2. 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

3. 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.

4. 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.

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

6. 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

7. Treatment of Nonresponders to PEG IFN and RBV
Retreatment with same or different PEG IFN yields SVR rates of 2% to 16%1-3
Induction therapy does not improve SVR1
Extended treatment duration to 72 weeks doubles SVR rates1
CIFN (9 to 15 µg/d) + RBV yields SVR in 7% to 11%4
Better in noncirrhotics with good response to prior therapy
Maintenance therapy studies have been negative5
Abbreviations: CIFN, consensus interferon; PEG IFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. 1. Jensen DM, et al. Ann Intern Med. 2009;150: 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.

8. 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

9. 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.

10. 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.

12. A Day in the Life of a Hepatology Practice …in the Future
Rosemarie Nelson, MS
Principal MGMA Health Care Consulting Group Englewood, Colorado

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

14. 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.

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

16. 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

17. 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.

18. 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.

19. 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.

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

21. 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:

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

23. Conversion to ICD-10 Code Set
Deadline for compliance October 1, 20131
ICD-9 (up to 5 characters)
ICD-10 (up to 7 characters)
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.

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

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

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

27. The Stimulus Bill (ARRA, HITECH)
Starting in 2011, “meaningful” electronic health record (EHR) users are eligible to earn up to $44,000 in Medicare incentive payments over 5 years and up to $63,750 under the Medicaid plan over 6 years1,2
Still to be determined
“Certified” technology that includes e-prescribing
Electronic exchange of health information
Submit info on clinical quality measures
Physicians who do not adopt EHR by 2015 will be penalized through % decreases in Medicare reimbursement rates1
1. US DHHS. Centers for Medicare and Medicaid Services. Available at: 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

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

29. 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

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

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

32. 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

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

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

36. Good, Better, and Best Practices in HCV Management Today
Bruce R. Bacon, MD
James F. King MD Endowed Chair in Gastroenterology Professor of Internal Medicine Director, Division of Gastroenterology and Hepatology Saint Louis University School of Medicine St. Louis, Missouri

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

38. Histologic Improvement After Successful Anti-HCV Therapy
Pretreatment biopsy:
Trichrome stain with
Ishak stage 3 fibrosis
(portal-to-portal bridging)
Long-term, follow-up biopsy obtained from the same patient 57 months after end of treatment:
Trichrome stain with
Ishak stage 1 fibrosis
With permission from George S, et al. Hepatology. 2009;49:

39. 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

40. 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:

41. 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:

42. 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:

43. 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:

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

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

46. 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:

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

48. 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.

49. 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.

50. Reasons for Identifying Metabolic Syndrome and Fatty Liver Coexistence in Hepatitis C
Insulin resistance, steatosis and steatohepatitis decrease SVR1,2
Steatosis is associated with fibrosis progression2
Insulin resistance is associated with higher viral loads3
Insulin resistance likely inhibits innate immune system function4
1. Romero-Gomez M, et al. Gastroenterology. 2005;128: 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.

51. 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.

52. 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.

53. 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.

54. rs12979860 Genotype Frequency by Population36 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:

55. 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:

56. 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:

57. 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:

58. 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

59. 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

61. 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

62. 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.

63. 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

64. 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

65. 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.

66. 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.

67. 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.

68. 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.

69. 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.

70. 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:

71. 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.

72. 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.

73. 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.

74. 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:

75. 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.

76. 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.

77. 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.

78. SPRINT 1—Virologic Breakthrough20 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.

79. 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.

80. 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.

81. 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.

82. 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.

83. 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

85. 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.

86. 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.

87. 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.

88. 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

89. 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?

90. Long-Term Consequences of Resistance
“Fitness”
Disease
progression
rates
Evolutionary
disadvantage
Class
effects
Prevention
strategies
Retreatment outcomes
Graphic courtesy of Dr. John McHutchison.

91. 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.

92. 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.

93. Key Drivers of Successful Therapy
Simplicity/
complexity
Tolerability
Efficacy
Cost
Duration
Resistance
Graphic courtesy of Dr. John McHutchison.

94. 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

95. 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

97. 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

98. 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.

99. 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.

100. 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?

101. 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

102. 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

103. 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.

104. 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.

105. Can We Leapfrog Ahead? Current SOC (2009) PEG IFN + RBV + STAT-C(1)
(1+2+…)
Graphic courtesy of Dr. Ira Jacobson.

106. 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

107. 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