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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
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Phases in the Evolution of Anti-HCV Therapy
Empiric Phase The Refinement Phase The Phase of Specifically Targeted Antiviral Therapy for HCV (STAT-C) The Final Phase— Small Molecule Combinations ??? Optimal dosing Viral kinetics Challenging populations Nonresponders Weisberg IW, et al. Current Hepatitis Reports. 2007;6: Graphic courtesy of Dr. Ira Jacobson.
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The Refinement Phase of Anti-HCV Therapy Reflections on the Past Decade
IFN dosing and formulation RBV dose The Refinement Phase Response-guided therapy Optimal dosing Viral kinetics Challenging populations Nonresponders African Americans, HIV, dialysis, decompensated, posttransplant Strategies for nonresponders and relapsers Graphic courtesy of Dr. Ira Jacobson.
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Viral Kinetics Positive Negative Predictive Predictive Value: Value:
4 Weeks Negative Predictive Value: 12 Weeks Graphic courtesy of Dr. Ira Jacobson.
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The “Accordion” Effect in Anti-HCV Therapy The 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: Dalgard O, et al. Hepatology. 2008;47: Jensen DM, et al. Hepatology. 2006;43: Mangia A, et al. N Engl J Med. 2005;352: Mangia A, et al. Hepatology. 2008;47: Sanchez-Tapias JM, et al. Gastroenterology. 2006;131: von Wagner MV, et al. Gastroenterology. 2005;129: Zeuzem S, et al. J Hepatology. 2006;44: Graphic courtesy of Dr. Ira Jacobson. 6
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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: Poynard T, et al. Gastroenterology. 3. Schiff E, et al. J Hepatol. 2008;48:S ;136: Bacon BR, et al. Hepatology. 2009;49: Di Bisceglie AM, et al. Hepatology. 2007;46:290A.
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To Treat or not to Treat: A Constellation of Considerations
Genotype Histologic stage Duration of infection Personal plans (marriage, pregnancy) Age Family and other support Patient "mindset" ALT Occupation Extrahepatic Features (Fatigue, EMC, PCT) HIV coinfection Contraindications & comorbidities
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Management of Viral Hepatitis—Huge Unmet Needs
Efficacy in Clinical Trials and Research Centers Effectiveness in Community Practice Slide 228 Prevention and Treatment of HCC Efficacy x Access x Correct Diagnosis x Recommendation x Acceptance x Adherence El-Serag HB. Gastroenterology. 2007;132:8-10.
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Real World Pressures in an Already Labor-Intensive Specialty
Electronic Records Declining Reimbursements PQRI (Physician Quality Reporting Initiative) Medicolegal Issues & Costs Coding and Billing Compliance Ambulatory Surgery Centers Increasingly Complicated Regimens Drug Costs & Potential Insurance Constraints E&M vs Procedures Abbreviations: E&M, evaluation and management; PQRI, Physician Quality Reporting Initiative. Graphic courtesy of Dr. Ira Jacobson.
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A Day in the Life of a Hepatology Practice …in the Future
Rosemarie Nelson, MS Principal MGMA Health Care Consulting Group Englewood, Colorado
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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 13
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Top 10 Challenges of Practice Management Percent Respondentsa Who Rated Issues as “Considerable” or “Extreme” Challenges Maintaining physician compensation with declining reimbursement 69.9% Dealing with operating costs rising more rapidly than revenues 68.0% Selecting and implementing a new electronic health record system 67.8% Recruiting physicians 61.4% Managing finances with uncertain Medicare reimbursement rates 56.9% Negotiating contracts with payers 54.4% Modifying physician compensation methodology 53.3% Hiring and retaining quality staff 50.3% Collecting from self-pay, high deductible, and/or HSA patients 50.1% Participating in Medicare Physician Quality Reporting Initiative 50.1% 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.
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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 15
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Drop in payments from commercial payersa
Lower Reimbursement Drop in payments from commercial payersa 2005 to 2006: 10% drop1 2006 to 2007: 6.5% drop2 Average Reimbursement, b $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 Available at: Accessed on October 3, Grace S. Physician's Practice. January 2008; Nelson R. Phone interview with Professional Beauty Association, November 2008. 16 16
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Patients’ Share of Medical Bills to Skyrocket
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 Hewitt Associates. Survey findings: challenges for health care in uncertain times. Lincolnshire, Ill; Available at: Accessed on: October 14, Graphic courtesy of Rosemarie Nelson, MS.
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Provider Total Revenues Attributable to Patient Receivables
Celent. Press release: The "retailish" future of patient collections. San Francisco, Calif: February 18, Available at: Accessed on: October 14, 2009.
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Annoyances Up Survey of Annual Administrative Costs in Group Practice (N = 91, multiple specialties and settings) Administrative Task Cost per Physiciana 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 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 Available at: Accessed on: October 2, Graphic courtesy of Rosemarie Nelson, MS.
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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: 20
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Mean Dollar Value of Hours Spent per
Physician per Year for All Health Plan Interactions
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 With permission from Casalino LP, et al. Health Affairs. 2009;28:
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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. 22
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Conversion to ICD-10 Code Set
Deadline for compliance October 1, 20131 ICD-9 (up to 5 characters) ICD-10 (up to 7 characters) Conversion–Estimate of Costs to Comply for a Typical Small Practice2a 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 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, Available at: Accessed on: October 3, (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, Nelson R. Unpublished data.
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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 Available at: Accessed on: October 3, 2009.
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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. 25
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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 26
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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: Accessed on: October 5, 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: Accessed on: October 8, 2009. 27
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Optimize to Get to “Meaningful Use”
Reporting quality initiatives Health maintenance alerts Exchange of information Results Engage the patient Portal services E-prescribing 28
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Business of Medicine Is Communications–Patient Portal
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 29
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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 30
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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 31 31
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Technology? Or improved operational efficiency?
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. 32
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Status Quo If we keep doing what we’ve always done, we’ll keep getting what we always got 33
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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
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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
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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: Craxi A, et al. Clin Liver Dis. 2005;9: Shiratori Y, et al. Ann Intern Med. 2005;142:
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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 patient 57 months after end of treatment: Trichrome stain with Ishak stage 1 fibrosis With permission from George S, et al. Hepatology. 2009;49:
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CLDF San Jose_June 2009 2/19/2019 9:13 AM 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 biopsy Antidepressant use “Other” race/ethnicity a529 cases and 1058 control patients. Markowitz JS, et al. J Viral Hepat. 2005;12: 2009 CLDF_CME_DM_6_18_Maddrey 39
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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: Fried M, et al. N Engl J Med. 2002;347:
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IDEAL—PEG IFN -2a vs -2b + RBV Study Design
PEG IFN -2b 1.5 μg/kg/wk + RBV 800–1400 mg/d n = 1019 Follow-up Treatment-Naive Patients, Genotype 1 PEG IFN -2b 1.0 μg/kg/wk + RBV 800–1400 mg/d n = 1016 Follow-up PEG IFN -2a 180 μg/wk + RBV 1000–1200 mg/d n = 1035 Follow-up Start Tx Wk 12a Wk 24a Wk 36 Wk 48 Wk 72 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:
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IDEAL—ETR, SVR, and Relapse Rates Genotype 1 Patients, Intent to Treat Analysis
PEG IFN -2b 1.5 µg/kg/wk + RBV 800–1400 mg/d P = .57a PEG IFN -2b 1.0 µg/kg/wk + RBV 800–1400 mg/d 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:
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IDEAL—Adverse Events, Dose Modification, and Treatment Discontinuation
PEG IFN -2b RBV n = 1019 PEG IFN -2b RBV n = 1016 PEG IFN -2a 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% 12%/4% Discontinued due to AEs 13% 10% Dose modification due to AEs 43% 33% Psychiatric disorders 1.9% 1.2% 1.4% Hematologic parameters Neutrophil count (<750/mm3/<500/mm3) 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% With permission from McHutchison JG, et al. N Engl J Med. 2009;361:
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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:
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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. J Hepatol. 2005;43: Davis GL, et al. Hepatology. 2003;38:
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Rates of Viral Clearance Predict SVR with PEG IFN/RBV
100 91 PEG IFN -2a 180 µg/wk + RBV 1000–1200 mg HCV RNA Wk 4: Neg 80 72 HCV RNA| Wk 4: ≥2-log Wk 12: Neg 60 60 48 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 43 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 n = 33 93 20 21 30 Ferenci P, et al. J Hepatol. 2005;43:
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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
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of moderately slow responders:
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 20 40 60 80 100 Randomization of slow responders Randomized if non-RVR 64 P = .003 P = .04 P = .03 P = .07 SVR (%) 44 38 38 28 29 17 18 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: Berg T, et al. Gastroenterology. 2006;130: Pearlman BL, et al. Hepatology. 2007;46: Mangia A, et al. Hepatology. 2008;47: Graphic courtesy of Dr. Ira Jacobson.
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SVR in Genotype 2/3 Patients with RVR
Short (12–16 wk) Standard (24 wk) 20 40 60 80 100 91 91 85 85 82 80 79 81 SVR (%) n = 71 71 213 70 732 731 148 150 PEG IFN α-2a + RBV 800–12001 PEG IFN α-2b + RBV 1000–12002 PEG IFN α-2a + RBV 8003 PEG IFN α-2b + RBV 800–14004 1. von Wagner M, et al. Gastroenterology. 2005;129: Mangia A , et al. N Engl J Med. 2005;352: Shiffman ML, et al. N Engl J Med. 2007;357: Dalgard O, et al. Hepatology. 2008;47: Graphic courtesy of Dr. Ira Jacobson.
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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: Poynard T, et al. Hepatology. 2003;38: Hsu CS, et al. Liver Int. 2008;28: Fernandez-Real JM, Pickup JC. Trends Endocrinol Metab. 2008;19:10-16.
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With Insulin Resistance Without Insulin Resistance
Impact of Insulin Resistance on SVR in Genotype-1 Patients PEG IFN + RBVa P = .007 With Insulin Resistance Without Insulin Resistance aTreatment: 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: Graphic courtesy of Dr. Bruce Bacon.
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Reduction of Insulin Resistance With Successful HCV Therapy
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-IRa Change at Week 20b Null responders (n = 38) +0.18 Partial responders (n = 37) –0.9 Responders (n = 21) –2.23 aMean values; bP = .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.
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A Polymorphism on Chromosome 19 Predicts SVR
60 Mb Chromosome 19 Polymorphism rs IL28B gene 3 kb 19q13.13 Ge D, et al. Nature. 2009;461: Chromosome 19 graphic courtesy of Oak Ridge National Laboratory. Available at: Accessed on: October 21, 2009.
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rs12979860 Genotype Frequency by Population
36 19 50 48 46 38 16 35 20 40 60 80 100 European African Hispanics Percent C/C T/C T/T Americans Americans Ge D, et al. Nature. 2009;461:
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C Allele is Associated with SVR Percentage SVR by Genotype of rs12979860
Combined T/T European Americans African Americans Hispanics n = 91 n = 35 n = 433 T/C n = 30 n = 26 n = 336 C/C P = 1.37 x vs T/T 20 40 60 80 100 SVR Ge D, et al. Nature. 2009;461:
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C/C Genotype Is Independently Associated with SVRa
IL28B rs 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) Ethnicity (European Americans/African Americans) 3.1 (2.1–4.7) 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) aOdds ratios and 95% confidence intervals from the logistic regression model. Ge D, et al. Nature. 2009;461:
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Impact of IL28/29 on IFN 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:
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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
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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
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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
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Where We Are with Treatment Now Genotype 1
SVR 40%–50% Relapse 20%–30% Discontinue 20% NR Abbreviations: NR, null response; SVR, sustained virologic response. Graphic courtesy of Dr. John McHutchison.
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Emerging Anti-HCV Therapies
Specifically Targeted Antiviral Therapy for HCV (STAT-C) Enzyme Inhibitors Genome Sequence-Based Other RNA interference IFN and RBV modifications Albinterferon, omega IFN, PEG IFN lambda (IL-29) Taribavirin (viramidine) Polymerase Protease Immune approaches Therapeutic vaccines Toll-like receptor agonists Hepatitis C immune globulin Monoclonal antibodies NS5A Targeting cellular factors Cyclophilin antagonists Nitazoxanide Abbreviations: HCV, hepatitis C virus; IFN, interferon; PEG IFN, peginterferon; RBV, ribavirin. Graphic courtesy of Dr. Ira Jacobson. 63
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Hepatitis C Drug Development–2009
IFN & PEG IFN Ribavirin On Market Boceprevir Albumin-IFN alfa Phase III Telaprevir Taribavirin KPE MK7009 HDV interferon R1728 ME-3738 Oglufanide TCM-700C ITMN 191 PF SCV-07 Thymalfasin A-831 Phase II Omega IFN SCY-635 TMC Nitazoxanide PYN-17 Silibinin Controlled-release IFN Medusa IFN BMS Debio25 PHX1766 VCH-759 ABT-333 BIT225 IPH-1101 IFN biopump DA-3021 BMS GS9190 ANA598 EGS21 Phase I BI Low-dose oral IFN NIM811 EMZ702 Bavituximab VX-813 BMS VCH-916 IDX184 IFN beta-1a JTK-652 IL-29 VBY-376 VX-500 VCH-222 MK-3281 CF102 CYT 107 Many others, including immune stimulants and gene therapy Interferons Research/ Preclinical Ribavirins Protease inhibitors Note: Not a complete list of products in development. Information from public sources. Graphic courtesy of Dr. John McHutchison. Polymerase inhibitors Immunomodulators Others
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Albinterferon alfa-2b Novel recombinant polypeptide1
Extended serum half-life supports dosing at 2-week intervals2,3 148 hours, median (range, 134–153 hours) Phase II findings show 900 µg has comparable efficacy to PEG IFN/RBV and 1200 µg has superior efficacy4 Both doses warranted evaluation in phase III trial IFN -2b Human albumin Molecular weight 85.7 kDa 1. Liu C, et al. Hepatol Res. 2007;37: Bain VG, et al. J Hepatol. 2006;44: Bain V, et al. J Hepatol. 2005;42 (suppl 1):abstract Zeuzem S, et al. J Hepatol. 2009;50:S377. Graphic courtesy of Dr. Nezam Afdhal.
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IFN- Treatment-Naive Patients, Genotype 1
ACHIEVE 1 Study Design Randomized, Open-Label, Active-Controlled, Phase III PEG IFN α-2a 180 µg q1wk + RBV 1000–1200 mg/d WBD n = 441 Follow-up IFN- Treatment-Naive Patients, Genotype 1 albIFN 900 µg q2wk + RBV 1000–1200 mg/d WBD n = 442 Follow-up albIFN 1200 µg q2wk + RBV 1000–1200 mg/d WBD n = 440 900 µg Follow-up Wk 24a Start Tx Wk 48 Wk 72 aData Monitoring Committee dose modification on ; 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.
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ACHIEVE 1–SVR and Relapse in Intent-to-Treat Population
P = .0029a P = .0008a PEG IFN 180 µg q1wk albIFN 900 µg q2wk albIFN µg q2wk PEG IFN 180 µg q1wk albIFN 900 µg q2wk albIFN µg q2wk aP-value for noninferiority. Zeuzem S, et al. J Hepatol. 2009;50:S377.
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Selected Common Adverse Events Albinterferon in ACHIEVE 1
PEG IFN 180 Q1w n = 441 albIFN 900 Q2w n = 442 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%) Alopeciaa 108 (24.5%) 182 (41.2%) 177 (40.2%) Nausea 148 (33.6%) 156 (35.3%) 157 (35.7%) Coughb 113 (25.6%) 166 (37.6%) 175 (39.8%) Mood altered 106 (24.0%) 89 (20.2%) Depression 84 (19.0%) 86 (19.5%) 93 (21.1%) aMild with resolution at end of treatment. bNot asssociated with pulmonary infection or chest X-ray changes. Zeuzem S, et al. J Hepatol. 2009;50:S377.
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Direct Viral Enzyme Inhibitors— Evolving Next Future Therapies
Polymerase STAT-C Specifically targeted Anti-viral therapy for HCV Protease NS5A Graphic courtesy of Dr. Ira Jacobson.
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Potential Antiviral Targets
(1) Virus entry (2) Uncoating (3) Polyprotein processing (4) RNA replication (5) Packing and assembly (6) Virion maturation and release With permission from Moradpour D, Blum HE. Liver Int. 2004;24:
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Adherence to Antiviral Therapy
Association Between Virologic Failure and Adherence to Antiretroviral Therapy in Patients with HIV1 Doses Taken in Virahep-C Study2 Physicians predicted adherence incorrectly for ~41% of patients1 1. Paterson DL, et al. Ann Intern Med. 2000;133: Conjeevaram HS, et al. Gastroenterology. 2006;131: Left graphic with permission from Paterson DL, et al. Ann Intern Med. 2000;133: Right graphic courtesy of Dr. Nezam Afdhal.
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PROVE 1—Telaprevir + PEG IFN/RBV SVR, Intent-to-Treat Analysis, Phase II
100 P = .020 80 67 61 60 SVR Rate (%) 41 40 35 20 31/75 6/17 48/79 53/79 PR 48 wk (Control) T 12 wk + PR 12 wk T 12 wk + PR 24 wk T 12 wk + PR 48 wk 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: With permission from Dr. John McHutchison.
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PROVE 1—Relapse Rates 50 40 30 20 10 33a Relapse Rate (%) 23 6 2a
8/35 3/9 1/41 3/51 PR 48 wk (Control) T 12 wk + PR 12 wk T 12 wk + PR 24 wk T 12 wk + PR 48 wk Denominator = number of subjects with undetectable HCV RNA at completion of assigned treatment duration. aIncludes 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: Graphic courtesy of Dr. John McHutchison.
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Can We Dispense with Ribavirin? PROVE 2
PR48 control (n = 82) T12PR24 (n = 81) T12PR12 (n = 82) T12P12 (n = 78) Abbreviations: P, PEG IFN alfa-2a 180 ug/wk; R, ribavirin 1000–1200 mg/day; T, telaprevir 750 mg q8h. Hézode C, et al. N Engl J Med. 2009;360:
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Sprint 1—Boceprevir + PEG IFN -2b + RBV Phase II, Part 1 and 2
No Lead-in Control Follow-up PR PR + B Lead-in Part 1 Treatment-Naive Genotype-1 (N = 520) Follow-up PR PR-LD R-LD Part 2 Wk 72 Start Wk 4 Wk 12a Wk 28 Wk 48 aInterim 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.
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SPRINT 1—SVR 24 Rates PEG IFN -2b + RBV +/- Boceprevir; Low-Dose RBV
100 Part 1 Part 2 80 75 67 60 56 54 50 36 PR Control (n = 16) PR-LD (n = 59) SVR (%) 38 40 20 PR Control (n = 104) PRB Lead-In (n = 103) PRB No Lead-In (n = 107) PRB Lead-In (n = 103) PRB No Lead-In (n = 103) Tx 28 Weeks Tx 48 Weeks aMain adverse effects: Fatigue, headache, nausea, and anemia. Kwo P, et al. J Hepatol. 2009;50:S4.
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SPRINT 1—SVR 24 in Those Who Achieved RVR
100 100 94 84 82 80 74 60 SVR (%) 40 20 8/8 54/66 32/43 62/66 32/38 PR Control (n = 104) PRB Lead-In (n = 103) PRB No Lead-In (n = 107) PRB Lead-In (n = 103) PRB No Lead-In (n = 103) Tx 28 Weeks Tx 48 Weeks Kwo P, et al. J Hepatol. 2009;50:S4.
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SPRINT 1—Virologic Breakthrough
20 15 12 Patients with Breakthrough (%) 10 7 5 5 4 PR Control (n = 104) PRB Lead-In (n = 103) PRB No Lead-In (n = 107) PRB Lead-In (n = 103) PRB No Lead-In (n = 103) Tx 28 Weeks Tx 48 Weeks Kwo P, et al. J Hepatol. 2009;50:S4.
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PROVE 3–Telaprevir + PEG IFN +/- RBV by Prior Response and Treatment Groupa
SVR (%) T12/ PR24 T24/ PR48 T24/ P24 PR48 Treatment failures 51 53 24 14 aIntent-to-treat analysis. McHutchison JG, et al. 60th AASLD. Boston, MA. October 30-November 3, Abstract 66.
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PROVE 3–Telaprevir + PEG IFN +/- RBV by Prior Response and Treatment Groupa
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 aIntent-to-treat analysis. McHutchison JG, et al. 60th AASLD. Boston, MA. October 30-November 3, Abstract 66.
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Weight-Based Taribavirin or RBV + PEG IFN Phase IIb Study Design
Taribavirin 20 mg/kg/d + PEG IFN -2b 1.5 µg/kg/wk n = 67 Follow-up Taribavirin 25 mg/kg/d + PEG IFN -2b µg/kg/wk n = 70 Follow-up Treatment-Naive Patients, Genotype 1 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 1.5µg/kg/wk n = 70 Follow-up Wk 72 Start Tx Wk 12 Wk 24 Wk 36 Wk 48 Poordad F, et al. J Hepatol. 2009;50:S8.
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Weight-Based Taribavirin or RBV + PEG IFN Virologic Response at Week 4, 12, 48 and SVR12a
TBV 20 mg/kg + PEG IFN TBV 25 mg/kg + PEG IFN TBV 30 mg/kg + PEG IFN RBV 800–1400 mg + PEG IFN aITT population. Abbreviation: TBV, taribavirin. Poordad F, et al. J Hepatol. 2009;50:S8.
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Taribavirin vs RBV + PEG IFN -2b Hemoglobin Event Rate
TBV 20 mg/kg + PEG IFN TBV 25 mg/kg + PEG IFN TBV 30 mg/kg + PEG IFN RBV 800–1400 mg + PEG IFN Poordad F, et al. J Hepatol. 2009;50:S8. P ≤.05 for TBV 20 mg/kg and TBV 25 mg/kg vs RBV
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Treatment-Naive Genotype-1
INFORM 1—Two Direct Antivirals Combined R R7227a, Phase 1b, First 4 Cohortsb n = active/ placebo R mg BID 8/0 PEG IFN -2a + RBV R mg q8h R mg q8h 8/0 PEG IFN -2a + RBV R mg BID A R mg BID PEG IFN + RBV 8/2 Treatment-Naive Genotype-1 R mg q8h B R mg BID PEG IFN + RBV R mg q8h 16/2 C R mg BID PEG IFN + RBV R mg q8h D R mg BID PEG IFN + RBV 8/4 R mg q8h Day 1 Day 4 Day 7 Day 14 40 Wk aAlso known as ITMN-191. bStudy expansion to include treatment failures and null responders. Gane EJ, et al. J Hepatol. 2009;50;S380.
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INFORM 1—Preliminary Viral Kinetics Day 1–14
Placebo R7128 D1–7 R7227 D4–7 R7227 D1–7 R7128 D4–7 HCV RNA Change from Baseline, Mean (IU/mL) R mg R mg R mg R mg R mg R mg R mg R mg With permission from Gane EJ, et al. J Hepatol. 2009;50;S380.
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INFORM 1—Virologic Response at Day 14 Change from BL, median (range)
Regimen (mg) n HCV RNA (IU/mL) BL Change from BL, median (range) Day 14, median (range) <LLOQ, n (%) <LLOD, n (%) R R 8 2.8 x 106 -3.9 (-5.0 to -2.9) 288 (<15 to 588) 1/8 (13%) 1/8 (13%) R R 8.3 x 106 -5.2 (-5.5 to -3.1) 35 (<15 to 701) 5/8 (63%) 2/8 (25%) R R 7 2.2 x 106 -4.8 (-5.7 to -4.5) 20 (<15 to 173) 5/7 (71%) 2/7 (29%) R R -4.8 (-5.5 to -2.7) 22 (<15 to 660) 2/8 (25%) 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.
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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
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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?
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Long-Term Consequences of Resistance
“Fitness” Disease progression rates Evolutionary disadvantage Class effects Prevention strategies Retreatment outcomes Graphic courtesy of Dr. John McHutchison.
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Limiting or Curtailing Resistance
Adherence Adequate PK/PD Value of Lead-in Length of therapy Combination therapy Dose and populations Foreseeable, Unavoidable, Preventable Abbreviation: PK/PD, pharmacokinetics/pharmacodynamics. Graphic courtesy of Dr. John McHutchison.
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More Drugs = More Toxicity
Cardiotoxicity Rash Liver test abnormalities Anemia Neutropenia Lymphopenia DC rates x 2-4 fold Abbreviation: DC, discontinuation. Graphic courtesy of Dr. John McHutchison.
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Key Drivers of Successful Therapy
Simplicity/ complexity Tolerability Efficacy Cost Duration Resistance Graphic courtesy of Dr. John McHutchison.
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Future Anti-HCV Therapy
HCV inhibitor IFN IFN HCV inhibitor HCV inhibitor RBV RBV RBV ? HCV inhibitor IFN? Graphic courtesy of Dr. Nezam Afdhal. 94
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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
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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
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Phases in the Evolution of Anti-HCV Therapy
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 The Empiric Phase The Refinement Phase The Phase of Specifically Targeted Antiviral Therapy for HCV (STAT-C) The Final Phase— Small Molecule Combinations ??? Optimal dosing Viral kinetics Challenging populations Nonresponders Weisberg IW, et al. Current Hepatitis Reports. 2007;6: Graphic courtesy of Dr. Ira Jacobson.
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A Polymorphism on Chromosome 19 Predicts SVR
60 Mb Chromosome 19 Polymorphism rs IL28B gene 3 kb 19q13.13 Ge D, et al. Nature. 2009;461: Chromosome 19 graphic courtesy of Oak Ridge National Laboratory. Available at: Accessed on: October 21, 2009.
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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?
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Emerging Anti-HCV Therapies
Specifically Targeted Antiviral Therapy for HCV (STAT-C) Enzyme Inhibitors Genome Sequence-Based Other Polymerase RNA interference IFN and RBV modifications Albinterferon, omega IFN, PEG IFN lambda (IL-29) Taribavirin (viramidine) Protease Immune approaches Therapeutic vaccines Toll-like receptor agonists Hepatitis C immune globulin Monoclonal antibodies NS5A Targeting cellular factors Cyclophilin antagonists Nitazoxanide 101
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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
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Anti-HCV Therapy Likely Picture—Near Future
Viral enzyme inhibitors RBV or related drugs Immune or host pathway modulators + Interferon as a platform for future combinations Need to study different IFNs to determine optimal characteristics Graphic courtesy of Dr. Ira Jacobson.
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The Goal of Combination Regimens
+ B + C Profound suppression of broad range of viral variants, including pre-existing Prevention of emergent resistance (pre-existing or de novo) 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.
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Can We Leapfrog Ahead? Current SOC (2009) PEG IFN + RBV + STAT-C(1)
(1+2+…) Graphic courtesy of Dr. Ira Jacobson.
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Treating HCV in the Next 5 Years
Opportunities Challenges Cure more patients Shorter duration of therapy Increased toxicity Increased complexity Increased costs Mandate to prevent resistance
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Increasing Complexity of HCV Management
STAT-C Agents Novel combinations New interferons Resistance mutations Increasing Complexity of HCV Management Genetic predictors Response Guided Therapy Cost, Toxicities & Compliance prescribing NPs, PAs Electronic health records
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