Transcript Slides - Projects In Knowledge
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
The Empiric Phase The Refinement Phase
• • •
Optimal dosing Viral kinetics Challenging populations
•
Nonresponders The Phase of Specifically Targeted Antiviral Therapy for HCV (STAT-C) The Final Phase — Small Molecule Combinations ???
Weisberg IW, et al.
Current Hepatitis Reports.
2007;6:75-82. Graphic courtesy of Dr. Ira Jacobson.
The Refinement Phase of Anti-HCV Therapy
Reflections on the Past Decade
The Refinement Phase
• • •
Optimal dosing Viral kinetics Challenging populations
•
Nonresponders 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
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.
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 Genotype Histologic stage Duration of infection Personal plans (marriage, pregnancy) Age Family and other support Patient "mindset" Extrahepatic Features (Fatigue, EMC, PCT) ALT HIV coinfection Occupation Contraindications & comorbidities
Management of Viral Hepatitis —Huge Unmet Needs
Efficacy in Clinical Trials and Research Centers Effectiveness in Community Practice
El-Serag HB.
Gastroenterology
. 2007;132:8-10.
Efficacy x Access x Correct Diagnosis x Recommendation x Acceptance x Adherence
Real World Pressures in an Already Labor-Intensive Specialty
Electronic Records Declining Reimbursements PQRI (Physician Quality Reporting Initiative) Ambulatory Surgery Centers Medicolegal Issues & Costs Coding and Billing Compliance Increasingly Complicated Regimens
Graphic courtesy of Dr. Ira Jacobson.
Drug Costs & Potential Insurance Constraints E-prescribing
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?
13
Top 10 Challenges of Practice Management
Percent Respondents a Who Rated Issues as “Considerable” or “Extreme” Challenges
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 61.4% 56.9% 54.4% 53.3% 50.3% 50.1% 50.1% 69.9% 68.0% 67.8% 0 10 20 30 40
a Survey of Medical Group Management Association members.
Abbreviation: HSA, health savings account.
50
With permission from Pope C, et al.
MGMA Connexion.
July 2008;18-23.
60 70
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.
Lower Reimbursement
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
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.
16
Patients’ Share of Medical Bills to Skyrocket Survey of 343 Executives Whose Companies Employ >5 Million Employees Employer Benefits Percent 65 Percentage of employers that intend to shift more health insurance costs to employees next year Percentage of employers that plan to reduce the number of health plan options Percentage of employers that plan to increase the number of consumer-directed health plans 49 40
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.
Provider Total Revenues Attributable to Patient Receivables
35 30 25 20 15 10 5 0 12 30 2007 2012
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
Survey of Annual Administrative Costs in Group Practice (N = 91, multiple specialties and settings) Administrative Task Physician time in response to pharmacy phone calls Cost per Physician a $12,731 $3876 Staff time in insurance verification, copays, and deductibles Support staff time to appeal denied claims Credentialing applications (physician and staff) $925 $808
a Cost 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.
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
Survey of US Physicians and Administrative Staff
730 Primary Care Physicians; 580 Specialists
1 –2 MDs 3 –9 MDs 10+ MDs Physician time Nursing staff time Clerical staff time Senior administrative time Lawyer/accountant time Total per practice $17,817 $14,897 $30,014 $5829 $1249 $69,806 $15,670 $26,225 $25,632 $3269 $626 $71,422
With permission from Casalino LP, et al.
Health Affairs.
2009;28:533-543.
$13,798 $24,314 $18,636 $1235 $4455 $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 1 200,000 155,000 ICD-9 (up to 5 characters) 150,000 100,000 50,000 ICD-10 (up to 7 characters) 17,000 0 Conversion –Estimate of Costs to Comply for a Typical Small Practice 2a Category Cost Training and education Business analysis Super-bill changes IT system changes Increased documentation costs Cash flow disruption Total Costs $2405 $6905 $2985 $7500 $44,000 $19,500 $83,295
Same group: $99,000 to move to EHR 3
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.
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.
Optimize to Get to “Meaningful Use”
Reporting quality initiatives
–
Health maintenance alerts Exchange of information
–
Results Engage the patient
–
Portal services E-prescribing
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
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
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;49:729-738.
The Problem –Who Gets Treated?
Factors Associated with Treatment in a Retrospective Analysis of California Medicaid Data a
Untreated Age >65 years Fibrosis Severe diabetes Renal disease High hospital or ER utilization Alcohol use Untreated 100 80 60 40 20 0 11 Treated 89 Treated Age 45 –64 years Male gender Mild disease Liver biopsy Antidepressant use “Other” race/ethnicity
a 529 cases and 1058 control patients.
Markowitz JS, et al.
J Viral Hepat.
2005;12:176-185.
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 —PEG IFN
-2a vs
-2b + RBV
Study Design
PEG IFN
-2b 1.5 μg/kg/wk + RBV 800 –1400 mg/d n = 1019 PEG IFN
-2b 1.0 μg/kg/wk + RBV 800 –1400 mg/d n = 1016 PEG IFN
-2a 180 μg/wk + RBV 1000 –1200 mg/d n = 1035 Follow-up Follow-up Follow-up Start Tx Wk 12 a Wk 24 a Wk 36 Wk 48
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
IDEAL
—
ETR, SVR, and Relapse Rates
Genotype 1 Patients, Intent to Treat Analysis
70 60 50 40 53 49 64 P = .57
a P = .20
b 40 38 41 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 32 30 24 20 20 10 0 ETR SVR Relapse
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 —Adverse Events, Dose Modification, and Treatment Discontinuation PEG IFN
-2b 1.5 + RBV n = 1019 PEG IFN
-2b 1.0 + RBV n = 1016 PEG IFN
-2a 180 + RBV n = 1035 5/1 (no.) 1/0 (no.) 6/1 (no.) Deaths (all/treatment-related) Serious adverse events (AEs) (all/treatment-related) Discontinued due to AEs Dose modification due to AEs Psychiatric disorders Hematologic parameters Neutrophil count (<750/mm 3 /<500/mm 3 ) Hemoglobin (<10 g/dL/<8.5 g/dL) Erythropoietin use 9%/4% 13% 43% 1.9% 22%/3% 31%/3% 16% 9%/4% 10% 33% 1.2% 14%/2% 25%/2% 14% 12%/4% 13% 43% 1.4% 27%/6% 30%/4% 17%
With permission from McHutchison JG, et al.
N Engl J Med.
2009;361:580-593.
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 “slow” 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.
Rates of Viral Clearance Predict SVR with PEG IFN/RBV
100 80 91 HCV RNA Wk 4: Neg 72 PEG IFN
2a 180 µg/wk + RBV 1000 –1200 mg 60 40 HCV RNA| Wk 4: ≥2-log
Wk 12: Neg 60 HCV RNA| Wk 4: <2-log
Wk 12: Neg The later a patient becomes HCV RNA undetectable, regardless of EVR, the lower the chance for SVR.
48 HCV RNA| Wk 4: ≥2-log
Wk 12: ≥2-log
WK 24: Neg 43 HCV RNA| Wk 4: <2-log
Wk 12: ≥2-log
WK 24: Neg 0 n = 33 93 20 21 30
Ferenci P, et al.
J Hepatol
. 2005;43:425-433.
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 100 80 60 40 20 RVR or Slow Response Standard 48 wk Extended 72 wk 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 64 P = .003
P = .04
P = .03
P = .07
44 38 38 29 28 18 17 n = 149 142 PEG IFN α -2a + RBV 800 1 100 106 PEG IFN α -2a + RBV 800 2 49 52 PEG IFN α -2b + RBV 800 –1400 3 21 PEG IFN 1000 α 52 -2a + RBV –1200 4
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.
SVR in Genotype 2/3 Patients with RVR
Short (12 –16 wk) Standard (24 wk) 100 80 60 82 80 85 91 79 85 81 91 40 20 n = 71 71 PEG IFN α -2a + RBV 800 –1200 1 213 70 PEG IFN α -2b + RBV 1000 –1200 2 732 731 PEG IFN α -2a + RBV 800 3 148 150 PEG IFN α -2b + RBV 800 –1400 4
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.
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
100
in Genotype-1 Patients
PEG IFN + RBV a
P = .007
80 61 60 40 33 20 0 With Insulin Resistance Without Insulin Resistance
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.
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-IR a Change at Week 20 b Null responders (n = 38) Partial responders (n = 37) Responders (n = 21) +0.18
–0.9
–2.23
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.
A Polymorphism on Chromosome 19 Predicts SVR
IL28B gene 19q13.13
Polymorphism rs12979860 Chromosome 19
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.
rs12979860 Genotype Frequency by Population
100 80 38 16 35 C/C T/C T/T 60 48 40 46 50 20 36 12 0 European African Americans Americans
Ge D, et al.
Nature.
2009;461:399-401.
19 Hispanics
C Allele is Associated with SVR
Percentage SVR by Genotype of rs12979860
T/T n = 186 n = 70 n = 14 n = 102 Combined European Americans African Americans Hispanics T/C n = 559 n = 91 n = 35 n = 433 C/C n = 392 n = 30 n = 26 n = 336 P = 1.37 x 10 -28 vs T/T 0 20
Ge D, et al.
Nature.
2009;461:399-401.
40 SVR 60 80 100
C/C Genotype Is Independently Associated with SVR
a 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
a Odds ratios and 95% confidence intervals from the logistic regression model.
Ge D, et al.
Nature.
2009;461:399-401.
–4.7)
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;461:399-401.
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
NR 20% Discontinue 20% Relapse 20% –30%
Abbreviations: NR, null response; SVR, sustained virologic response.
Graphic courtesy of Dr. John McHutchison.
SVR 40% –50%
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
Abbreviations: HCV, hepatitis C virus; IFN, interferon; PEG IFN, peginterferon; RBV, ribavirin.
Graphic courtesy of Dr. Ira Jacobson.
• •
Targeting cellular factors Cyclophilin antagonists Nitazoxanide
Hepatitis C Drug Development –2009
Ribavirin On Market IFN & PEG IFN Boceprevir Phase III Albumin-IFN alfa Telaprevir Taribavirin HDV interferon ITMN 191 MK7009 R1728 Phase II PF-868554 Omega IFN TMC 435350 Controlled-release IFN Medusa IFN BMS-790052 ME-3738 SCV-07 Nitazoxanide Thymalfasin Debio25 Oglufanide A-831 PYN-17 KPE02001003 TCM-700C SCY-635 Silibinin Phase I PHX1766 VCH-759 ABT-333 IFN biopump DA-3021 EMZ702 IL-29 Low-dose oral IFN IFN beta-1a BI-201335 VX-813 VBY-376 GS9190 BMS-650032 VX-500 ANA598 VCH-916 VCH-222 IPH-1101 EGS21 IDX184 MK-3281 BIT225 NIM811 JTK-652 CYT 107 BMS-791325 Bavituximab CF102 Research/ Preclinical Many others, including immune stimulants and gene therapy
Note: Not a complete list of products in development.
Information from public sources.
Graphic courtesy of Dr. John McHutchison.
Interferons Ribavirins Protease inhibitors Polymerase inhibitors Immunomodulators Others
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 µg has comparable efficacy to PEG IFN/RBV and 1200 µg has superior efficacy 4
–
Both doses warranted evaluation in phase III trial Human albumin IFN
-2b Molecular weight 85.7 kDa
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.
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 albIFN 900 µg q2wk + RBV 1000 –1200 mg/d WBD n = 442 albIFN 1200 µg q2wk + RBV 1000 –1200 mg/d WBD 900 µg n = 440 Follow-up Follow-up Follow-up Start Tx Wk 24 a Wk 48 Wk 72
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.
ACHIEVE 1 –SVR and Relapse in Intent-to-Treat Population
SVR P = .0029
a P = .0008
a Relapse PEG IFN 180 µg q1wk albIFN 900 µg q2wk albIFN 1200 µg q2wk
a
P
-value for noninferiority.
Zeuzem S, et al.
J Hepatol.
2009;50:S377.
PEG IFN 180 µg q1wk albIFN 900 µg q2wk albIFN 1200 µg q2wk
Selected Common Adverse Events
Albinterferon in ACHIEVE 1
Adverse Event PEG IFN 180 Q1w n = 441 albIFN 900 Q2w n = 442 albIFN 1200 Q2w n = 440 Fatigue Headache Pyrexia 245 (55.6%) 200 (45.4%) 149 (33.8%) 230 (52.0%) 248 (56.4%) 205 (46.4%) 217 (49.3%) 163 (36.9%) 185 (42.0%) Insomnia Alopecia a Nausea Cough b Mood altered 157 (35.6%) 108 (24.5%) 148 (33.6%) 113 (25.6%) 108 (24.5%) 162 (36.7%) 164 (37.3%) 182 (41.2%) 177 (40.2%) 156 (35.3%) 157 (35.7%) 166 (37.6%) 175 (39.8%) 106 (24.0%) 89 (20.2%) Depression 84 (19.0%) 86 (19.5%) 93 (21.1%)
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.
Direct Viral Enzyme Inhibitors — Evolving Next Future Therapies
Viral Enzyme Inhibitors Polymerase Protease STAT-C Specifically targeted Anti-viral therapy for HCV NS5A
Graphic courtesy of Dr. Ira Jacobson.
Potential Antiviral Targets
(1) Virus entry (3) Polyprotein processing (2) Uncoating (6) Virion maturation and release (5) Packing and assembly (4) RNA replication
With permission from Moradpour D, Blum HE.
Liver Int
. 2004;24:519-525.
Adherence to Antiviral Therapy
100 Association Between Virologic Failure and Adherence to Antiretroviral Therapy in Patients with HIV 1 82.1
80 71.4
66.7
60 54.6
100 80 60 Doses Taken in Virahep-C Study 2 82 64 40 40 21.7
20 20 0 0 ≥95 90–<95 80–<90 70–<80 <70 PEG IFN
Physicians predicted adherence incorrectly for ~41% of patients 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.
RBV
PROVE 1 —Telaprevir + PEG IFN/RBV
SVR, Intent-to-Treat Analysis, Phase II
P = .001
100 80 P = .020
67 61 60 40 41 35 20 0 31/75 PR 48 wk (Control) 6/17 T 12 wk + PR 12 wk 48/79 T 12 wk + PR 24 wk 53/79 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;360:1827-1838.
With permission from Dr. John McHutchison.
PROVE 1 —Relapse Rates
50 40 30 33 a 23 20 10 6 0 8/35 PR 48 wk (Control) 3/9 T 12 wk + PR 12 wk 2 a 1/41 T 12 wk + PR 24 wk 3/51 T 12 wk + PR 48 wk
Denominator = number of subjects with undetectable HCV RNA at completion of assigned treatment duration.
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.
Can We Dispense with Ribavirin?
PROVE 2
PR48 control (n = 82) T12PR24 (n = 81) 100 T12PR12 (n = 82) T12P12 (n = 78) 80 80 80 69 73 69 62 60 60 50 46 43 36 40 20 13 0 Week 4 Week 12 SVR
Abbreviations: P, PEG IFN alfa-2a 180 ug/wk; R, ribavirin 1000 –1200 mg/day; T, telaprevir 750 mg q8h.
H ézode C, et al.
N Engl J Med.
2009;360:1839-1850.
Sprint 1 —Boceprevir + PEG IFN
-2b + RBV
Phase II, Part 1 and 2
PR Follow-up PR PR + B PR PR + B Follow-up Follow-up PR + B PR + B Follow-up Follow-up PR PR-LD Follow-up Follow-up Start Wk 4 Wk 12 a Wk 28 Wk 48
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
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 38 40 36 20 0 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
a Main adverse effects: Fatigue, headache, nausea, and anemia.
Kwo P, et al.
J Hepatol.
2009;50:S4.
PR Control (n = 16) Tx 48 Weeks PR-LD (n = 59)
SPRINT 1 —SVR 24 in Those Who Achieved RVR
100 100 94 84 82 80 74 60 40 20 0 8/8 PR Control (n = 104) 54/66 PRB Lead-In (n = 103) 32/43 PRB No Lead-In (n = 107) 62/66 PRB Lead-In (n = 103) 32/38 PRB No Lead-In (n = 103) Tx 28 Weeks Tx 48 Weeks
Kwo P, et al.
J Hepatol.
2009;50:S4.
SPRINT 1 —Virologic Breakthrough
20 15 10 5 0 0 PR Control (n = 104) 4 7 5 12 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.
PROVE 3
—
Telaprevir + PEG IFN +/- RBV by Prior Response and Treatment Group a Treatment failures T12/ PR24 51 T24/ PR48 53 SVR (%) T24/ P24 24 PR48 14
a Intent-to-treat analysis.
McHutchison JG, et al. 60th AASLD. Boston, MA. October 30-November 3, 2009. Abstract 66.
PROVE 3
—
Telaprevir + PEG IFN +/- RBV by Prior Response and Treatment Group a Treatment failures Prior nonresponders Prior relapsers T12/ PR24 51 39 69 T24/ PR48 53 SVR (%) T24/ P24 24 38 11 76 42 PR48 14 9 20
a Intent-to-treat analysis.
McHutchison JG, et al. 60th AASLD. Boston, MA. October 30-November 3, 2009. Abstract 66.
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 Taribavirin 25 mg/kg/d + PEG IFN
2b µg/kg/wk n = 70 Taribavirin 30 mg/kg/d + PEG IFN
-2b µg/kg/wk n = 68 RBV 800/1000/1200/1400 mg/d + PEG IFN
-2b 1.5
µg/kg/wk n = 70 Follow-up Follow-up Follow-up Follow-up Wk 72 Start Tx Wk 12
Poordad F, et al.
J Hepatol.
2009;50:S8.
Wk 24 Wk 36 Wk 48
Weight-Based Taribavirin or RBV + PEG IFN
Virologic Response at Week 4, 12, 48 and SVR12 a
60 42 41 43 TBV 20 mg/kg + PEG IFN TBV 25 mg/kg + PEG IFN TBV 30 mg/kg + PEG IFN RBV 800 –1400 mg + PEG IFN 40 25 31 30 29 33 28 24 21 21 20 16 14 16 11 0 Wk 4
a ITT population.
Abbreviation: TBV, taribavirin.
Poordad F, et al.
J Hepatol.
2009;50:S8.
Wk 12 Wk 48 SVR Wk 12
Taribavirin vs RBV + PEG IFN
-2b
Hemoglobin Event Rate
60 TBV 20 mg/kg + PEG IFN TBV 25 mg/kg + PEG IFN TBV 30 mg/kg + PEG IFN RBV 800 –1400 mg + PEG IFN 40 33 30 28 24 19 20 15 13 11 13 16 9 7 0 Wk 12
Poordad F, et al.
J Hepatol.
2009;50:S8.
Wk 24 Wk 48
P
≤.05 for TBV 20 mg/kg and TBV 25 mg/kg vs RBV
INFORM 1 —Two Direct Antivirals Combined n = active/ placebo
R7128 + R7227 a , Phase 1b, First 4 Cohorts b
R7128 500 mg BID 8/0 PEG IFN
-2a + RBV R7227 100 mg q8h A B 8/0 R7227 100 mg q8h R7128 500 mg BID 8/2 C 16/2 R7128 500 mg BID R7227 100 mg q8h R7128 500 mg BID R7227 200 mg q8h R7128 1000 mg BID R7227 100 mg q8h D 8/4 R7128 1000 mg BID R7227 200 mg q8h PEG IFN
-2a + RBV PEG IFN + RBV PEG IFN + RBV PEG IFN + RBV PEG IFN + RBV Day 1 Day 4 Day 7 Day 14
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.
40 Wk
INFORM 1 —Preliminary Viral Kinetics Day 1 –14 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
With permission from Gane EJ, et al.
J Hepatol.
2009;50;S380.
INFORM 1 —Virologic Response at Day 14 HCV RNA (IU/mL) Regimen (mg) n BL Change from BL, median (range) Day 14, median (range)
(-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%)
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.
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 Class effects Prevention strategies Retreatment outcomes
Graphic courtesy of Dr. John McHutchison.
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.
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.
Key Drivers of Successful Therapy
Simplicity/ complexity Tolerability Efficacy Cost Duration Resistance
Graphic courtesy of Dr. John McHutchison.
IFN RBV
Future Anti-HCV Therapy
IFN RBV HCV inhibitor HCV inhibitor HCV inhibitor HCV inhibitor RBV ?
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
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
• • •
Optimal dosing Viral kinetics Challenging populations
•
Nonresponders The Phase of Specifically Targeted Antiviral Therapy for HCV (STAT-C) The Final Phase — Small Molecule Combinations ???
Weisberg IW, et al.
Current Hepatitis Reports.
2007;6:75-82. Graphic courtesy of Dr. Ira Jacobson.
A Polymorphism on Chromosome 19 Predicts SVR
IL28B gene 19q13.13
Polymorphism rs12979860 Chromosome 19
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.
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
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 NS5A
• • • •
Immune approaches Therapeutic vaccines Toll-like receptor agonists Hepatitis C immune globulin Monoclonal antibodies
• •
Targeting cellular factors Cyclophilin antagonists Nitazoxanide
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 + 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.
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.
Can We Leapfrog Ahead?
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+…)
Graphic courtesy of Dr. Ira Jacobson.
Treating HCV in the Next 5 Years
Opportunities
Cure more patients
Shorter duration of therapy
Challenges
Increased toxicity Increased complexity Increased costs Mandate to prevent resistance
STAT-C Agents Novel combinations New interferons Genetic predictors
Increasing Complexity of HCV Management
Cost, Toxicities & Compliance NPs, PAs Resistance mutations Response Guided Therapy E-prescribing Electronic health records