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  •  
  • Introduction Ira M. Jacobson, MD Vincent Astor Professor of Medicine Chief, Division of Gastroenterology and Hepatology Medical Director of the Center for the Study of Hepatitis C Weill Cornell Medical College New York, New York
  • Phases in the Evolution of Anti-HCV Therapy Weisberg IW, et al. Current Hepatitis Reports. 2007;6:75-82. Graphic courtesy of Dr. Ira Jacobson. The Empiric Phase The Phase of S pecifically T argeted A ntiviral T herapy for H C V (STAT-C) The Final Phase— Small Molecule Combinations ???
    • Optimal dosing
    • Viral kinetics
    • Challenging populations
    • Nonresponders
    The Refinement Phase
  • The Refinement Phase of Anti-HCV Therapy Reflections on the Past Decade
    • Optimal dosing
    • Viral kinetics
    • Challenging populations
    • Nonresponders
    The Refinement Phase IFN dosing and formulation RBV dose Response-guided therapy African Americans, HIV, dialysis, decompensated, posttransplant Strategies for nonresponders and relapsers Graphic courtesy of Dr. Ira Jacobson.
  • Viral Kinetics Negative Predictive Value: 12 Weeks Positive Predictive Value: 4 Weeks Graphic courtesy of Dr. Ira Jacobson.
  • The “Accordion” Effect in Anti-HCV Therapy The Earlier HCV RNA Clears, the Shorter the Treatment Required 1-8 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. 72 wk: Gt 1 slow responders 48 wk: Gt 1 standard 12 –16 wk: Gt 2/3 with RVR 24 wk: Gt 1 LVL with RVR 72 (wk) 4 24 48 12 8 Start Time to First RNA Neg 16 End of Treatment
  • 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 SVR 1
    • Extended treatment duration to 72 weeks doubles SVR rates 1
    • 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 negative 5
    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.
    • To Treat or not to Treat:
    • A Constellation of Considerations
    Duration of infection Personal plans (marriage, pregnancy) Age ALT HIV coinfection Extrahepatic Features (Fatigue, EMC, PCT) Patient "mindset" Genotype Contraindications & comorbidities Histologic stage Family and other support Occupation
  • Management of Viral Hepatitis —H uge Unmet Needs Efficacy x Access x Correct Diagnosis x Recommendation x Acceptance x Adherence El-Serag HB. Gastroenterology . 2007;132:8-10. Efficacy in Clinical Trials and Research Centers Effectiveness in Community Practice
  • Real World Pressures in an Already Labor-Intensive Specialty Graphic courtesy of Dr. Ira Jacobson. E-prescribing Electronic Records Increasingly Complicated Regimens Coding and Billing Compliance Medicolegal Issues & Costs PQRI (Physician Quality Reporting Initiative) Drug Costs & Potential Insurance Constraints Declining Reimbursements Ambulatory Surgery Centers
  •  
  • A Day in the Life of a Hepatology Practice …in the Future Rosemarie Nelson, MS Principal MGMA Health Care Consulting Group Englewood, Colorado
  • 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?
  • Top 10 Challenges of Practice Management Percent Respondents a Who Rated Issues as “Considerable” or “Extreme” Challenges 50.1% 50.1% 50.3% 53.3% 54.4% 56.9% 61.4% 67.8% 68.0% 69.9% 0 20 30 40 50 60 70 Maintaining physician compensation with declining reimbursement Dealing with operating costs rising more rapidly than revenues Selecting and implementing a new electronic health record system Recruiting physicians Managing finances with uncertain Medicare reimbursement rates Negotiating contracts with payers Modifying physician compensation methodology Hiring and retaining quality staff Collecting from self-pay, high deductible, and/or HSA patients Participating in Medicare Physician Quality Reporting Initiative a Survey of Medical Group Management Association members. Abbreviation: HSA, health savings account. With permission from Pope C, et al. MGMA Connexion. July 2008;18-23. 10
    • Providing standard of care
    • Giving more informed advice to patients
    • Screening for hepatitis C virus
    Commitments of Surveyed Hepatologists Projects In Knowledge, Inc. Internal proprietary survey. 2009.
  • Lower Reimbursement a Evaluation and management codes; b level 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. Drop in payments from commercial payers a 2005 to 2006: 10% drop 1 2006 to 2007: 6.5% drop 2 Average Reimbursement, 99213 1b $47 Average Price of a Haircut 3 $45
  • 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. Survey of 343 Executives Whose Companies Employ >5 Million Employees Employer Benefits Percent Percentage of employers that intend to shift more health insurance costs to employees next year 65 Percentage of employers that plan to reduce the number of health plan options 49 Percentage of employers that plan to increase the number of consumer-directed health plans 40
  • 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.
  • Annoyances Up 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. a Cost per full-time equivalent (FTE) assuming a 10-FTE practice. Survey of Annual Administrative Costs in Group Practice (N = 91, multiple specialties and settings) Administrative Task Cost per Physician a Physician time in response to pharmacy phone calls $12,731 Staff time in insurance verification, copays, and deductibles $3876 Support staff time to appeal denied claims $925 Credentialing applications (physician and staff) $808
  • 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.
  • 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. Survey of US Physicians and Administrative Staff 730 Primary Care Physicians; 580 Specialists 1–2 MDs 3–9 MDs 10+ MDs Physician time $17,817 $15,670 $13,798 Nursing staff time $14,897 $26,225 $24,314 Clerical staff time $30,014 $25,632 $18,636 Senior administrative time $5829 $3269 $1235 Lawyer/accountant time $1249 $626 $4455 Total per practice $69,806 $71,422 $62,438
  • Better-Performing Practices
    • Over 62% of better-performing practices employ nonphysician providers to increase physician productivity performance levels 1
      • 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.
  • Conversion to ICD-10 Code Set
    • Deadline for compliance October 1, 2013 1
    ICD-9 (up to 5 characters) ICD-10 (up to 7 characters) a Small 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.
    • Same group: $99,000 to move to EHR 3
    Conversion–Estimate of Costs to Comply for a Typical Small Practice 2a Category Cost Training and education $2405 Business analysis $6905 Super-bill changes $2985 IT system changes $7500 Increased documentation costs $44,000 Cash flow disruption $19,500 Total Costs $83,295
  • 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.
  • The Bonus Isn’t the Only Payoff!
    • Reduced chart pulls for phone calls
      • Average cost of a chart pull is $5–$12 each 1
      • Average hepatology practice gets 12–15 calls per day regarding prescription issues 1
      • 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.
  • 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
  • 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 years 1,2
      • 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 rates 1
    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.
    • Reporting quality initiatives
      • Health maintenance alerts
    • Exchange of information
      • Results
    • Engage the patient
      • Portal services
    • E-prescribing
    Optimize to Get to “Meaningful Use”
    • 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
  • 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
  • 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
  • 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 technologies 1
    Technology? Or improved operational efficiency? 1. Gans N. MGMA Connexion. July 2005;22-23.
  • Status Quo
    • If we keep doing what we’ve always done, we’ll keep getting what we always got
  • 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
  •  
  • Good, Better, and Best
Practices in HCV Management Today Bruce R. Bacon, MD James F. King MD Endowed Chair in Gastroenterology Professor of Internal Medicine Director, Division of Gastroenterology and Hepatology Saint Louis University School of Medicine St. Louis, Missouri
  • 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 fibrosis 1
      • SVR leads to lower risk for liver failure and HCC, and improved survival 2,3
    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.
  • Histologic Improvement After Successful Anti-HCV Therapy Long-term, follow-up biopsy obtained from the same patient 57 months after end of treatment: Trichrome stain with Ishak stage 1 fibrosis Pretreatment biopsy: Trichrome stain with Ishak stage 3 fibrosis (portal-to-portal bridging) With permission from George S, et al. Hepatology . 2009;49:729-738.
  • The Problem–Who Gets Treated? Factors Associated with Treatment in a Retrospective Analysis of California Medicaid Data a a 529 cases and 1058 control patients. Markowitz JS, et al. J Viral Hepat. 2005;12:176-185. Treated Age 45–64 years Male gender Mild disease Liver biopsy Antidepressant use “Other” race/ethnicity Untreated Age >65 years Fibrosis Severe diabetes Renal disease High hospital or ER utilization Alcohol use
  • Treatment of Chronic Hepatitis C 2001–2009
    • 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.
  • IDEAL —P EG IFN  -2a vs  -2b + RBV Study Design Start Tx Wk 12 a Wk 24 a Wk 36 Wk 48 PEG IFN  -2b 1.5 μ g/kg/wk + RBV 800–1400 mg/d n = 1019 PEG IFN  -2b 1.0 μ g/kg/wk + RBV 800–1400 mg/d n = 1016 Follow-up Follow-up PEG IFN  -2a 180 μ g/wk + RBV 1000–1200 mg/d n = 1035 Follow-up Treatment-Naive Patients, Genotype 1 a Standard 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. Wk 72
  • P = .57 a P = .20 b 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 PEG IFN  -2a 180 µg/wk + RBV 1000–1200 mg/d a 95% CI -13.2% to -2.8%. b 95% 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. IDEAL — ETR, SVR, and Relapse Rates Genotype 1 Patients, Intent to Treat Analysis
  • IDEAL —A dverse Events, Dose Modification, and Treatment Discontinuation With permission from McHutchison JG, et al. N Engl J Med. 2009;361:580-593. PEG IFN  -2b 1.5 + RBV n = 1019 PEG IFN  -2b 1.0 + RBV n = 1016 PEG IFN  -2a 180 + RBV n = 1035 Deaths (all/treatment-related) 5/1 (no.) 1/0 (no.) 6/1 (no.) Serious adverse events (AEs) (all/treatment-related) 9%/4% 9%/4% 12%/4% Discontinued due to AEs 13% 10% 13% Dose modification due to AEs 43% 33% 43% Psychiatric disorders 1.9% 1.2% 1.4% Hematologic parameters Neutrophil count (<750/mm 3 /<500/mm 3 ) 22%/3% 14%/2% 27%/6% Hemoglobin (<10 g/dL/<8.5 g/dL) 31%/3% 25%/2% 30%/4% Erythropoietin use 16% 14% 17%
  • 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/day 1
      • Consider extension of therapy in “s low” responders
      • Aggressively manage side effects
    1. McHutchison JG, et al. N Engl J Med. 2009;361:580-593.
  • Maximizing Response to PEG IFN/RBV in HCV Genotype 1-Infected Patients
    • Treatment response at weeks 4 and 12 are more predictive than baseline factors 1-3
      • 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. J Hepatol . 2005;43:425-433. 3. Davis GL, et al. Hepatology. 2003;38:645-652.
  • Ferenci P, et al. J Hepatol . 2005;43:425-433. Rates of Viral Clearance Predict SVR with PEG IFN/RBV PEG IFN  -2a 180 µg/wk + RBV 1000 – 1200 mg Patients with SVR (%) 0 20 40 60 80 100 HCV RNA Wk 4: Neg HCV RNA| Wk 4: ≥2-log  Wk 12: Neg HCV RNA| Wk 4: <2-log  Wk 12: Neg HCV RNA| Wk 4: ≥2-log  Wk 12: ≥2-log  WK 24: Neg HCV RNA| Wk 4: <2-log  Wk 12: ≥2-log  WK 24: Neg n = 33 93 20 21 30 The later a patient becomes HCV RNA undetectable, regardless of EVR, the lower the chance for SVR. 91 72 60 48 43
  • 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
  • SVR with Standard vs Extended Therapy in Genotype-1 Patients with Failure of RVR or Slow Response 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. Standard 48 wk Extended 72 wk PEG IFN α -2a + RBV 800 1 PEG IFN α -2a + RBV 800 2 PEG IFN α -2b + RBV 800–1400 3 SVR (%) 28 44 17 29 18 38 38 64 PEG IFN α -2a + RBV 1000–1200 4 n = 149 100 49 21 142 106 52 52 P = .07 P = .03 P = .04 P = .003 Randomized if non-RVR Retrospective subset analysis of patients with RNA+ at 12 wk Randomization of slow responders Randomization of moderately slow responders: RNA+ at 8 wk RNA– at 12 wk 20 40 60 80 100
  • SVR in Genotype 2/3 Patients with RVR 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. Short (12–16 wk) Standard (24 wk) 79 85 81 91 82 80 85 91 PEG IFN α -2a + RBV 800 3 PEG IFN α -2a + RBV 800–1200 1 PEG IFN α -2b + RBV 1000–1200 2 PEG IFN α -2b + RBV 800–1400 4 SVR (%) n = 71 71 213 732 148 70 731 150 20 40 60 80 100
  • Reasons for Identifying Metabolic Syndrome and Fatty Liver Coexistence in Hepatitis C
    • Insulin resistance, steatosis and steatohepatitis decrease SVR 1,2
    • Steatosis is associated with fibrosis progression 2
    • Insulin resistance is associated with higher viral loads 3
    • Insulin resistance likely inhibits innate immune system function 4
    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.
  • Impact of Insulin Resistance on SVR in Genotype-1 Patients PEG IFN + RBV a a Treatment: PEG IFN  -2a 180  g/wk or PEG IFN  -2b 1.5  g/kg/wk + RBV 800–1200/d. Romero-Gomez M, et al. Gastroenterology. 2005;128:636-641. Graphic courtesy of Dr. Bruce Bacon. P = .007 With Insulin Resistance Without Insulin Resistance
  • Reduction of Insulin Resistance With Successful HCV Therapy a Mean values; b P = .017 Abbreviations: HALT-C, Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis; HOMA, Homeostasis model assessment; IR, insulin resistance. Delgado-Borrego A, et al. Hepatology 2008;48:433A. Data from Longitudinal Study Within Lead-In Phase of HALT-C Trial to Evaluate Change in IR with HCV Therapy N = 96; genotype-non3 prior nonresponders with evidence of advanced fibrosis and no uncontrolled diabetes Group Based on Status at Week 20 of PEG IFN/RBV HOMA2-IR a Change at Week 20 b Null responders (n = 38) +0.18 Partial responders (n = 37) – 0.9 Responders (n = 21) – 2.23
  • A Polymorphism on Chromosome 19 Predicts SVR Ge D, et al. Nature. 2009;461:399-401. Chromosome 19 graphic courtesy of Oak Ridge National Laboratory. Available at: http://www.ornl.gov/sci/techresources/meetings/ecr2/olsen.gif. Accessed on: October 21, 2009. 60 Mb Chromosome 19 Polymorphism rs12979860 IL28B gene 3 kb 19q13.13
  • Americans Americans rs12979860 Genotype Frequency by Population Ge D, et al. Nature. 2009;461:399-401. 12 36 19 50 48 46 38 16 35 0 20 40 60 80 100 European African Hispanics Percent C/C T/C T/T
  • C Allele is Associated with SVR Percentage SVR by Genotype of rs12979860 0 20 40 60 80 100 C/C T/C T/T SVR Combined European Americans African Americans Hispanics P = 1.37 x 10 -28 vs T/T Ge D, et al. Nature. 2009;461:399-401. n = 70 n = 14 n = 102 n = 91 n = 35 n = 433 n = 186 n = 559 n = 392 n = 30 n = 26 n = 336
  • C/C Genotype Is Independently Associated with SVR a a Odds ratios and 95% confidence intervals from the logistic regression model. Ge D, et al. Nature. 2009;461:399-401. IL28B rs 12979860 Genotype (CC vs CT and TT) European Americans 7.3 (5.1–10.4) African Americans 6.1 (2.3–15.9) Hispanics 5.6 (1.4–22.1) Baseline Viral Load (≤600,000 IU/mL vs ≥600,000 IU/mL) European Americans 4.2 (2.6–6.6) African Americans 5.1 (1.9–13.9) Hispanics 2.4 (0.7–8.8) Baseline Fibrosis (Metavir F0–2 vs F3–4) European Americans 3.0 (1.8–5.1) African Americans 1.1 (0.3–5.2) Hispanics 4.1 (0.7–25.5) Ethnicity (European Americans/African Americans) 3.1 (2.1–4.7)
    • IFN lambda proteins encoded by the IL28A/B and IL29 genes
    • These IFNs signal through a unique receptor, but share common downstream signaling with type 1 IFNs, including IFN- 
    • IFN-lambda (rIL-29) is currently in clinical trials and has antiviral activity
    Ge D, et al. Nature. 2009;461:399-401. Impact of IL28/29 on IFN
  • Impact of IL28/29 on STAT-C Therapy
    • Impact of testing for IL28B will be important with PEG IFN and RBV
    • IL28B testing will need to be investigated when using STAT-C agents
  • Conclusions
    • PEG IFN plus RBV is the current standard-of-care therapy
      • Overall SVR about 55%
    • Insulin resistance has a significant impact on SVR
    • Response-guided therapy is important now and will be a prominent theme with novel therapies
    • IL28B status influences effectiveness of IFN
  •  
  • The Future of Anti-HCV Treatment—Emerging Therapies and Their Integration into the Medical Office of the Future Nezam H. Afdhal, MD Associate Professor of Medicine Harvard Medical School Chief of Hepatology Beth Israel Deaconess Medical Center
 Boston, Massachusetts
  • Where We Are with Treatment Now Genotype 1 Abbreviations: NR, null response; SVR, sustained virologic response. Graphic courtesy of Dr. John McHutchison. SVR 40%–50% Relapse 20%–30% Discontinue 20% NR 20%
  • Emerging Anti-HCV Therapies Genome Sequence-Based RNA interference Enzyme Inhibitors Protease Polymerase Other
    • IFN and RBV modifications
    • Albinterferon, omega IFN, PEG IFN lambda (IL-29)
    • Taribavirin (viramidine)
    • Immune approaches
    • Therapeutic vaccines
    • Toll-like receptor agonists
    • Hepatitis C immune globulin
    • Monoclonal antibodies
    • Targeting cellular factors
    • Cyclophilin antagonists
    • Nitazoxanide
    S pecifically T argeted A ntiviral T herapy for H C V (STAT-C) NS5A Abbreviations: HCV, hepatitis C virus; IFN, interferon; PEG IFN, peginterferon; RBV, ribavirin. Graphic courtesy of Dr. Ira Jacobson.
  • Hepatitis C Drug Development–2009 MK7009 Phase II On Market Phase III Phase I Research/ Preclinical Thymalfasin Albumin-IFN alfa IFN & PEG IFN Many others, including immune stimulants and gene therapy Ribavirin Taribavirin Medusa IFN A-831 Telaprevir Debio25 Omega IFN Boceprevir R1728 TMC 435350 Note: Not a complete list of products in development. Information from public sources. Graphic courtesy of Dr. John McHutchison. Silibinin BI-201335 GS9190 BMS-650032 Interferons Ribavirins Immunomodulators Protease inhibitors Polymerase inhibitors BMS-790052 ITMN 191 VBY-376 Others MK-3281 ANA598 VCH-759 JTK-652 BIT225 BMS-791325 Controlled-release IFN Low-dose oral IFN IFN biopump DA-3021 IL-29 ME-3738 SCV-07 Oglufanide IPH-1101 CYT 107 EGS21 SCY-635 KPE02001003 TCM-700C PYN-17 Nitazoxanide VX-500 ABT-333 PHX1766 IDX184 EMZ702 HDV interferon NIM811 Bavituximab CF102 VX-813 VCH-222 IFN beta-1a PF-868554 VCH-916
  • Albinterferon alfa-2b
    • Novel recombinant polypeptide 1
    • Extended serum half-life supports dosing at 2-week intervals 2,3
      • 148 hours, median (range, 134–153 hours)
    • Phase II findings show 900 µ g has comparable efficacy to PEG IFN/RBV and 1200 µ g has superior efficacy 4
      • Both doses warranted evaluation in phase III trial
    1. Liu C, et al. Hepatol Res. 2007;37:941-947. 2. Bain VG, et al. J Hepatol. 2006;44:671-678. 3. Bain V, et al. J Hepatol. 2005;42 (suppl 1):abstract 18. 4. Zeuzem S, et al. J Hepatol. 2009;50:S377. Graphic courtesy of Dr. Nezam Afdhal. IFN  -2b Human albumin Molecular weight 85.7 kDa
  • ACHIEVE 1 Study Design Randomized, Open-Label, Active-Controlled, Phase III Wk 72 Start Tx Wk 48 PEG IFN α-2a 180 µg q1wk + RBV 1000–1200 mg/d WBD n = 441 albIFN 900 µg q2wk + RBV 1000–1200 mg/d WBD n = 442 Follow-up Follow-up Follow-up IFN-  Treatment-Naive Patients, Genotype 1 a Data Monitoring Committee dose modification on 1-23-08; 51% of patients in albIFN 1200 µg arm reduced to 900 µg q2wk. Abbreviations: albIFN, albinterferon; PEG IFN, peginterferon; RBV, ribavirin; WBD, weight-based dosing. Zeuzem S, et al. J Hepatol. 2009;50:S377. albIFN 1200 µg q2wk + RBV 1000–1200 mg/d WBD n = 440 900 µg Wk 24 a
  • SVR Relapse PEG IFN 180 µg q1wk PEG IFN 180 µg q1wk albIFN 900 µg q2wk albIFN 1200 µg q2wk albIFN 900 µg q2wk albIFN 1200 µg q2wk ACHIEVE 1–SVR and Relapse in Intent-to-Treat Population Zeuzem S, et al. J Hepatol. 2009;50:S377. P = .0029 a P = .0008 a a P -value for noninferiority.
  • Selected Common Adverse Events Albinterferon in ACHIEVE 1 a Mild with resolution at end of treatment. b Not asssociated with pulmonary infection or chest X-ray changes. Zeuzem S, et al. J Hepatol. 2009;50:S377. Adverse Event PEG IFN 180 Q1w n = 441 albIFN 900 Q2w n = 442 albIFN 1200 Q2w n = 440 Fatigue 245 (55.6%) 230 (52.0%) 248 (56.4%) Headache 200 (45.4%) 205 (46.4%) 217 (49.3%) Pyrexia 149 (33.8%) 163 (36.9%) 185 (42.0%) Insomnia 157 (35.6%) 162 (36.7%) 164 (37.3%) Alopecia a 108 (24.5%) 182 (41.2%) 177 (40.2%) Nausea 148 (33.6%) 156 (35.3%) 157 (35.7%) Cough b 113 (25.6%) 166 (37.6%) 175 (39.8%) Mood altered 108 (24.5%) 106 (24.0%) 89 (20.2%) Depression 84 (19.0%) 86 (19.5%) 93 (21.1%)
  • Direct Viral Enzyme Inhibitors — E volving Next Future Therapies Viral Enzyme Inhibitors Protease Polymerase STAT-C S pecifically t argeted A nti-viral t herapy for H C V NS5A Graphic courtesy of Dr. Ira Jacobson.
  • With permission from Moradpour D, Blum HE. Liver Int . 2004;24:519-525. (1) Virus entry (2) Uncoating (3) Polyprotein processing (4) RNA replication (5) Packing and assembly (6) Virion maturation and release Potential Antiviral Targets
  • Adherence to Antiviral Therapy Doses Taken in Virahep-C Study 2 Physicians predicted adherence incorrectly for ~41% of patients 1 Association Between Virologic Failure and Adherence to Antiretroviral Therapy in Patients with HIV 1 1. Paterson DL, et al. Ann Intern Med. 2000;133:21-30. 2. Conjeevaram HS, et al. Gastroenterology. 2006;131:470-477. Left graphic with permission from Paterson DL, et al. Ann Intern Med. 2000;133:21-30. Right graphic courtesy of Dr. Nezam Afdhal.
  • PROVE 1 —T elaprevir + PEG IFN/RBV SVR, Intent-to-Treat Analysis, Phase II 0 20 40 60 80 100 SVR Rate (%) 41 31/75 PR 48 wk (Control) 35 6/17 T 12 wk + PR 12 wk 61 48/79 T 12 wk + PR 24 wk 67 53/79 T 12 wk + PR 48 wk P = .001 P = .020 Abbreviations: P, PEG IFN alfa-2a 180 ug/wk; R, ribavirin 1000–1200 mg/day; T, telaprevir 750 mg q8h. McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838. With permission from Dr. John McHutchison.
  • PROVE 1 —R elapse Rates 0 10 20 30 40 50 Relapse Rate (%) 23 8/35 33 a 3/9 2 a 6 3/51 PR 48 wk (Control) T 12 wk + PR 12 wk T 12 wk + PR 24 wk T 12 wk + PR 48 wk a Includes subjects who met the rapid virologic response criterion and stopped at 12 or 24 total weeks of treatment. McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838. Graphic courtesy of Dr. John McHutchison. Denominator = number of subjects with undetectable HCV RNA at completion of assigned treatment duration. 1/41
  • Can We Dispense with Ribavirin? PROVE 2 PR48 control (n = 82) T12PR24 (n = 81) T12PR12 (n = 82) Abbreviations: P, PEG IFN alfa-2a 180 ug/wk; R, ribavirin 1000–1200 mg/day; T, telaprevir 750 mg q8h. H ézo de C, et al. N Engl J Med. 2009;360:1839-1850. T12P12 (n = 78)
  • Sprint 1—Boceprevir + PEG IFN  -2b + RBV Phase II, Part 1 and 2 Treatment-Naive Genotype-1 (N = 520) a Interim analysis. Abbreviations: B, boceprevir 800 mg TID; P, PEG IFN  -2b 1.5 µg/kg/wk; R, ribavirin 800–1400 mg/d; R-LD, low-dose ribavirin 400–1000 mg/d. Kwo P, et al. J Hepatol. 2009;50:S4. Wk 72 Start Wk 4 Wk 12 a Wk 28 Wk 48 No Lead-in Control Follow-up PR Follow-up PR PR + B Follow-up PR PR + B Follow-up PR + B Follow-up PR + B Lead-in Part 1 Follow-up PR Follow-up PR-LD R-LD Part 2
  • SPRINT 1 —S VR 24 Rates PEG IFN -2b + RBV +/- Boceprevir; Low-Dose RBV 38 56 75 54 67 0 20 40 60 80 100 SVR (%) PRB Lead-In (n = 103) PRB No Lead-In (n = 103) PRB Lead-In (n = 103) PRB No Lead-In (n = 107) PR Control (n = 104) Tx 28 Weeks Tx 48 Weeks Part 2 Part 1 a Main adverse effects: Fatigue, headache, nausea, and anemia. Kwo P, et al. J Hepatol. 2009;50:S4. 50 36 PR Control (n = 16) PR-LD (n = 59)
  • SPRINT 1 —S VR 24 in Those Who Achieved RVR 100 82 94 74 84 0 20 40 60 80 100 SVR (%) PR Control (n = 104) PRB Lead-In (n = 103) PRB No Lead-In (n = 103) PRB Lead-In (n = 103) PRB No Lead-In (n = 107) Tx 28 Weeks Tx 48 Weeks Kwo P, et al. J Hepatol. 2009;50:S4. 32/38 62/66 32/43 54/66 8/8
  • SPRINT 1 —V irologic Breakthrough 0 4 5 7 12 0 5 10 15 20 PRB Lead-In (n = 103) PRB No Lead-In (n = 103) PRB Lead-In (n = 103) PRB No Lead-In (n = 107) Patients with Breakthrough (%) PR Control (n = 104) Tx 28 Weeks Tx 48 Weeks Kwo P, et al. J Hepatol. 2009;50:S4.
  • PROVE 3 — Telaprevir + PEG IFN +/- RBV by Prior Response and Treatment Group a McHutchison JG, et al. 60th AASLD. Boston, MA. October 30-November 3, 2009. Abstract 66. a Intent-to-treat analysis. SVR (%) T12/ PR24 T24/ PR48 T24/ P24 PR48 Treatment failures 51 53 24 14
  • PROVE 3 — Telaprevir + PEG IFN +/- RBV by Prior Response and Treatment Group a McHutchison JG, et al. 60th AASLD. Boston, MA. October 30-November 3, 2009. Abstract 66. a Intent-to-treat analysis. SVR (%) T12/ PR24 T24/ PR48 T24/ P24 PR48 Treatment failures 51 53 24 14 Prior nonresponders 39 38 11 9 Prior relapsers 69 76 42 20
  • Weight-Based Taribavirin or RBV + PEG IFN Phase IIb Study Design Treatment-Naive Patients, Genotype 1 Poordad F, et al. J Hepatol. 2009;50:S8. Taribavirin 25 mg/kg/d + PEG IFN  -2b µg/kg/wk n = 70 Follow-up Taribavirin 20 mg/kg/d + PEG IFN  -2b 1.5 µg/kg/wk n = 67 Follow-up Taribavirin 30 mg/kg/d + PEG IFN  -2b µg/kg/wk n = 68 Follow-up RBV 800/1000/1200/1400 mg/d + PEG IFN  -2b 1.5 µg/kg/wk n = 70 Follow-up Wk 72 Start Tx Wk 12 Wk 24 Wk 36 Wk 48
  • Weight-Based Taribavirin or RBV + PEG IFN Virologic Response at Week 4, 12, 48 and SVR12 a a ITT population. Abbreviation: TBV, taribavirin. Poordad F, et al. J Hepatol. 2009;50:S8. TBV 20 mg/kg + PEG IFN TBV 25 mg/kg + PEG IFN TBV 30 mg/kg + PEG IFN RBV 800–1400 mg + PEG IFN
  • Taribavirin vs RBV + PEG IFN  -2b Hemoglobin Event Rate Poordad F, et al. J Hepatol. 2009;50:S8. TBV 20 mg/kg + PEG IFN TBV 25 mg/kg + PEG IFN TBV 30 mg/kg + PEG IFN RBV 800–1400 mg + PEG IFN P ≤.05 for TBV 20 mg/kg and TBV 25 mg/kg vs RBV
  •  
  • INFORM 1—Two Direct Antivirals Combined R7128 + R7227 a , Phase 1b, First 4 Cohorts b 40 Wk Day 1 Day 4 Day 7 Day 14 Treatment-Naive Genotype-1 R7128 500 mg BID R7227 100 mg q8h R7128 500 mg BID R7227 200 mg q8h R7128 1000 mg BID R7227 100 mg q8h R7128 1000 mg BID R7227 200 mg q8h R7128 500 mg BID R7227 100 mg q8h R7128 500 mg BID R7227 100 mg q8h n = active/ placebo 8/0 8/0 8/2 8/4 A B C D 16/2 PEG IFN  -2a + RBV PEG IFN  -2a + RBV PEG IFN + RBV PEG IFN + RBV PEG IFN + RBV PEG IFN + RBV a Also known as ITMN-191. b Study expansion to include treatment failures and null responders. Gane EJ, et al. J Hepatol. 2009;50;S380.
  • INFORM 1—Preliminary Viral Kinetics Day 1–14 With permission from Gane EJ, et al. J Hepatol. 2009;50;S380. Placebo R7128 D1–7 R7227 D4–7 R7227 D1–7 R7128 D4–7 R7128 500 mg R7227 100 mg R7128 500 mg R7227 200 mg R7128 1000 mg R7227 100 mg R7128 1000 mg R7227 200 mg HCV RNA Change from Baseline, Mean (IU/mL)
  • INFORM 1—Virologic Response at Day 14 Abbreviations: BL, baseline; LLOD, lower limit of detection (<15 IU/mL, Roche Taqman); LLOQ, lower limit of quantification (<40 IU/mL, Roche Taqman). With permission from Gane EJ, et al. J Hepatol. 2009;50;S380. Regimen (mg) n HCV RNA (IU/mL) BL Change from BL, median (range) Day 14, median (range) <LLOQ, n (%) <LLOD, n (%) R7128 500 R7227 100 8 2.8 x 10 6 -3.9 (-5.0 to -2.9) 288 (<15 to 588) 1/8 (13%) 1/8 (13%) R7128 500 R7227 200 8 8.3 x 10 6 -5.2 (-5.5 to -3.1) 35 (<15 to 701) 5/8 (63%) 2/8 (25%) R7128 1000 R7227 100 7 2.2 x 10 6 -4.8 (-5.7 to -4.5) 20 (<15 to 173) 5/7 (71%) 2/7 (29%) R7128 1000 R7227 200 8 2.2 x 10 6 -4.8 (-5.5 to -2.7) 22 (<15 to 660) 5/8 (63%) 2/8 (25%)
  • Resistance to HCV Direct Antivirals What We Know So Far
    • Detection depends on how carefully you look for it
    • Occurs rapidly with monotherapy
    • Partially abrogated by addition of peginterferon
    • Effect of ribavirin important
    • Reversion to the wild type partially occurs 3 – 7 months after cessation of therapy
    • Cross-resistance will probably occur for each target
  • Resistance to HCV Direct Antivirals What We Don ’t Know So Far
    • Magnitude of the effect of adherence
    • Long-term clinical effects of development of resistant variants
    • Effect of combination directly acting antiviral agents
    • How much PEG IFN and RBV is needed?
    • How long is PEG IFN and RBV needed?
  • Long-Term Consequences of Resistance “ Fitness” Disease progression rates Evolutionary disadvantage Retreatment outcomes Prevention strategies Class effects Graphic courtesy of Dr. John McHutchison.
  • Adherence Adequate PK/PD Value of Lead-in Dose and populations Combination therapy Length of therapy Foreseeable, Unavoidable, Preventable Abbreviation: PK/PD, pharmacokinetics/pharmacodynamics. Graphic courtesy of Dr. John McHutchison. Limiting or Curtailing Resistance
  • Cardiotoxicity Rash Liver test abnormalities DC rates x 2-4 fold Neutropenia Lymphopenia Anemia Abbreviation: DC, discontinuation. Graphic courtesy of Dr. John McHutchison. More Drugs = More Toxicity
  • Simplicity/ complexity Tolerability Efficacy Resistance Duration Cost Graphic courtesy of Dr. John McHutchison. Key Drivers of Successful Therapy
  • IFN RBV IFN RBV HCV inhibitor HCV inhibitor HCV inhibitor HCV inhibitor RBV ? Future Anti-HCV Therapy IFN? Graphic courtesy of Dr. Nezam Afdhal.
  • Conclusions
    • Multidrug therapy is on the horizon, but
      • Don’t slip on efficacy
      • Cure, don’t suppress
      • Limit and prevent resistance
    • Significant knowledge gaps remain in special populations—HIV, posttransplant
    • Integrating new treatment into patient care strategies will require expertise and teamwork
  •  
  • Concluding Remarks Ira M. Jacobson, MD Vincent Astor Professor of Medicine Chief, Division of Gastroenterology and Hepatology Medical Director of the Center for the Study
 of Hepatitis C
 Weill Cornell Medical College 
 New York, New York
  • Phases in the Evolution of Anti-HCV Therapy The Empiric Phase The Phase of S pecifically T argeted A ntiviral T herapy for H C V (STAT-C) Weisberg IW, et al. Current Hepatitis Reports. 2007;6:75-82. Graphic courtesy of Dr. Ira Jacobson. The Final Phase— Small Molecule Combinations ???
    • Optimal dosing
    • Viral kinetics
    • Challenging populations
    • Nonresponders
    The Refinement Phase
    • Less focus on which PEG IFN
    • Response-guided therapy – principle clear but variable penetrance
    • Limited choices for nonresponders – huge unmet need
    • Other populations with unmet needs abound
  • A Polymorphism on Chromosome 19 Predicts SVR Ge D, et al. Nature. 2009;461:399-401. Chromosome 19 graphic courtesy of Oak Ridge National Laboratory. Available at: http://www.ornl.gov/sci/techresources/meetings/ecr2/olsen.gif. Accessed on: October 21, 2009. 60 Mb Chromosome 19 Polymorphism rs12979860 IL28B gene 3 kb 19q13.13
  • The IL28B Single Nucleotide Polymorphism A Major Discovery Leads to Many New Questions
    • What insights does this give into the mechanism of IFN responsiveness?
      • Relationship to upregulation of IFN-specific genes in nonresponders?
      • Why connected to spontaneous clearance as well?
    • Role in clinical practice (assuming availability)?
    • Role as new treatments become available?
  • Emerging Anti-HCV Therapies Genome Sequence-Based RNA interference Enzyme Inhibitors Protease Polymerase Other
    • IFN and RBV modifications
    • Albinterferon, omega IFN, PEG IFN lambda (IL-29)
    • Taribavirin (viramidine)
    • Immune approaches
    • Therapeutic vaccines
    • Toll-like receptor agonists
    • Hepatitis C immune globulin
    • Monoclonal antibodies
    • Targeting cellular factors
    • Cyclophilin antagonists
    • Nitazoxanide
    S pecifically T argeted A ntiviral T herapy for H C V (STAT-C) NS5A
  • A Glimpse of the Near Future
    • First wave of new agents likely available in next 2 years
    • First-generation protease inhibitors being studied as TID drugs in phase III
    • Second-generation protease inhibitors – less frequent dosing
    • Potential for ritonavir boosting to enable daily dosing
    • Polymerase inhibitors look promising in combination with PEG IFN and RBV
    • Resistance will be a key theme
  • Anti-HCV Therapy Likely Picture—Near Future Viral enzyme inhibitors Immune or host pathway modulators RBV or related drugs + ± Interferon as a platform for future combinations Need to study different IFNs to determine optimal characteristics Graphic courtesy of Dr. Ira Jacobson.
  • The Goal of Combination Regimens A B C + +
    • Different drugs may contribute variably to each of these goals
    • Not all components have to be STAT-C agents
    Graphic courtesy of Dr. Ira Jacobson. Prevention of emergent resistance (pre-existing or de novo) A Profound suppression of broad range of viral variants, including pre-existing
  • Current SOC (2009) PEG IFN + RBV + STAT-C(1) PEG IFN + RBV + STAT-C(2) PEG IFN + RBV + STAT-C(1+2) STAT-C (1+2+…) Can We Leapfrog Ahead? Graphic courtesy of Dr. Ira Jacobson.
  • Treating HCV in the Next 5 Years
    • Cure more patients
    • Shorter duration of therapy
    • Increased toxicity
    • Increased complexity
    • Increased costs
    • Mandate to prevent resistance
     Opportunities  Challenges
  • Increasing Complexity of HCV Management Electronic health records Resistance mutations New interferons Cost, Toxicities & Compliance STAT-C Agents Genetic predictors Response Guided Therapy NPs, PAs Novel combinations E-prescribing