0
IntroductionIntroduction
Ira M. Jacobson, MDIra M. Jacobson, MD
Vincent Astor Professor of MedicineVincent Astor Professor...
Phases in the EvolutionPhases in the Evolution
of Anti-HCV Therapyof Anti-HCV Therapy
Weisberg IW, et al. Current Hepatiti...
The Refinement Phase of Anti-HCVThe Refinement Phase of Anti-HCV
TherapyTherapy
Reflections on the Past DecadeReflections ...
Viral Kinetics
Negative
Predictive
Value:
12 Weeks
Positive
Predictive
Value:
4 Weeks
Graphic courtesy of Dr. Ira Jacobson.
The “Accordion” Effect in Anti-HCV TherapyThe “Accordion” Effect in Anti-HCV Therapy
The Earlier HCV RNA Clears, the Short...
Treatment of Nonresponders toTreatment of Nonresponders to
PEG IFN and RBVPEG IFN and RBV
 Retreatment with same or diffe...
To Treat or not to Treat:To Treat or not to Treat:
A Constellation of ConsiderationsA Constellation of Considerations
Dura...
Management of ViralManagement of Viral
HepatitisHepatitis—H—Huge Unmet Needsuge Unmet Needs
Efficacy x Access x CorrectEff...
Real World Pressures in an AlreadyReal World Pressures in an Already
Labor-Intensive SpecialtyLabor-Intensive Specialty
Gr...
A Day in the Life of aA Day in the Life of a
Hepatology PracticeHepatology Practice
…in the Future…in the Future
Rosemarie...
13
AgendaAgenda
 State of the industryState of the industry
– The American Recovery and ReinvestmentThe American Recovery...
50.1%
50.1%
50.3%
53.3%
54.4%
56.9%
61.4%
67.8%
68.0%
69.9%
0 20 30 40 50 60 70
Top 10 Challenges of Practice ManagementTo...
 Providing standard of careProviding standard of care
 Giving more informed advice to patientsGiving more informed advic...
16
a
Evaluation and management codes; b
level 3 office visit, 2007 overall regional average.
1. Moore, P. The 2006 Fee Sch...
Survey of 343 Executives Whose Companies
Employ >5 Million Employees
Employer BenefitsEmployer Benefits PercentPercent
Per...
Provider Total Revenues Attributable toProvider Total Revenues Attributable to
Patient ReceivablesPatient Receivables
12
3...
Annoyances UpAnnoyances Up
Survey of Annual Administrative Costs in Group PracticeAnnual Administrative Costs in Group Pra...
Casalino LP, et al. Health Affairs. 2009;28:533-543.
Administrative BurdenAdministrative Burden
 Average physician in a s...
Mean Dollar Value of Hours Spent perMean Dollar Value of Hours Spent per
Physician per Year for All Health PlanPhysician p...
Better-Performing PracticesBetter-Performing Practices
 Over 62% of better-performing practicesOver 62% of better-perform...
Conversion to ICD-10 Code SetConversion to ICD-10 Code Set
 Deadline for compliance October 1, 2013Deadline for complianc...
Centers for Medicare and MedicaidCenters for Medicare and Medicaid
ServicesServices
E-Prescribing Incentive ProgramE-Presc...
The Bonus Isn’t the Only Payoff!The Bonus Isn’t the Only Payoff!
 Reduced chart pulls for phone callsReduced chart pulls ...
E-Prescribing Reduces Overhead andE-Prescribing Reduces Overhead and
Management HeadachesManagement Headaches
 Bonus mone...
The Stimulus Bill (ARRA, HITECH)The Stimulus Bill (ARRA, HITECH)
 Starting in 2011, “meaningful” electronic healthStartin...
 Reporting quality initiativesReporting quality initiatives
– Health maintenance alertsHealth maintenance alerts
 Exchan...
 Gather information (past medical, social,Gather information (past medical, social,
and family history)and family history...
Incremental Approach to EHRIncremental Approach to EHR
 E-prescribingE-prescribing
 Patient portalPatient portal
 Docum...
EHR Deliverables and GoalsEHR Deliverables and Goals
 Benefits of EHR to the hepatology practiceBenefits of EHR to the he...
No Excuse to WaitNo Excuse to Wait
Survey findings:Survey findings:
Net medical revenue was consistently greaterNet medica...
Status QuoStatus Quo
If we keep doing what we’ve alwaysIf we keep doing what we’ve always
done, we’ll keep getting what we...
Conclusions
 EHR is a significant undertaking
– Tool to improve effectiveness in delivery
of care to patients
– Approach ...
Good, Better, and BestPractices inGood, Better, and BestPractices in
HCV Management TodayHCV Management Today
Bruce R. Bac...
Why Treat Chronic Hepatitis C?Why Treat Chronic Hepatitis C?
 The diseaseThe disease
– Common, chronic, and potentially p...
Histologic Improvement AfterHistologic Improvement After
Successful Anti-HCV TherapySuccessful Anti-HCV Therapy
Long-term,...
The Problem–Who Gets Treated?The Problem–Who Gets Treated?
Factors Associated with Treatment in aFactors Associated with T...
Treatment of Chronic Hepatitis CTreatment of Chronic Hepatitis C
2001–20092001–2009
 Combination of peginterferon (PEG IF...
IDEALIDEAL—P—PEG IFNEG IFN αα-2a vs-2a vs αα-2b + RBV-2b + RBV
Study DesignStudy Design
Start Tx Wk 12a Wk 24a
Wk 36 Wk 48...
53
40
24
49
38
20
64
41
32
0
10
20
30
40
50
60
70
ETR SVR Relapse
Percent
P = .57a
P = .20b
PEG IFN α-2b 1.5 µg/kg/wk
+ RB...
IDEALIDEAL—A—Adverse Events, Dosedverse Events, Dose
Modification, and TreatmentModification, and Treatment
Discontinuatio...
Maximizing Response to PEG IFN/RBVMaximizing Response to PEG IFN/RBV
in HCV Genotype 1-Infected Patientsin HCV Genotype 1-...
Maximizing Response to PEG IFN/RBVMaximizing Response to PEG IFN/RBV
in HCV Genotype 1-Infected Patientsin HCV Genotype 1-...
Ferenci P, et al. J Hepatol. 2005;43:425-433.
Rates of Viral ClearanceRates of Viral Clearance
Predict SVR with PEG IFN/RB...
Response-Guided TherapyResponse-Guided Therapy
 HCV RNA determination is essential at week 4HCV RNA determination is esse...
SVR with Standard vs Extended TherapySVR with Standard vs Extended Therapy
in Genotype-1 Patients with Failure ofin Genoty...
SVR in Genotype 2/3 Patients with RVRSVR in Genotype 2/3 Patients with RVR
1. von Wagner M, et al. Gastroenterology. 2005;...
Reasons for Identifying MetabolicReasons for Identifying Metabolic
Syndrome and Fatty Liver CoexistenceSyndrome and Fatty ...
Impact of Insulin Resistance on SVRImpact of Insulin Resistance on SVR
in Genotype-1 Patientsin Genotype-1 Patients
PEG IF...
Reduction of Insulin Resistance With
Successful HCV Therapy
Data from Longitudinal Study Within Lead-In Phase of HALT-C
Tr...
60Mb
Chromosome 19
A Polymorphism on Chromosome 19A Polymorphism on Chromosome 19
Predicts SVRPredicts SVR
Polymorphism rs...
Americans Americans
12
36
19
50
48
46
38
16
35
0
20
40
60
80
100
European African Hispanics
Percent
C/C
T/C
T/T
rs12979860...
C Allele is Associated with SVRC Allele is Associated with SVR
Percentage SVR by Genotype of rs12979860Percentage SVR by G...
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 ...
 IFN lambda proteins encoded by theIFN lambda proteins encoded by the IL28A/BIL28A/B
andand IL29IL29 genesgenes
 These I...
Impact ofImpact of IL28/29IL28/29 on STAT-C Therapyon STAT-C Therapy
 Impact of testing forImpact of testing for IL28BIL2...
ConclusionsConclusions
 PEG IFN plus RBV is the current standard-PEG IFN plus RBV is the current standard-
of-care therap...
The Future of Anti-HCV Treatment—The Future of Anti-HCV Treatment—
Emerging Therapies and TheirEmerging Therapies and Thei...
Where We Are with Treatment NowWhere We Are with Treatment Now
Genotype 1Genotype 1
Abbreviations: NR, null response;
SVR,...
Emerging Anti-HCV TherapiesEmerging Anti-HCV Therapies
Genome
Sequence-Based
RNA
interference
Enzyme
Inhibitors
Protease
P...
MK7009
Hepatitis C Drug Development–2009Hepatitis C Drug Development–2009
Phase IIPhase II
On MarketOn Market
Phase IIIPha...
Albinterferon alfa-2bAlbinterferon alfa-2b
 Novel recombinant polypeptideNovel recombinant polypeptide11
 Extended serum...
Wk 72Start Tx Wk 48Wk 24a
PEG IFN α-2a 180 µg q1wk
+ RBV 1000–1200 mg/d WBD
n = 441
albIFN 900 µg q2wk
+ RBV 1000–1200 mg/...
SVRSVR RelapseRelapse
PEG IFNPEG IFN
180 µg180 µg
q1wkq1wk
PEG IFNPEG IFN
180 µg180 µg
q1wkq1wk
albIFNalbIFN
900 µg900 µg
...
Selected Common Adverse EventsSelected Common Adverse Events
Albinterferon in ACHIEVE 1Albinterferon in ACHIEVE 1
Adverse ...
Direct Viral Enzyme InhibitorsDirect Viral Enzyme Inhibitors——
EEvolving Next Future Therapiesvolving Next Future Therapie...
With permission from Moradpour D, Blum HE. Liver Int. 2004;24:519-525.
(1) Virus entry
(2) Uncoating
(3) Polyprotein
proce...
Doses Taken inDoses Taken in
Virahep-C StudyVirahep-C Study22
Physicians predicted adherence incorrectly
for ~41% of patie...
PROVE 1PROVE 1—T—Telaprevir + PEG IFN/RBVelaprevir + PEG IFN/RBV
SVR, Intent-to-Treat Analysis, Phase IISVR, Intent-to-Tre...
PROVE 1PROVE 1—R—Relapse Rateselapse Rates
0
10
20
30
40
50
RelapseRate(%)
23
8/35
33a
3/9
2a
6
3/51
PR 48 wk
(Control)
T ...
Can We Dispense with Ribavirin?Can We Dispense with Ribavirin?
PROVE 2PROVE 2
13
43
46
69
73
69
80 80
60
50
62
36
0
20
40
...
Wk 72Start Wk 4 Wk 12a
Wk 28 Wk 48
Sprint 1—Boceprevir + PEG IFNSprint 1—Boceprevir + PEG IFN αα-2b + RBV-2b + RBV
Phase I...
SPRINT 1SPRINT 1—S—SVR 24 RatesVR 24 Rates
PEG IFN -2b + RBVPEG IFN -2b + RBV +/-+/- Boceprevir; Low-Dose RBVBoceprevir; L...
SPRINT 1SPRINT 1—S—SVR 24 in Those WhoVR 24 in Those Who
Achieved RVRAchieved RVR
100
82
94
74
84
0
20
40
60
80
100
SVR(%)...
SPRINT 1SPRINT 1—V—Virologic Breakthroughirologic Breakthrough
0
4
5
7
12
0
5
10
15
20
PRB
Lead-In
(n = 103)
PRB
No Lead-I...
PROVE 3PROVE 3——Telaprevir + PEG IFN +/- RBV byTelaprevir + PEG IFN +/- RBV by
Prior Response and Treatment GroupPrior Res...
PROVE 3PROVE 3——Telaprevir + PEG IFN +/- RBV byTelaprevir + PEG IFN +/- RBV by
Prior Response and Treatment GroupPrior Res...
Weight-Based Taribavirin or RBV + PEG IFNWeight-Based Taribavirin or RBV + PEG IFN
Phase IIb Study DesignPhase IIb Study D...
Weight-Based Taribavirin or RBV + PEG IFNWeight-Based Taribavirin or RBV + PEG IFN
Virologic Response at Week 4, 12, 48 an...
9
13 13
7
11
1615
19
28
24
30
33
0
20
40
60
Wk 12 Wk 24 Wk 48
Patients with Hb <10 g/dL (%)
Poordad F, et al. J Hepatol. 2...
40 WkDay 1 Day 4 Day 7 Day 14
Treatment-NaiveGenotype-1INFORM 1—Two Direct Antivirals CombinedINFORM 1—Two Direct Antivira...
INFORM 1—Preliminary Viral KineticsINFORM 1—Preliminary Viral Kinetics
Day 1–14Day 1–14
With permission from Gane EJ, et a...
Regimen
(mg)
n
HCV RNA
(IU/mL)
BL Change from
BL, median
(range)
Day 14,
median
(range)
<LLOQ,
n (%)
<LLOD,
n (%)
R7128 50...
Resistance to HCV Direct AntiviralsResistance to HCV Direct Antivirals
What We Know So FarWhat We Know So Far
 Detection ...
Resistance to HCV Direct AntiviralsResistance to HCV Direct Antivirals
What We DonWhat We Don’t’t Know So FarKnow So Far
...
Long-Term Consequences ofLong-Term Consequences of
ResistanceResistance
“Fitness”
Disease
progression
rates
Evolutionary
d...
Adherence
Adequate
PK/PD
Value of
Lead-in
Dose and
populations
Combination
therapy
Length of
therapy
Foreseeable, Unavoida...
Cardiotoxicity Rash
Liver test
abnormalities
DC rates
x 2-4 fold
Neutropenia
Lymphopenia
Anemia
Abbreviation: DC, disconti...
Simplicity/
complexity
Tolerability Efficacy
ResistanceDurationCost
Graphic courtesy of Dr. John McHutchison.
Key Drivers ...
IFN
RBVRBV
IFNIFN
RBVRBV
HCVHCV
inhibitorinhibitor
HCVHCV
inhibitorinhibitor
HCVHCV
inhibitorinhibitor
HCVHCV
inhibitorinh...
ConclusionsConclusions
 Multidrug therapy is on the horizon, butMultidrug therapy is on the horizon, but
– Don’t slip on ...
Concluding RemarksConcluding Remarks
Ira M. Jacobson, MDIra M. Jacobson, MD
Vincent Astor Professor of MedicineVincent Ast...
Phases in the Evolution of Anti-HCVPhases in the Evolution of Anti-HCV
TherapyTherapy
The
Empiric
Phase
The Phase
of
Speci...
A Polymorphism on Chromosome 19A Polymorphism on Chromosome 19
Predicts SVRPredicts SVR
60Mb
Chromosome 19
Polymorphism rs...
TheThe IL28BIL28B Single NucleotideSingle Nucleotide
PolymorphismPolymorphism
A Major Discovery Leads to Many New Question...
Emerging Anti-HCV TherapiesEmerging Anti-HCV Therapies
Genome
Sequence-Based
RNA
interference
Enzyme
Inhibitors
Protease
P...
A Glimpse of the Near FutureA Glimpse of the Near Future
 First wave of new agents likely available in nextFirst wave of ...
Anti-HCV TherapyAnti-HCV Therapy
Likely Picture—Near FutureLikely Picture—Near Future
Viral enzyme
inhibitors
Immune or
ho...
A B C
Prevention of
emergent
resistance
(pre-existing or
de novo)
+ +A
Profound
suppression
of broad range of
viral varian...
Current SOC
(2009)
PEG IFN +
RBV +
STAT-C(1)
PEG IFN +
RBV +
STAT-C(2)
PEG IFN +
RBV +
STAT-C(1+2)
STAT-C
(1+2+…)
Can We L...
Treating HCV in the Next 5 YearsTreating HCV in the Next 5 Years
 Cure moreCure more
patientspatients
 Shorter durationS...
Electronic health
records
Electronic health
records
Resistance
mutations
Resistance
mutationsNew interferonsNew interferon...
Slides
Slides
Slides
Slides
Slides
Slides
Upcoming SlideShare
Loading in...5
×

Slides

373

Published on

0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total Views
373
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
9
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide
  • Slide 228
    Prevention and Treatment of HCC
  • Transcript of "Slides"

    1. 1. IntroductionIntroduction Ira M. Jacobson, MDIra M. Jacobson, MD Vincent Astor Professor of MedicineVincent Astor Professor of Medicine Chief, Division of Gastroenterology and HepatologyChief, Division of Gastroenterology and Hepatology Medical Director of the Center for the StudyMedical Director of the Center for the Study of Hepatitis Cof Hepatitis C Weill Cornell Medical CollegeWeill Cornell Medical College New York, New YorkNew York, New York
    2. 2. Phases in the EvolutionPhases in the Evolution of Anti-HCV Therapyof Anti-HCV Therapy Weisberg IW, et al. Current Hepatitis Reports. 2007;6:75-82. Graphic courtesy of Dr. Ira Jacobson. The Empiric Phase The Phase of Specifically Targeted Antiviral Therapy for HCV (STAT-C) The Final Phase— Small Molecule Combinations ??? • Optimal dosing • Viral kinetics • Challenging populations • Nonresponders The Refinement Phase
    3. 3. The Refinement Phase of Anti-HCVThe Refinement Phase of Anti-HCV TherapyTherapy Reflections on the Past DecadeReflections on the Past Decade • Optimal dosing • Viral kinetics • Challenging populations • Nonresponders The Refinement Phase IFN dosing and formulation RBV dose Response-guided therapy African Americans, HIV, dialysis, decompensated, posttransplant Strategies for nonresponders and relapsers Graphic courtesy of Dr. Ira Jacobson.
    4. 4. Viral Kinetics Negative Predictive Value: 12 Weeks Positive Predictive Value: 4 Weeks Graphic courtesy of Dr. Ira Jacobson.
    5. 5. The “Accordion” Effect in Anti-HCV TherapyThe “Accordion” Effect in Anti-HCV Therapy The Earlier HCV RNA Clears, the Shorter the Treatment RequiredThe Earlier HCV RNA Clears, the Shorter the Treatment Required1-81-8 Abbreviations: Gt, genotype; LVL, low viral load; RVR, rapid viral response. 1. Berg T, et al. Gastroenterology. 2006;130:1086-1097. 2. Dalgard O, et al. Hepatology. 2008;47:35-42. 3. Jensen DM, et al. Hepatology. 2006;43:954-960. 4. Mangia A, et al. N Engl J Med. 2005;352:2609-2617. 5. Mangia A, et al. Hepatology. 2008;47:43-50. 6. Sanchez-Tapias JM, et al. Gastroenterology. 2006;131:451-460. 7. von Wagner MV, et al. Gastroenterology. 2005;129:522-527. 8. Zeuzem S, et al. J Hepatology. 2006;44:97-103. Graphic courtesy of Dr. Ira Jacobson. 72 wk: Gt 1 slow responders 48 wk: Gt 1 standard 12–16 wk: Gt 2/3 with RVR 24 wk: Gt 1 LVL with RVR 72 (wk)4 24 48128Start Time to First RNA Neg 16 End of Treatment
    6. 6. Treatment of Nonresponders toTreatment of Nonresponders to PEG IFN and RBVPEG IFN and RBV  Retreatment with same or different PEG IFN yieldsRetreatment with same or different PEG IFN yields SVR rates of 2% to 16%SVR rates of 2% to 16%1-31-3  Induction therapy does not improve SVRInduction therapy does not improve SVR11  Extended treatment duration to 72 weeks doubles SVRExtended treatment duration to 72 weeks doubles SVR ratesrates11  CIFN (9 to 15 µg/d) + RBV yields SVR in 7% to 11%CIFN (9 to 15 µg/d) + RBV yields SVR in 7% to 11%44 – Better in noncirrhotics with good response to prior therapyBetter in noncirrhotics with good response to prior therapy  Maintenance therapy studies have been negativeMaintenance therapy studies have been negative55 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.
    7. 7. To Treat or not to Treat:To Treat or not to Treat: A Constellation of ConsiderationsA Constellation of Considerations Duration of infection Personal plans (marriage, pregnancy) Age ALT HIV coinfection Extrahepatic Features (Fatigue, EMC, PCT) Patient "mindset" Genotype Contraindications & comorbidities Histologic stage Family and other support Occupation
    8. 8. Management of ViralManagement of Viral HepatitisHepatitis—H—Huge Unmet Needsuge Unmet Needs Efficacy x Access x CorrectEfficacy x Access x Correct Diagnosis x RecommendationDiagnosis x Recommendation x Acceptance x Adherencex Acceptance x Adherence El-Serag HB. Gastroenterology. 2007;132:8-10. Efficacy in Clinical Trials and Research Centers Effectiveness in Community Practice
    9. 9. Real World Pressures in an AlreadyReal World Pressures in an Already Labor-Intensive SpecialtyLabor-Intensive Specialty Graphic courtesy of Dr. Ira Jacobson. E-prescribingE-prescribing Electronic Records Electronic Records Increasingly Complicated Regimens Increasingly Complicated Regimens Coding and Billing Compliance Coding and Billing Compliance Medicolegal Issues & Costs Medicolegal Issues & Costs PQRI (Physician Quality Reporting Initiative) PQRI (Physician Quality Reporting Initiative) Drug Costs & Potential Insurance Constraints Drug Costs & Potential Insurance Constraints Declining Reimbursements Declining Reimbursements Ambulatory Surgery Centers Ambulatory Surgery Centers
    10. 10. A Day in the Life of aA Day in the Life of a Hepatology PracticeHepatology Practice …in the Future…in the Future Rosemarie Nelson, MSRosemarie Nelson, MS PrincipalPrincipal MGMA Health Care Consulting GroupMGMA Health Care Consulting Group Englewood, ColoradoEnglewood, Colorado
    11. 11. 13 AgendaAgenda  State of the industryState of the industry – The American Recovery and ReinvestmentThe American Recovery and Reinvestment Act of 2009 (ARRA) = “stimulus package”Act of 2009 (ARRA) = “stimulus package”  The Health Information Technology forThe Health Information Technology for Economic and Clinical Health (HITECH) ActEconomic and Clinical Health (HITECH) Act – Encourage adoption of electronic health recordEncourage adoption of electronic health record – Reimbursement shiftsReimbursement shifts  Operational questions and technologicOperational questions and technologic answersanswers  What does it mean for your patients?What does it mean for your patients?
    12. 12. 50.1% 50.1% 50.3% 53.3% 54.4% 56.9% 61.4% 67.8% 68.0% 69.9% 0 20 30 40 50 60 70 Top 10 Challenges of Practice ManagementTop 10 Challenges of Practice Management Percent RespondentsPercent Respondentsaa Who Rated Issues asWho Rated Issues as “Considerable” or “Extreme” Challenges“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 a Survey of Medical Group Management Association members. Abbreviation: HSA, health savings account. With permission from Pope C, et al. MGMA Connexion. July 2008;18-23. 10
    13. 13.  Providing standard of careProviding standard of care  Giving more informed advice to patientsGiving more informed advice to patients  Screening for hepatitis C virusScreening for hepatitis C virus Commitments of SurveyedCommitments of Surveyed HepatologistsHepatologists Projects In Knowledge, Inc. Internal proprietary survey. 2009.
    14. 14. 16 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. Lower ReimbursementLower Reimbursement Drop in payments from commercial payersa 2005 to 2006: 10% drop1 2006 to 2007: 6.5% drop2 Average Reimbursement, 992131b $47 Average Price of a Haircut3 $45
    15. 15. Survey of 343 Executives Whose Companies Employ >5 Million Employees Employer BenefitsEmployer Benefits PercentPercent Percentage of employers that intend to shiftPercentage of employers that intend to shift more health insurance costs to employeesmore health insurance costs to employees next yearnext year 6565 Percentage of employers that plan to reducePercentage of employers that plan to reduce the number of health plan optionsthe number of health plan options 4949 Percentage of employers that plan to increasePercentage of employers that plan to increase the number of consumer-directed health plansthe number of consumer-directed health plans 4040 Patients’ Share of Medical Bills to SkyrocketPatients’ Share of Medical Bills to Skyrocket Hewitt Associates. Survey findings: challenges for health care in uncertain times. Lincolnshire, Ill; 2009. Available at: http://www.hewittassociates.com. Accessed on: October 14, 2009. Graphic courtesy of Rosemarie Nelson, MS.
    16. 16. Provider Total Revenues Attributable toProvider Total Revenues Attributable to Patient ReceivablesPatient Receivables 12 30 0 5 10 15 20 25 30 35 2007 2012% Revenue Attributable to Patient Receivables Celent. Press release: The "retailish" future of patient collections. San Francisco, Calif: February 18, 2009. Available at: http://reports.celent.com/PressReleases/20090217/Retailish.asp. Accessed on: October 14, 2009.
    17. 17. Annoyances UpAnnoyances Up Survey of Annual Administrative Costs in Group PracticeAnnual Administrative Costs in Group Practice (N = 91, multiple specialties and settings)(N = 91, multiple specialties and settings) Administrative TaskAdministrative Task Cost perCost per PhysicianPhysicianaa Physician time in response to pharmacy phone callsPhysician time in response to pharmacy phone calls $12,731$12,731 Staff time in insurance verification, copays, andStaff time in insurance verification, copays, and deductiblesdeductibles $3876$3876 Support staff time to appeal denied claimsSupport staff time to appeal denied claims $925$925 Credentialing applications (physician and staff)Credentialing applications (physician and staff) $808$808 Medical Group Management Association Center for Research. Analyzing the cost of administrative complexity. September 2004. Available at: http://www.mgma.com/about/default.aspx?id=280. Accessed on: October 2, 2009. Graphic courtesy of Rosemarie Nelson, MS. a Cost per full-time equivalent (FTE) assuming a 10-FTE practice.
    18. 18. Casalino LP, et al. Health Affairs. 2009;28:533-543. Administrative BurdenAdministrative Burden  Average physician in a solo orAverage physician in a solo or 2-physician practice spends 3.5 hours2-physician practice spends 3.5 hours weekly interacting with health plansweekly interacting with health plans – 4.3 hours for primary care physicians4.3 hours for primary care physicians  Physicians in practices with 10 or morePhysicians in practices with 10 or more physicians spend 2.6 hours weeklyphysicians spend 2.6 hours weekly
    19. 19. Mean Dollar Value of Hours Spent perMean Dollar Value of Hours Spent per Physician per Year for All Health PlanPhysician per Year for All Health Plan InteractionsInteractions Survey of US Physicians and Administrative Staff 730 Primary Care Physicians; 580 Specialists 1–2 MDs1–2 MDs 3–9 MDs3–9 MDs 10+ MDs10+ MDs Physician timePhysician time $17,817$17,817 $15,670$15,670 $13,798$13,798 Nursing staff timeNursing staff time $14,897$14,897 $26,225$26,225 $24,314$24,314 Clerical staff timeClerical staff time $30,014$30,014 $25,632$25,632 $18,636$18,636 Senior administrative timeSenior administrative time $5829$5829 $3269$3269 $1235$1235 Lawyer/accountant timeLawyer/accountant time $1249$1249 $626$626 $4455$4455 Total per practiceTotal per practice $69,806$69,806 $71,422$71,422 $62,438$62,438 With permission from Casalino LP, et al. Health Affairs. 2009;28:533-543.
    20. 20. Better-Performing PracticesBetter-Performing Practices  Over 62% of better-performing practicesOver 62% of better-performing practices employ nonphysician providers toemploy nonphysician providers to increase physician productivityincrease physician productivity performance levelsperformance levels11 – vs 50% of other practicesvs 50% of other practices  Improved access for patientsImproved access for patients  Maximize physician timeMaximize 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.
    21. 21. Conversion to ICD-10 Code SetConversion to ICD-10 Code Set  Deadline for compliance October 1, 2013Deadline for compliance October 1, 201311 155,000 17,000 0 50,000 100,000 150,000 200,000 Total Diagnostic and Procedure Codes ICD-9 (up to 5 characters) ICD-10 (up to 7 characters) a Small practice defined as 3 physicians and 2 administrative staff. 1. US HSS. Press release. January 15, 2009. Available at: http://www.hhs.gov/news/press/2009pres/01/20090115f.html. Accessed on: October 3, 2009. 2. (Bottom graphic) With permission from Nachimson Advisors, LLC. The impact of implementing ICD 10 on physician practices and clinical laboratories: a report to the ICD-10 coalition. October 8, 2008.‐ 3. Nelson R. Unpublished data. Conversion–Estimate of Costs to Comply for a Typical Small PracticeConversion–Estimate of Costs to Comply for a Typical Small Practice2a2a CategoryCategory CostCost Training and educationTraining and education $2405$2405 Business analysisBusiness analysis $6905$6905 Super-bill changesSuper-bill changes $2985$2985 IT system changesIT system changes $7500$7500 Increased documentation costsIncreased documentation costs $44,000$44,000 Cash flow disruptionCash flow disruption $19,500$19,500 Total CostsTotal Costs $83,295$83,295 Same group: $99,000 to move to EHRSame group: $99,000 to move to EHR33
    22. 22. Centers for Medicare and MedicaidCenters for Medicare and Medicaid ServicesServices E-Prescribing Incentive ProgramE-Prescribing Incentive Program  Medicare Improvements for PatientsMedicare Improvements for Patients and Providers Act of 2008 (MIPPA)and Providers Act of 2008 (MIPPA)  Bonus of 2% of Medicare allowedBonus of 2% of Medicare allowed charges for 2009charges for 2009 – Bonus 1% in 2012 and to 0.5% in 2013Bonus 1% in 2012 and to 0.5% in 2013 – Bonus eliminated in 2014Bonus eliminated in 2014  Simple reportingSimple reporting -- only 3 G-codesonly 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.
    23. 23. The Bonus Isn’t the Only Payoff!The Bonus Isn’t the Only Payoff!  Reduced chart pulls for phone callsReduced chart pulls for phone calls – Average cost of a chart pull is $5–$12 eachAverage cost of a chart pull is $5–$12 each11 – Average hepatology practice gets 12–15 calls per dayAverage hepatology practice gets 12–15 calls per day regarding prescription issuesregarding prescription issues11 – Get half that number?Get half that number?  Save >$60 per day per physician!Save >$60 per day per physician!11  Patient safety and quality of carePatient safety and quality of care  Handwriting legibilityHandwriting legibility  Oral miscommunicationsOral miscommunications  Applications provide warnings and alerts at point ofApplications provide warnings and alerts at point of prescribingprescribing – vs 4 hours later with interrupting phone call fromvs 4 hours later with interrupting phone call from pharmacypharmacy  And where is the chart then??And where is the chart then?? 1. Nelson R. Unpublished data.
    24. 24. E-Prescribing Reduces Overhead andE-Prescribing Reduces Overhead and Management HeadachesManagement Headaches  Bonus money now, penalty reduction laterBonus money now, penalty reduction later  Operational efficiency drives reduced costsOperational efficiency drives reduced costs  Transition and implementation is manageableTransition and implementation is manageable  Address patient safety and quality of careAddress patient safety and quality of care  Gain experience to carry over to electronicGain experience to carry over to electronic health record implementationhealth record implementation
    25. 25. The Stimulus Bill (ARRA, HITECH)The Stimulus Bill (ARRA, HITECH)  Starting in 2011, “meaningful” electronic healthStarting in 2011, “meaningful” electronic health record (EHR) users are eligible to earn up to $44,000record (EHR) users are eligible to earn up to $44,000 in Medicare incentive payments over 5 years and upin Medicare incentive payments over 5 years and up to $63,750 under the Medicaid plan over 6 yearsto $63,750 under the Medicaid plan over 6 years1,21,2 – Still to be determinedStill to be determined  ““Certified” technology that includes e-prescribingCertified” technology that includes e-prescribing  Electronic exchange of health informationElectronic exchange of health information  Submit info on clinical quality measuresSubmit info on clinical quality measures  Physicians who do not adopt EHR by 2015 will bePhysicians who do not adopt EHR by 2015 will be penalized through % decreases in Medicarepenalized through % decreases in Medicare reimbursement ratesreimbursement rates11 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.
    26. 26.  Reporting quality initiativesReporting quality initiatives – Health maintenance alertsHealth maintenance alerts  Exchange of informationExchange of information – ResultsResults  Engage the patientEngage the patient – Portal servicesPortal services  E-prescribingE-prescribing Optimize to Get to “Meaningful Use”Optimize to Get to “Meaningful Use”
    27. 27.  Gather information (past medical, social,Gather information (past medical, social, and family history)and family history)  Manage requestsManage requests – AppointmentsAppointments – Prescription re-issuesPrescription re-issues – ““Old” telephone triage questionsOld” telephone triage questions  Deliver lab/test resultsDeliver lab/test results  Generate revenue by recallGenerate revenue by recall – Follow-up and health maintenance remindersFollow-up and health maintenance reminders  Get nurses off the phones with FAQsGet nurses off the phones with FAQs Business of Medicine IsBusiness of Medicine Is Communications–Patient PortalCommunications–Patient Portal
    28. 28. Incremental Approach to EHRIncremental Approach to EHR  E-prescribingE-prescribing  Patient portalPatient portal  Document image management systemDocument image management system  Results reporting and messagingResults reporting and messaging – ““Dealbreaker” – importance of labs inDealbreaker” – importance of labs in hepatology (to patient too!)hepatology (to patient too!)  Online clinical documentationOnline clinical documentation – Transcribed reportsTranscribed reports – Result reportsResult reports
    29. 29. EHR Deliverables and GoalsEHR Deliverables and Goals  Benefits of EHR to the hepatology practiceBenefits of EHR to the hepatology practice – Increased quality of care through information accessIncreased quality of care through information access  Standards-of-care guidelinesStandards-of-care guidelines  Lab flow sheets and graphsLab flow sheets and graphs – Improved patient care experience by increasingImproved patient care experience by increasing practice efficiencypractice efficiency  What is your vision for the future?What is your vision for the future? – Access to dataAccess to data – Work with data (retrieve, annotate, assign)Work with data (retrieve, annotate, assign) – Document and improve workflowDocument and improve workflow – Decision support – clinical guidelines, evidence-Decision support – clinical guidelines, evidence- based medical protocolsbased medical protocols
    30. 30. No Excuse to WaitNo Excuse to Wait Survey findings:Survey findings: Net medical revenue was consistently greaterNet medical revenue was consistently greater across single-specialty and multispecialtyacross single-specialty and multispecialty groups using a clinical information solutiongroups using a clinical information solution compared with peers not using similarcompared with peers not using similar technologiestechnologies11 Technology?Technology? Or improved operational efficiency?Or improved operational efficiency? 1. Gans N. MGMA Connexion. July 2005;22-23.
    31. 31. Status QuoStatus Quo If we keep doing what we’ve alwaysIf we keep doing what we’ve always done, we’ll keep getting what wedone, we’ll keep getting what we always gotalways got
    32. 32. 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
    33. 33. Good, Better, and BestPractices inGood, Better, and BestPractices in HCV Management TodayHCV Management Today Bruce R. Bacon, MDBruce R. Bacon, MD James F. King MD Endowed Chair in GastroenterologyJames F. King MD Endowed Chair in Gastroenterology Professor of Internal MedicineProfessor of Internal Medicine Director, Division of Gastroenterology and HepatologyDirector, Division of Gastroenterology and Hepatology Saint Louis University School of MedicineSaint Louis University School of Medicine St. Louis, MissouriSt. Louis, Missouri
    34. 34. Why Treat Chronic Hepatitis C?Why Treat Chronic Hepatitis C?  The diseaseThe disease – Common, chronic, and potentially progressiveCommon, chronic, and potentially progressive – Complications are becoming more commonComplications are becoming more common  Liver failureLiver failure  Hepatocellular carcinoma (HCC)Hepatocellular carcinoma (HCC)  The treatmentThe treatment – Viral cure, or sustained virologic response (SVR), isViral cure, or sustained virologic response (SVR), is achievableachievable – SVR associated with histologic improvement andSVR associated with histologic improvement and gradual regression of fibrosisgradual regression of fibrosis11 – SVR leads to lower risk for liver failure and HCC, andSVR leads to lower risk for liver failure and HCC, and improved survivalimproved survival2,32,3 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.
    35. 35. Histologic Improvement AfterHistologic Improvement After Successful Anti-HCV TherapySuccessful Anti-HCV Therapy Long-term, follow-up biopsy obtained from the same patient 57 months after end of treatment: Trichrome stain with Ishak stage 1 fibrosis Pretreatment biopsy: Trichrome stain with Ishak stage 3 fibrosis (portal-to-portal bridging) With permission from George S, et al. Hepatology. 2009;49:729-738.
    36. 36. The Problem–Who Gets Treated?The Problem–Who Gets Treated? Factors Associated with Treatment in aFactors Associated with Treatment in a Retrospective Analysis of California Medicaid DataRetrospective Analysis of California Medicaid Dataaa a 529 cases and 1058 control patients. Markowitz JS, et al. J Viral Hepat. 2005;12:176-185. Treated Age 45–64 years Male gender Mild disease Liver biopsy Antidepressant use “Other” race/ethnicity Untreated Age >65 years Fibrosis Severe diabetes Renal disease High hospital or ER utilization Alcohol use 11 89 0 20 40 60 80 100 Proportion of HCV-Infected Patients (%) Untreated Treated
    37. 37. Treatment of Chronic Hepatitis CTreatment of Chronic Hepatitis C 2001–20092001–2009  Combination of peginterferon (PEG IFN) andCombination of peginterferon (PEG IFN) and ribavirin (RBV)ribavirin (RBV) – PEG IFNPEG IFN αα-2b and RBV-2b and RBV – PEG IFNPEG IFN αα-2a and RBV-2a and RBV  Genotype-specific duration and responseGenotype-specific duration and response  6–12 months6–12 months  Overall sustained virologic response ~55%Overall sustained virologic response ~55%1,21,2 1. Manns M, et al. Lancet. 2001;358:958-965. 2. Fried M, et al. N Engl J Med. 2002;347:975-982.
    38. 38. IDEALIDEAL—P—PEG IFNEG IFN αα-2a vs-2a vs αα-2b + RBV-2b + RBV Study DesignStudy Design Start Tx Wk 12a Wk 24a Wk 36 Wk 48 PEG IFN α-2b 1.5 μg/kg/wk + RBV 800–1400 mg/d n = 1019 PEG IFN α-2b 1.0 μg/kg/wk + RBV 800–1400 mg/d n = 1016 Follow-up Follow-up PEG IFN α-2a 180 μg/wk + RBV 1000–1200 mg/d n = 1035 Follow-up Treatment-NaivePatients,Treatment-NaivePatients, Genotype1Genotype1 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
    39. 39. 53 40 24 49 38 20 64 41 32 0 10 20 30 40 50 60 70 ETR SVR Relapse Percent P = .57a P = .20b PEG IFN α-2b 1.5 µg/kg/wk + RBV 800–1400 mg/d PEG IFN α-2b 1.0 µg/kg/wk + RBV 800–1400 mg/d PEG IFN α-2a 180 µg/wk + RBV 1000–1200 mg/d a 95% CI -13.2% to -2.8%. b 95% CI -1.6% to 8.6%. Abbreviations: ETR, end-of-treatment response; SVR, sustained virologic response. McHutchison JG, et al. N Engl J Med. 2009;361:580-593. IDEALIDEAL——ETR, SVR, and Relapse RatesETR, SVR, and Relapse Rates Genotype 1 Patients, Intent to Treat AnalysisGenotype 1 Patients, Intent to Treat Analysis
    40. 40. IDEALIDEAL—A—Adverse Events, Dosedverse Events, Dose Modification, and TreatmentModification, and Treatment DiscontinuationDiscontinuation PEG IFN α-2b 1.5 + RBV n = 1019 PEG IFN α-2b 1.0 + RBV n = 1016 PEG IFN α-2a 180 + RBV n = 1035 Deaths (all/treatment-related) 5/1 (no.) 1/0 (no.) 6/1 (no.) Serious adverse events (AEs) (all/treatment-related) 9%/4% 9%/4% 12%/4% Discontinued due to AEs 13% 10% 13% Dose modification due to AEs 43% 33% 43% Psychiatric disorders 1.9% 1.2% 1.4% Hematologic parameters Neutrophil count (<750/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;361:580-593.
    41. 41. Maximizing Response to PEG IFN/RBVMaximizing Response to PEG IFN/RBV in HCV Genotype 1-Infected Patientsin HCV Genotype 1-Infected Patients  Evaluate and correct modifiable factors priorEvaluate and correct modifiable factors prior to therapyto therapy – Insulin resistance and obesityInsulin resistance and obesity – DepressionDepression  Deliver expert treatmentDeliver expert treatment – Adequate RBV dose >13 mg/kg/dayAdequate RBV dose >13 mg/kg/day11 – Consider extension of therapy inConsider extension of therapy in “s“slow”low” respondersresponders – Aggressively manage side effectsAggressively manage side effects 1. McHutchison JG, et al. N Engl J Med. 2009;361:580-593.
    42. 42. Maximizing Response to PEG IFN/RBVMaximizing Response to PEG IFN/RBV in HCV Genotype 1-Infected Patientsin HCV Genotype 1-Infected Patients  Treatment response at weeks 4 and 12 areTreatment response at weeks 4 and 12 are more predictive than baseline factorsmore predictive than baseline factors1-31-3 – May help tailor treatment to improve responseMay help tailor treatment to improve response or curtail therapy when it is futileor curtail therapy when it is futile – Rapid virologic response is not a stopping ruleRapid 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.
    43. 43. Ferenci P, et al. J Hepatol. 2005;43:425-433. Rates of Viral ClearanceRates of Viral Clearance Predict SVR with PEG IFN/RBVPredict SVR with PEG IFN/RBV PEG IFN α-2a 180 µg/wk + RBV 1000–1200 mg PatientswithSVR(%) 91 72 60 0 20 40 60 80 100 HCV RNA Wk 4: Neg HCV RNA| Wk 4: ≥2-log ↓ Wk 12: Neg HCV RNA| Wk 4: <2-log ↓ Wk 12: Neg HCV RNA| Wk 4: ≥2-log ↓ Wk 12: ≥2-log ↓ WK 24: Neg HCV RNA| Wk 4: <2-log ↓ Wk 12: ≥2-log ↓ WK 24: Neg 48 n = 33 93 20 21 30 43 The later a patient becomes HCV RNA undetectable, regardless of EVR, the lower the chance for SVR.
    44. 44. Response-Guided TherapyResponse-Guided Therapy  HCV RNA determination is essential at week 4HCV RNA determination is essential at week 4 (RVR) and week 12 (EVR)(RVR) and week 12 (EVR)  Shortened therapy vs standard therapy vsShortened therapy vs standard therapy vs extended therapyextended therapy – GenotypeGenotype – RVR or EVRRVR or EVR – Viral loadViral load  Response-guided therapy will be a prominentResponse-guided therapy will be a prominent theme with the advent of novel therapiestheme with the advent of novel therapies
    45. 45. SVR with Standard vs Extended TherapySVR with Standard vs Extended Therapy in Genotype-1 Patients with Failure ofin Genotype-1 Patients with Failure of RVR or Slow ResponseRVR or Slow Response 1. Sanchez-Tapias J, et al. Gastroenterology. 2006;131:451-460. 2. Berg T, et al. Gastroenterology. 2006;130:1086-1097. 3. Pearlman BL, et al. Hepatology. 2007;46:1688-1694. 4. Mangia A, et al. Hepatology. 2008;47:43-50. Graphic courtesy of Dr. Ira Jacobson. Standard 48 wk Extended 72 wk PEG IFN α-2a + RBV 8001 PEG IFN α-2a + RBV 8002 PEG IFN α-2b + RBV 800–14003 SVR(%) 28 44 17 29 18 38 38 64 PEG IFN α-2a + RBV 1000–12004 20 40 60 80 100 n = 149 100 49 21142 106 52 52 P = .07P = .03P = .04P = .003 Randomized if non-RVR Retrospective subset analysis of patients with RNA+ at 12 wk Randomization of slow responders Randomization of moderately slow responders: RNA+ at 8 wk RNA– at 12 wk
    46. 46. SVR in Genotype 2/3 Patients with RVRSVR in Genotype 2/3 Patients with RVR 1. von Wagner M, et al. Gastroenterology. 2005;129:522-527. 2. Mangia A , et al. N Engl J Med. 2005;352:2609-2617. 3. Shiffman ML, et al. N Engl J Med. 2007;357:124-134. 4. Dalgard O, et al. Hepatology. 2008;47:35-42. Graphic courtesy of Dr. Ira Jacobson. Short (12–16 wk) Standard (24 wk) 79 85 81 91 82 80 85 91 PEG IFN α-2a + RBV 8003 PEG IFN α-2a + RBV 800–12001 PEG IFN α-2b + RBV 1000–12002 PEG IFN α-2b + RBV 800–14004 20 40 60 80 100 SVR(%) n = 7171 213 732 14870 731 150
    47. 47. Reasons for Identifying MetabolicReasons for Identifying Metabolic Syndrome and Fatty Liver CoexistenceSyndrome and Fatty Liver Coexistence in Hepatitis Cin Hepatitis C  Insulin resistance, steatosis andInsulin resistance, steatosis and steatohepatitis decrease SVRsteatohepatitis decrease SVR1,21,2  Steatosis is associated with fibrosisSteatosis is associated with fibrosis progressionprogression22  Insulin resistance is associated with higherInsulin resistance is associated with higher viral loadsviral loads33  Insulin resistance likely inhibits innateInsulin resistance likely inhibits innate immune system functionimmune system function44 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.
    48. 48. Impact of Insulin Resistance on SVRImpact of Insulin Resistance on SVR in Genotype-1 Patientsin Genotype-1 Patients PEG IFN + RBVPEG IFN + RBVaa a Treatment: PEG IFN α-2a 180 µg/wk or PEG IFN α-2b 1.5 µg/kg/wk + RBV 800–1200/d. Romero-Gomez M, et al. Gastroenterology. 2005;128:636-641. Graphic courtesy of Dr. Bruce Bacon. 33 61 0 20 40 60 80 100 SVR (%) P = .007 With Insulin Resistance Without Insulin Resistance
    49. 49. 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 atGroup Based on Status at Week 20 of PEG IFN/RBVWeek 20 of PEG IFN/RBV HOMA2-IRHOMA2-IRaa Change at Week 20Change at Week 20bb Null responders (n = 38)Null responders (n = 38) +0.18+0.18 Partial responders (n = 37)Partial responders (n = 37) ––0.90.9 Responders (n = 21)Responders (n = 21) ––2.232.23 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.
    50. 50. 60Mb Chromosome 19 A Polymorphism on Chromosome 19A Polymorphism on Chromosome 19 Predicts SVRPredicts SVR Polymorphism rs12979860 IL28B gene 3kb 19q13.13 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.
    51. 51. Americans Americans 12 36 19 50 48 46 38 16 35 0 20 40 60 80 100 European African Hispanics Percent C/C T/C T/T rs12979860 Genotype Frequencyrs12979860 Genotype Frequency by Populationby Population Ge D, et al. Nature. 2009;461:399-401.
    52. 52. C Allele is Associated with SVRC Allele is Associated with SVR Percentage SVR by Genotype of rs12979860Percentage SVR by Genotype of rs12979860 0 20 40 60 80 100 C/C T/C T/T SVR Combined European Americans African Americans Hispanics n = 70 n = 14 n = 102 n = 91 n = 35 n = 433 n = 186 n = 559 n = 392 n = 30 n = 26 n = 336 P = 1.37 x 10-28 vs T/T Ge D, et al. Nature. 2009;461:399-401.
    53. 53. IL28B rs 12979860 Genotype (CC vs CT and TT) European Americans 7.3 (5.1–10.4) African Americans 6.1 (2.3–15.9) Hispanics 5.6 (1.4–22.1) Baseline Viral Load (≤600,000 IU/mL vs ≥600,000 IU/mL) European Americans 4.2 (2.6–6.6) African Americans 5.1 (1.9–13.9) Hispanics 2.4 (0.7–8.8) Baseline Fibrosis (Metavir F0–2 vs F3–4) European Americans 3.0 (1.8–5.1) African Americans 1.1 (0.3–5.2) Hispanics 4.1 (0.7–25.5) Ethnicity (European Americans/African Americans) 3.1 (2.1–4.7) C/C Genotype Is IndependentlyC/C Genotype Is Independently Associated with SVRAssociated with SVRaa a Odds ratios and 95% confidence intervals from the logistic regression model. Ge D, et al. Nature. 2009;461:399-401.
    54. 54.  IFN lambda proteins encoded by theIFN lambda proteins encoded by the IL28A/BIL28A/B andand IL29IL29 genesgenes  These IFNs signal through a unique receptor,These IFNs signal through a unique receptor, but share common downstream signalingbut share common downstream signaling with type 1 IFNs, including IFN-with type 1 IFNs, including IFN-αα  IFN-lambda (rIL-29) is currently in clinicalIFN-lambda (rIL-29) is currently in clinical trials and has antiviral activitytrials and has antiviral activity Ge D, et al. Nature. 2009;461:399-401. Impact ofImpact of IL28/29IL28/29 on IFNon IFN
    55. 55. Impact ofImpact of IL28/29IL28/29 on STAT-C Therapyon STAT-C Therapy  Impact of testing forImpact of testing for IL28BIL28B will be importantwill be important with PEG IFN and RBVwith PEG IFN and RBV  IL28BIL28B testing will need to be investigatedtesting will need to be investigated when using STAT-C agentswhen using STAT-C agents
    56. 56. ConclusionsConclusions  PEG IFN plus RBV is the current standard-PEG IFN plus RBV is the current standard- of-care therapyof-care therapy – Overall SVR about 55%Overall SVR about 55%  Insulin resistance has a significant impactInsulin resistance has a significant impact on SVRon SVR  Response-guided therapy is important nowResponse-guided therapy is important now and will be a prominent theme with noveland will be a prominent theme with novel therapiestherapies  IL28BIL28B status influences effectiveness of IFNstatus influences effectiveness of IFN
    57. 57. The Future of Anti-HCV Treatment—The Future of Anti-HCV Treatment— Emerging Therapies and TheirEmerging Therapies and Their Integration into the Medical Office ofIntegration into the Medical Office of the Futurethe Future Nezam H. Afdhal, MDNezam H. Afdhal, MD Associate Professor of MedicineAssociate Professor of Medicine Harvard Medical SchoolHarvard Medical School Chief of HepatologyChief of Hepatology Beth Israel Deaconess Medical CenterBeth Israel Deaconess Medical Center Boston, MassachusettsBoston, Massachusetts
    58. 58. Where We Are with Treatment NowWhere We Are with Treatment Now Genotype 1Genotype 1 Abbreviations: NR, null response; SVR, sustained virologic response. Graphic courtesy of Dr. John McHutchison. SVR 40%–50% Relapse 20%–30% Discontinue 20% NR 20%
    59. 59. Emerging Anti-HCV TherapiesEmerging Anti-HCV Therapies Genome Sequence-Based RNA interference Enzyme Inhibitors Protease Polymerase Other IFN and RBV modifications • Albinterferon, omega IFN, PEG IFN lambda (IL-29) • Taribavirin (viramidine) Immune approaches • Therapeutic vaccines • Toll-like receptor agonists • Hepatitis C immune globulin • Monoclonal antibodies Targeting cellular factors • Cyclophilin antagonists • Nitazoxanide Specifically Targeted Antiviral Therapy for HCV (STAT-C) NS5A Abbreviations: HCV, hepatitis C virus; IFN, interferon; PEG IFN, peginterferon; RBV, ribavirin. Graphic courtesy of Dr. Ira Jacobson.
    60. 60. MK7009 Hepatitis C Drug Development–2009Hepatitis C Drug Development–2009 Phase IIPhase II On MarketOn Market Phase IIIPhase III Phase IPhase I Research/Research/ PreclinicalPreclinical Thymalfasin Albumin-IFN alfa IFN & PEG IFN Many others, including immune stimulants and gene therapy Ribavirin Taribavirin Medusa IFN A-831 Telaprevir Debio25 Omega IFN Boceprevir R1728 TMC 435350 Note: Not a complete list of products in development. Information from public sources. Graphic courtesy of Dr. John McHutchison. Silibinin BI-201335 GS9190 BMS-650032 Interferons Ribavirins Immunomodulators Protease inhibitors Polymerase inhibitors BMS-790052 ITMN 191 VBY-376 Others MK-3281 ANA598 VCH-759 JTK-652 BIT225 BMS-791325 Controlled-release IFN Low-dose oral IFN IFN biopump DA-3021 IL-29 ME-3738 SCV-07 Oglufanide IPH-1101 CYT 107 EGS21 SCY-635 KPE02001003 TCM-700C PYN-17Nitazoxanide VX-500 ABT-333PHX1766 IDX184 EMZ702 HDV interferon NIM811 Bavituximab CF102 VX-813 VCH-222 IFN beta-1a PF-868554 VCH-916
    61. 61. Albinterferon alfa-2bAlbinterferon alfa-2b  Novel recombinant polypeptideNovel recombinant polypeptide11  Extended serum half-life supports dosing at 2-weekExtended serum half-life supports dosing at 2-week intervalsintervals2,32,3 – 148 hours, median (range, 134–153 hours)148 hours, median (range, 134–153 hours)  Phase II findings showPhase II findings show 900900 µµg has comparableg has comparable efficacy to PEG IFN/RBVefficacy to PEG IFN/RBV and 1200and 1200 µµg has superiorg has superior efficacyefficacy44 – Both doses warrantedBoth doses warranted evaluation in phase III trialevaluation in phase III trial 1. Liu C, et al. Hepatol Res. 2007;37:941-947. 2. Bain VG, et al. J Hepatol. 2006;44:671-678. 3. Bain V, et al. J Hepatol. 2005;42 (suppl 1):abstract 18. 4. Zeuzem S, et al. J Hepatol. 2009;50:S377. Graphic courtesy of Dr. Nezam Afdhal. IFN α-2b Human albumin Molecular weight 85.7 kDa
    62. 62. Wk 72Start Tx Wk 48Wk 24a PEG IFN α-2a 180 µg q1wk + RBV 1000–1200 mg/d WBD n = 441 albIFN 900 µg q2wk + RBV 1000–1200 mg/d WBD n = 442 Follow-up Follow-up Follow-up IFN-IFN-ααTreatment-NaivePatients,Treatment-NaivePatients, Genotype1Genotype1 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 Study DesignACHIEVE 1 Study Design Randomized, Open-Label, Active-Controlled,Randomized, Open-Label, Active-Controlled, Phase IIIPhase III albIFN 1200 µg q2wk + RBV 1000–1200 mg/d WBD n = 440 900 µg
    63. 63. SVRSVR RelapseRelapse PEG IFNPEG IFN 180 µg180 µg q1wkq1wk PEG IFNPEG IFN 180 µg180 µg q1wkq1wk albIFNalbIFN 900 µg900 µg q2wkq2wk albIFNalbIFN 1200 µg1200 µg q2wkq2wk albIFNalbIFN 900 µg900 µg q2wkq2wk albIFNalbIFN 1200 µg1200 µg q2wkq2wk ACHIEVE 1–SVR and Relapse in Intent-to-Treat Population Zeuzem S, et al. J Hepatol. 2009;50:S377. P = .0029a P = .0008a a P-value for noninferiority.
    64. 64. Selected Common Adverse EventsSelected Common Adverse Events Albinterferon in ACHIEVE 1Albinterferon in ACHIEVE 1 Adverse EventAdverse Event PEG IFNPEG IFN 180 Q1w180 Q1w n = 441n = 441 albIFNalbIFN 900 Q2w900 Q2w n = 442n = 442 albIFNalbIFN 1200 Q2w1200 Q2w n = 440n = 440 FatigueFatigue 245 (55.6%)245 (55.6%) 230 (52.0%)230 (52.0%) 248 (56.4%)248 (56.4%) HeadacheHeadache 200 (45.4%)200 (45.4%) 205 (46.4%)205 (46.4%) 217 (49.3%)217 (49.3%) PyrexiaPyrexia 149 (33.8%)149 (33.8%) 163 (36.9%)163 (36.9%) 185 (42.0%)185 (42.0%) InsomniaInsomnia 157 (35.6%)157 (35.6%) 162 (36.7%)162 (36.7%) 164 (37.3%)164 (37.3%) Alopeciaa 108 (24.5%) 182 (41.2%) 177 (40.2%) NauseaNausea 148 (33.6%)148 (33.6%) 156 (35.3%)156 (35.3%) 157 (35.7%)157 (35.7%) Coughb 113 (25.6%) 166 (37.6%) 175 (39.8%) Mood alteredMood altered 108 (24.5%)108 (24.5%) 106 (24.0%)106 (24.0%) 89 (20.2%)89 (20.2%) DepressionDepression 84 (19.0%)84 (19.0%) 86 (19.5%)86 (19.5%) 93 (21.1%)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.
    65. 65. Direct Viral Enzyme InhibitorsDirect Viral Enzyme Inhibitors—— EEvolving Next Future Therapiesvolving Next Future Therapies Viral Enzyme Inhibitors Protease Polymerase STAT-C Specifically targeted Anti-viral therapy for HCV NS5A Graphic courtesy of Dr. Ira Jacobson.
    66. 66. With permission from Moradpour D, Blum HE. Liver Int. 2004;24:519-525. (1) Virus entry (2) Uncoating (3) Polyprotein processing (4) RNA replication(5) Packing and assembly (6) Virion maturation and release Potential Antiviral Targets
    67. 67. Doses Taken inDoses Taken in Virahep-C StudyVirahep-C Study22 Physicians predicted adherence incorrectly for ~41% of patients1 Association Between Virologic FailureAssociation Between Virologic Failure and Adherence to Antiretroviraland Adherence to Antiretroviral Therapy in Patients with HIVTherapy in Patients with HIV11 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. 21.7 54.6 66.7 71.4 82.1 0 20 40 60 80 100 ≥95 90–<95 80–<90 70–<80 <70 Patients with Virologic Failure (%) 82 64 0 20 40 60 80 100 PEG IFN RBV Patients with >80% Doses Taken (%) Adherence to Antiviral TherapyAdherence to Antiviral Therapy
    68. 68. PROVE 1PROVE 1—T—Telaprevir + PEG IFN/RBVelaprevir + PEG IFN/RBV SVR, Intent-to-Treat Analysis, Phase IISVR, Intent-to-Treat Analysis, Phase II 0 20 40 60 80 100 SVRRate(%) 41 31/75 PR 48 wk (Control) 35 6/17 T 12 wk + PR 12 wk 61 48/79 T 12 wk + PR 24 wk 67 53/79 T 12 wk + PR 48 wk P = .001 P = .020 Abbreviations: P, PEG IFN alfa-2a 180 ug/wk; R, ribavirin 1000–1200 mg/day; T, telaprevir 750 mg q8h. McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838. With permission from Dr. John McHutchison.
    69. 69. PROVE 1PROVE 1—R—Relapse Rateselapse Rates 0 10 20 30 40 50 RelapseRate(%) 23 8/35 33a 3/9 2a 6 3/51 PR 48 wk (Control) T 12 wk + PR 12 wk T 12 wk + PR 24 wk T 12 wk + PR 48 wk a Includes subjects who met the rapid virologic response criterion and stopped at 12 or 24 total weeks of treatment. McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838. Graphic courtesy of Dr. John McHutchison. Denominator = number of subjects with undetectable HCV RNA at completion of assigned treatment duration. 1/41
    70. 70. Can We Dispense with Ribavirin?Can We Dispense with Ribavirin? PROVE 2PROVE 2 13 43 46 69 73 69 80 80 60 50 62 36 0 20 40 60 80 100 Week 4 Week 12 SVR Patients with Virologic Response (%) PR48 control (n = 82) T12PR24 (n = 81) T12PR12 (n = 82) Abbreviations: P, PEG IFN alfa-2a 180 ug/wk; R, ribavirin 1000–1200 mg/day; T, telaprevir 750 mg q8h. Hézode C, et al. N Engl J Med. 2009;360:1839-1850. T12P12 (n = 78)
    71. 71. Wk 72Start Wk 4 Wk 12a Wk 28 Wk 48 Sprint 1—Boceprevir + PEG IFNSprint 1—Boceprevir + PEG IFN αα-2b + RBV-2b + RBV Phase II, Part 1 and 2Phase II, Part 1 and 2 Treatment-NaiveGenotype-1(N=520) a Interim analysis. Abbreviations: B, boceprevir 800 mg TID; P, PEG IFN α-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. NoLead-inControl Follow-upPR Follow-upPR PR + B Follow-upPR PR + B Follow-upPR + B Follow-upPR + B Lead-in Part1 Follow-upPR Follow-upPR-LD R-LD Part2
    72. 72. SPRINT 1SPRINT 1—S—SVR 24 RatesVR 24 Rates PEG IFN -2b + RBVPEG IFN -2b + RBV +/-+/- Boceprevir; Low-Dose RBVBoceprevir; Low-Dose RBV 38 56 75 54 67 0 20 40 60 80 100 SVR(%) PRB Lead-In (n = 103) PRB No Lead-In (n = 103) PRB Lead-In (n = 103) PRB No Lead-In (n = 107) PR Control (n = 104) Tx 28 Weeks Tx 48 Weeks 50 36 PR Control (n = 16) PR-LD (n = 59) Part 2Part 1 a Main adverse effects: Fatigue, headache, nausea, and anemia. Kwo P, et al. J Hepatol. 2009;50:S4.
    73. 73. SPRINT 1SPRINT 1—S—SVR 24 in Those WhoVR 24 in Those Who Achieved RVRAchieved RVR 100 82 94 74 84 0 20 40 60 80 100 SVR(%) PR Control (n = 104) PRB Lead-In (n = 103) PRB No Lead-In (n = 103) PRB Lead-In (n = 103) PRB No Lead-In (n = 107) Tx 28 Weeks Tx 48 Weeks Kwo P, et al. J Hepatol. 2009;50:S4. 32/3862/6632/4354/668/8
    74. 74. SPRINT 1SPRINT 1—V—Virologic Breakthroughirologic Breakthrough 0 4 5 7 12 0 5 10 15 20 PRB Lead-In (n = 103) PRB No Lead-In (n = 103) PRB Lead-In (n = 103) PRB No Lead-In (n = 107) PatientswithBreakthrough(%) PR Control (n = 104) Tx 28 Weeks Tx 48 Weeks Kwo P, et al. J Hepatol. 2009;50:S4.
    75. 75. PROVE 3PROVE 3——Telaprevir + PEG IFN +/- RBV byTelaprevir + PEG IFN +/- RBV by Prior Response and Treatment GroupPrior Response and Treatment Groupaa SVR (%)SVR (%) T12/T12/ PR24PR24 T24/T24/ PR48PR48 T24/T24/ P24P24 PR48PR48 Treatment failuresTreatment failures 5151 5353 2424 1414 McHutchison JG, et al. 60th AASLD. Boston, MA. October 30-November 3, 2009. Abstract 66. a Intent-to-treat analysis.
    76. 76. PROVE 3PROVE 3——Telaprevir + PEG IFN +/- RBV byTelaprevir + PEG IFN +/- RBV by Prior Response and Treatment GroupPrior Response and Treatment Groupaa SVR (%)SVR (%) T12/T12/ PR24PR24 T24/T24/ PR48PR48 T24/T24/ P24P24 PR48PR48 Treatment failuresTreatment failures 5151 5353 2424 1414 PriorPrior nonrespondersnonresponders 3939 3838 1111 99 Prior relapsersPrior relapsers 6969 7676 4242 2020 McHutchison JG, et al. 60th AASLD. Boston, MA. October 30-November 3, 2009. Abstract 66. a Intent-to-treat analysis.
    77. 77. Weight-Based Taribavirin or RBV + PEG IFNWeight-Based Taribavirin or RBV + PEG IFN Phase IIb Study DesignPhase IIb Study Design Wk 72Start Tx Wk 12 Wk 24 Wk 36 Wk 48 Treatment-NaivePatients,Treatment-NaivePatients, Genotype1Genotype1 Poordad F, et al. J Hepatol. 2009;50:S8. Taribavirin 25 mg/kg/d + PEG IFN α-2b µg/kg/wk n = 70 Follow-up Taribavirin 20 mg/kg/d + PEG IFN α-2b 1.5 µg/kg/wk n = 67 Follow-up Taribavirin 30 mg/kg/d + PEG IFN α-2b µg/kg/wk n = 68 Follow-up RBV 800/1000/1200/1400 mg/d + PEG IFN α-2b 1.5µg/kg/wk n = 70 Follow-up
    78. 78. Weight-Based Taribavirin or RBV + PEG IFNWeight-Based Taribavirin or RBV + PEG IFN Virologic Response at Week 4, 12, 48 and SVR12Virologic Response at Week 4, 12, 48 and SVR12aa 16 42 43 28 14 41 30 24 16 25 29 21 11 31 33 21 0 20 40 60 Wk 4 Wk 12 Wk 48 SVR Wk 12 Patients with Undetectable HCV RNA (%) a ITT population. Abbreviation: TBV, taribavirin. Poordad F, et al. J Hepatol. 2009;50:S8. TBV 20 mg/kg + PEG IFN TBV 25 mg/kg + PEG IFN TBV 30 mg/kg + PEG IFN RBV 800–1400 mg + PEG IFN
    79. 79. 9 13 13 7 11 1615 19 28 24 30 33 0 20 40 60 Wk 12 Wk 24 Wk 48 Patients with Hb <10 g/dL (%) Poordad F, et al. J Hepatol. 2009;50:S8. TBV 20 mg/kg + PEG IFN TBV 25 mg/kg + PEG IFN TBV 30 mg/kg + PEG IFN RBV 800–1400 mg + PEG IFN Taribavirin vs RBV + PEG IFNTaribavirin vs RBV + PEG IFN αα-2b-2b Hemoglobin Event RateHemoglobin Event Rate P ≤.05 for TBV 20 mg/kg and TBV 25 mg/kg vs RBV
    80. 80. 40 WkDay 1 Day 4 Day 7 Day 14 Treatment-NaiveGenotype-1INFORM 1—Two Direct Antivirals CombinedINFORM 1—Two Direct Antivirals Combined R7128 + R7227R7128 + R7227aa , Phase 1b, First 4 Cohorts, Phase 1b, First 4 Cohortsbb R7128 500 mg BID R7227 100 mg q8h R7128 500 mg BID R7227 200 mg q8h R7128 1000 mg BID R7227 100 mg q8h R7128 1000 mg BID R7227 200 mg q8h R7128 500 mg BID R7227 100 mg q8h R7128 500 mg BID R7227 100 mg q8h n = active/ placebo 8/0 8/0 8/2 8/4 A B C D 16/2 PEG IFN α-2a + RBV PEG IFN α-2a + RBV PEG IFN + RBV PEG IFN + RBV PEG IFN + RBV PEG IFN + RBV a Also known as ITMN-191. b Study expansion to include treatment failures and null responders. Gane EJ, et al. J Hepatol. 2009;50;S380.
    81. 81. INFORM 1—Preliminary Viral KineticsINFORM 1—Preliminary Viral Kinetics Day 1–14Day 1–14 With permission from Gane EJ, et al. J Hepatol. 2009;50;S380. Placebo R7128 D1–7 R7227 D4–7 R7227 D1–7 R7128 D4–7 R7128 500 mg R7227 100 mg R7128 500 mg R7227 200 mg R7128 1000 mg R7227 100 mg R7128 1000 mg R7227 200 mg HCVRNAChangefromBaseline, Mean(IU/mL)
    82. 82. Regimen (mg) n HCV RNA (IU/mL) BL Change from BL, median (range) Day 14, median (range) <LLOQ, n (%) <LLOD, n (%) R7128 500 R7227 100 8 2.8 x 106 -3.9 (-5.0 to -2.9) 288 (<15 to 588) 1/8 (13%) 1/8 (13%) R7128 500 R7227 200 8 8.3 x 106 -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 106 -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 106 -4.8 (-5.5 to -2.7) 22 (<15 to 660) 5/8 (63%) 2/8 (25%) INFORM 1—Virologic Response at Day 14INFORM 1—Virologic Response at Day 14 Abbreviations: BL, baseline; LLOD, lower limit of detection (<15 IU/mL, Roche Taqman); LLOQ, lower limit of quantification (<40 IU/mL, Roche Taqman). With permission from Gane EJ, et al. J Hepatol. 2009;50;S380.
    83. 83. Resistance to HCV Direct AntiviralsResistance to HCV Direct Antivirals What We Know So FarWhat We Know So Far  Detection depends on how carefully you look for itDetection depends on how carefully you look for it  Occurs rapidly with monotherapyOccurs rapidly with monotherapy  Partially abrogated by addition of peginterferonPartially abrogated by addition of peginterferon  Effect of ribavirin importantEffect of ribavirin important  Reversion to the wild type partially occursReversion to the wild type partially occurs 33––7 months after cessation of therapy7 months after cessation of therapy  Cross-resistance will probably occur forCross-resistance will probably occur for each targeteach target
    84. 84. Resistance to HCV Direct AntiviralsResistance to HCV Direct Antivirals What We DonWhat We Don’t’t Know So FarKnow So Far  Magnitude of the effect of adherenceMagnitude of the effect of adherence  Long-term clinical effects of development ofLong-term clinical effects of development of resistant variantsresistant variants  Effect of combination directly acting antiviralEffect of combination directly acting antiviral agentsagents  How much PEG IFN and RBV is needed?How much PEG IFN and RBV is needed?  How long is PEG IFN and RBV needed?How long is PEG IFN and RBV needed?
    85. 85. Long-Term Consequences ofLong-Term Consequences of ResistanceResistance “Fitness” Disease progression rates Evolutionary disadvantage Retreatment outcomes Prevention strategies Class effects Graphic courtesy of Dr. John McHutchison.
    86. 86. Adherence Adequate PK/PD Value of Lead-in Dose and populations Combination therapy Length of therapy Foreseeable, Unavoidable, PreventableForeseeable, Unavoidable, Preventable Abbreviation: PK/PD, pharmacokinetics/pharmacodynamics. Graphic courtesy of Dr. John McHutchison. Limiting or Curtailing ResistanceLimiting or Curtailing Resistance
    87. 87. Cardiotoxicity Rash Liver test abnormalities DC rates x 2-4 fold Neutropenia Lymphopenia Anemia Abbreviation: DC, discontinuation. Graphic courtesy of Dr. John McHutchison. More Drugs = More ToxicityMore Drugs = More Toxicity
    88. 88. Simplicity/ complexity Tolerability Efficacy ResistanceDurationCost Graphic courtesy of Dr. John McHutchison. Key Drivers of Successful TherapyKey Drivers of Successful Therapy
    89. 89. IFN RBVRBV IFNIFN RBVRBV HCVHCV inhibitorinhibitor HCVHCV inhibitorinhibitor HCVHCV inhibitorinhibitor HCVHCV inhibitorinhibitor RBVRBV ?? Future Anti-HCV Therapy IFN?IFN? Graphic courtesy of Dr. Nezam Afdhal.
    90. 90. ConclusionsConclusions  Multidrug therapy is on the horizon, butMultidrug therapy is on the horizon, but – Don’t slip on efficacyDon’t slip on efficacy – Cure, don’t suppressCure, don’t suppress – Limit and prevent resistanceLimit and prevent resistance  Significant knowledge gaps remain in specialSignificant knowledge gaps remain in special populations—HIV, posttransplantpopulations—HIV, posttransplant  Integrating new treatment into patient careIntegrating new treatment into patient care strategies will require expertise andstrategies will require expertise and teamworkteamwork
    91. 91. Concluding RemarksConcluding Remarks Ira M. Jacobson, MDIra M. Jacobson, MD Vincent Astor Professor of MedicineVincent Astor Professor of Medicine Chief, Division of Gastroenterology and HepatologyChief, Division of Gastroenterology and Hepatology Medical Director of the Center for the StudyMedical Director of the Center for the Study of Hepatitis Cof Hepatitis C Weill Cornell Medical CollegeWeill Cornell Medical College New York, New YorkNew York, New York
    92. 92. Phases in the Evolution of Anti-HCVPhases in the Evolution of Anti-HCV TherapyTherapy The Empiric Phase The Phase of Specifically Targeted Antiviral Therapy for HCV (STAT-C) Weisberg IW, et al. Current Hepatitis Reports. 2007;6:75-82. Graphic courtesy of Dr. Ira Jacobson. The Final Phase— Small Molecule Combinations ??? • Optimal dosing • Viral kinetics • Challenging populations • Nonresponders The Refinement Phase  Less focus on which PEG IFNLess focus on which PEG IFN  Response-guided therapy – principle clear but variable penetranceResponse-guided therapy – principle clear but variable penetrance  Limited choices for nonresponders – huge unmet needLimited choices for nonresponders – huge unmet need  Other populations with unmet needs aboundOther populations with unmet needs abound
    93. 93. A Polymorphism on Chromosome 19A Polymorphism on Chromosome 19 Predicts SVRPredicts SVR 60Mb Chromosome 19 Polymorphism rs12979860 IL28B gene 3kb 19q13.13 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.
    94. 94. TheThe IL28BIL28B Single NucleotideSingle Nucleotide PolymorphismPolymorphism A Major Discovery Leads to Many New QuestionsA Major Discovery Leads to Many New Questions  What insights does this give into theWhat insights does this give into the mechanism of IFN responsiveness?mechanism of IFN responsiveness? – Relationship to upregulation of IFN-specificRelationship to upregulation of IFN-specific genes in nonresponders?genes in nonresponders? – Why connected to spontaneous clearanceWhy connected to spontaneous clearance as well?as well?  Role in clinical practice (assumingRole in clinical practice (assuming availability)?availability)?  Role as new treatments become available?Role as new treatments become available?
    95. 95. Emerging Anti-HCV TherapiesEmerging Anti-HCV Therapies Genome Sequence-Based RNA interference Enzyme Inhibitors Protease Polymerase Other IFN and RBV modifications • Albinterferon, omega IFN, PEG IFN lambda (IL-29) • Taribavirin (viramidine) Immune approaches • Therapeutic vaccines • Toll-like receptor agonists • Hepatitis C immune globulin • Monoclonal antibodies Targeting cellular factors • Cyclophilin antagonists • Nitazoxanide Specifically Targeted Antiviral Therapy for HCV (STAT-C) NS5A
    96. 96. A Glimpse of the Near FutureA Glimpse of the Near Future  First wave of new agents likely available in nextFirst wave of new agents likely available in next 2 years2 years  First-generation protease inhibitors being studiedFirst-generation protease inhibitors being studied as TID drugs in phase IIIas TID drugs in phase III  Second-generation protease inhibitors – lessSecond-generation protease inhibitors – less frequent dosingfrequent dosing  Potential for ritonavir boosting to enable dailyPotential for ritonavir boosting to enable daily dosingdosing  Polymerase inhibitors look promising inPolymerase inhibitors look promising in combination with PEG IFN and RBVcombination with PEG IFN and RBV  Resistance will be a key themeResistance will be a key theme
    97. 97. Anti-HCV TherapyAnti-HCV Therapy Likely Picture—Near FutureLikely Picture—Near Future Viral enzyme inhibitors Immune or host pathway modulators RBV or related drugs+ ± Interferon as a platform for future combinations Need to study different IFNs to determine optimal characteristics Graphic courtesy of Dr. Ira Jacobson.
    98. 98. A B C Prevention of emergent resistance (pre-existing or de novo) + +A Profound suppression of broad range of viral variants, including pre-existing  Different drugs may contribute variably to each of these goalsDifferent drugs may contribute variably to each of these goals  Not all components have to be STAT-C agentsNot all components have to be STAT-C agents Graphic courtesy of Dr. Ira Jacobson. The Goal of Combination RegimensThe Goal of Combination Regimens
    99. 99. Current SOC (2009) PEG IFN + RBV + STAT-C(1) PEG IFN + RBV + STAT-C(2) PEG IFN + RBV + STAT-C(1+2) STAT-C (1+2+…) Can We Leapfrog Ahead? Graphic courtesy of Dr. Ira Jacobson.
    100. 100. Treating HCV in the Next 5 YearsTreating HCV in the Next 5 Years  Cure moreCure more patientspatients  Shorter durationShorter duration of therapyof therapy  Increased toxicityIncreased toxicity  IncreasedIncreased complexitycomplexity  Increased costsIncreased costs  Mandate to preventMandate to prevent resistanceresistance ↑ Opportunities ↑ Challenges
    101. 101. Electronic health records Electronic health records Resistance mutations Resistance mutationsNew interferonsNew interferons Cost, Toxicities & Compliance Cost, Toxicities & Compliance STAT-C AgentsSTAT-C Agents Genetic predictorsGenetic predictors Response Guided Therapy Response Guided Therapy NPs, PAsNPs, PAs Novel combinationsNovel combinations E-prescribingE-prescribing IncreasingIncreasing ComplexityComplexity of HCVof HCV ManagementManagement
    1. A particular slide catching your eye?

      Clipping is a handy way to collect important slides you want to go back to later.

    ×