVR with Standard vs Extended Therapy in Genotype-1 Patients with Failure of RVR or Slow Response Standard 48 wk Extended 72 wk Randomization of moderately slow responders: RNA+ at 8 wk RNA– at 12 wk Retrospective subset analysis of patients with RNA+ at 12 wk Randomization of slow responders Randomized if non-RVR 64 P = .003 P = .04 P = .03 P = .07 SVR (%) 44 38 38 29 28 18 17 n = 149 142 100 106 49 52 21 52 PEG IFN α-2a + RBV 8001 PEG IFN α-2a + RBV 8002 PEG IFN α-2a + RBV 1000–12004 PEG IFN α-2b + RBV 800–14003 1. Sanchez-Tapias J, et al. Gastroenterology. 2006;131:451-460. 2. Berg T, et al. Gastroenterology. 2006;130:1086-1097. 3. Pearlman BL, et al. Hepatology. 2007;46:1688-1694. 4. Mangia A, et al. Hepatology. 2008;47:43-50. Graphic courtesy of Dr. Ira Jacobson.

49. SVR in Genotype 2/3 Patients with RVR 100 80 60 40 20 Short (12–16 wk) Standard (24 wk) 91 91 85 85 82 81 80 79 SVR (%) n = 71 71 213 70 732 731 148 150 PEG IFN α-2a + RBV 8003 PEG IFN α-2b + RBV 800–14004 PEG IFN α-2a + RBV 800–12001 PEG IFN α-2b + RBV 1000–12002 1. von Wagner M, et al. Gastroenterology. 2005;129:522-527. 2. Mangia A , et al. N Engl J Med. 2005;352:2609-2617. 3. Shiffman ML, et al. N Engl J Med. 2007;357:124-134. 4. Dalgard O, et al. Hepatology. 2008;47:35-42. Graphic courtesy of Dr. Ira Jacobson.

50. Reasons for Identifying Metabolic Syndrome and Fatty Liver Coexistence in Hepatitis C • Insulin resistance, steatosis and steatohepatitis decrease SVR1,2 • Steatosis is associated with fibrosis progression2 • Insulin resistance is associated with higher viral loads3 • Insulin resistance likely inhibits innate immune system function4 1. Romero-Gomez M, et al. Gastroenterology. 2005;128:636-641. 2. Poynard T, et al. Hepatology. 2003;38:75-85. 3. Hsu CS, et al. Liver Int. 2008;28:271-277. 4. Fernandez-Real JM, Pickup JC. Trends Endocrinol Metab. 2008;19:10-16.