Jacobson

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Social Media

• The use of web-based technology to facilitate
  interaction with others.

3
ARS QuestionWith the exception of e-mail, how
often do you interact with peers online through
social networking sites like Facebook Twitter?

• Always
• Very Often
• Sometimes
• Rarely
• Never

4
ARS Question How likely are you to use social
media to help increase public awareness of
chronic hepatitis C?

• Very likely
• Likely
• Maybe
• Probably not
• Never

5
ARS Question In patients who present with non
liver related complaints, how often do you
evaluate a patients risk factors for chronic
hepatitis C infection?

• Always
• Very Often
• Sometimes
• Rarely
• Never

6
ARS Question Among all your genotype 1
patients who are eligible for current therapy,
how often are you withholding therapy while
waiting for novel drugs?

• Always
• Very Often
• Sometimes
• Rarely
• Never

7
ARS Question Among your genotype 1 patients,
how frequently will you be incorporating novel
agents once they are approved?

• Always
• Very Often
• Sometimes
• Rarely
• Never

8
How Will Social Media Impact Your Practice?

• Bryan S. Vartabedian, MD, FAAPAssistant
  Professor of Pediatrics
• Section of Gastroenterology, Hepatology, 
  Nutrition
• Baylor College of Medicine
• Houston, Texas

9
How Health Information Was Shared
MD
Patient
Graphic courtesy of Dr. Bryan Vartabedian.
10
Evolution of Social Health
Graphic courtesy of Dr. Bryan Vartabedian.
11
4 Individuals email lists
3 Closed networks MySpace, Facebook
2 Open networks blogs, feeds, YouTube
1 Mainstream media press, influencers
Armano D. Influence ripples. Available at
http//darmano.typepad.com. Accessed on April
13, 2010.
12
You dont need to go any further doctor. Just
spell eosinophil if you would.
13
CureTogether
Available at http//www.curetogether.com.
Accessed on April 13, 2010.
14
CureTogether

• Patient to patient
• Crowdsourced data
• Clinical trials

Available at http//www.curetogether.com/Irritabl
e-Bowel-Syndrome/treatments/. Accessed on April
13, 2010.
15
Participatory Medicine

• User-generated healthcare is shifting the balance
  of power from doctor to patient
• The physician encounter is evolving as a narrow,
  more defined element in a patients quest to
  understand whats wrong with them

16
What Is Social Media?

• Content created by people using scalable online
  publishing technologies intended to facilitate
  communication and interaction
• Most often refers to activities that integrate
  technology, telecommunications, and social
  interaction, with the construction of words,
  pictures, videos, and audio

17
With permission from Solis B, et al. The
conversation prism. Available at
http//www.theconversationprism.com. Accessed
on April 13, 2010.
18
Percentage of Adults Who Look Online for Health
Information
61
Fox S. The social life of health information.
January 14, 2009. Pew Internet American Life
Project. Available at http//pewinternet.org//m
edia//Files/Reports/2009/PIP_Health_2009.pdf.
Accessed on April 13, 2010.
19
The Social Media RevolutionHow Is Its Use in
Adults Growing?
2005
2009
Lenhart A. Adult and Social Network Websites.
January 14, 2009. Pew Internet American Life
Project. Available at http//pewinternet.org/Rep
orts/2009/Adults-and-Social-Network-Websites.aspx.
Accessed onApril 13, 2010.
20
US Hospitals on YouTube and Twitter
With permission from Bennett E. Hospital social
network data and charts. Available at
http//ebennett.org/hsnl/data/. Accessed on
April 13, 2010.
21
Where Are the Doctors? The Absence of MDs in
Social Media Space

• Late adopters
• Time/impatience
• Concerns over privacy, liability, and image

22
What Can You Do on Social Networks?

• Educate patients
• Influence behavior
• Promote awareness of yourself or your hospital
• Build relationships
• Filter information

23
Armano D. Human feed. Available at
http//darmano.typepad.com. Accessed on April
13, 2010.
24
Do Physicians Have an Obligation To Be in the
Online Space?
60,000
Number of Pediatricians in the AAP
KevinMD.com. Available at http//www.kevinmd.com/
blog/2009/08/delayed-vaccine-schedule-dangerous.ht
ml. Accessed on April 13, 2010.
25
DDWs 4 Sponsoring Societies
Abbreviations AASLD, American Society for the
Study of Liver Diseases AGA, American
Gastroenterological Association ASGE, American
Society for Gastrointestinal Endoscopy DDW,
Digestive Disease Week SSAT, The Society for
Surgery of the Alimentary Tract. DDW 2010. FAQs.
Available at http//www.ddw.org/wmspage.cfm?parm1
710. Accessed on April 13, 2010.
26
How Should Physicians Handle Patient Encounters
in the Social Media Space?
They Shouldnt
27
Staying Safe on Social Networks

• Never discuss patients
• Patients, boss, future employer will read
  everything you write
• Be nice
• Dont be anonymous

28
Put a stake in the ground
Graphic courtesy of Dr. Bryan Vartabedian.
29
Graphic courtesy of Dr. Bryan Vartabedian.
30
Visibility in Action
Left graphic Kaplan Publishing. Spring 2009
Catalog. Available at http//www.kaptest.com/pdf_
files/publishing/seasonal-catalogs/KPSpring09Catal
og.pdf. Accessed on April 13, 2010. Upper right
graphic Courtesy of Dr. Bryan Vartabedian. 33
Charts blog. Available at http//www.33charts.com
. Lower graphic Courtesy of Dr. Bryan
Vartabedian. Personal Correspondence. 2010.
31
Armano D. Conversion. Available at
http//darmano.typepad.com. Accessed on April
13, 2010.
32
The Low Rates of Chronic HCV Diagnosis and
Treatment Why and What Can We Do?

• Hashem B. El-Serag, MD, MPH
• Professor of MedicineChief, Section of
  Gastroenterology and HepatologyBaylor College of
  Medicine Michael E. DeBakey VA Medical
  CenterHouston, Texas

33
Past and Future US Incidenceand Prevalence of
HCV Infection
Decline among IDUs
Overall incidence
Overall prevalence
Infected 20 years
Armstrong GL, et al. Hepatology. 200031777-782.
Graphic courtesy of the CDC.
34
Histologic Fibrosis Stage by Year
Number of Persons
Year
Davis GL, Alter MJ, El-Serag H, Poynard T,
Jennings L . Gastroenterology 2010
35
Slide Not Available
36
Hepatitis CAge-Adjusted Rates of Ambulatory Care
Visits and Hospital Discharges with All-Listed
Diagnoses in the United States, 19792004
Data from National Ambulatory Medical Care Survey
(NAMCS) and National Hospital Ambulatory Medical
Care Survey (NHAMCS) (averages 1992-1993,
1994-1996, 1997-1999, 2000-2002, 2003-2005), and
National Hospital Discharge Survey (NHDS).
Everhart JE, ed. The burden of digestive
diseases in the United States. 2008. NIDDK US
Government Printing Office, 2008 NIH Publication
No. 09-6443.
37
Efficacy of Peginterferon Ribavirin in
Achieving Sustained Virologic Response (SVR)
1. Manns M, et al. Lancet. 2001358958-965. 2.
Fried M, et al. N Engl J Med. 2002347975-982.
3. Kamal SM, et al. Hepatology.
2007461732-1740. 4. Khuroo MS, et al. Aliment
Pharmacol Ther. 200420931-938. 5. Conjeevaram
H, et al. Gastroenterology. 2006131470-477.
38
HCV Patients Most Likely to Achieve SVR
39
Treatment of HCV
Efficacy in clinical trials and research centers
El-Serag HB. Gastroenterology. 20071328-10.
40
Efficacy and EffectivenessA Demonstration of the
Multiplicative Effect of Factors
Example 1 Rx X
Example 2 Rx Y
Example 3 Rx X Modified
El-Serag HB. Gastroenterology. 20071328-10.
41
Awareness of HCV Infection Among HCV-Infected
Persons
Colvin HM, Mitchell AE, eds. Hepatitis and liver
cancer a national strategy for prevention and
control of hepatitis B and C. Institute of
Medicine. Washington, DC The National Academies
Press, 2009.
42
Predictors of Treatment
Patient factors
Provider factors
Receipt of Treatment
Facility factors
Graphic courtesy of Dr. Hashem El-Serag.
43
Eligibility and Acceptability of HCV Treatment

• 4084 HCV patients in VA Multicenter Study
  12/9912/00
• Eligibility 32 by standard criteria, 41 by
  treating physician
• Predictors of noneligibility
• Ongoing substance abuse OR 17.68
• Comorbid medical disease OR 9.62
• Psychiatric disease OR 9.45
• Advanced liver disease OR 8.43
• Acceptability 76 of eligible patients
• Reasons for nonacceptance
• Defer Rx until better therapies 50
• Concerns regarding side effects 22
• Treatment completion rates
• 50 of those treated (8 of all patients)

Bini E, et al. Am J Gastroenterol.
20051001772-1779.
44
Treatment Outcomes Retrospective Observational
Cohort
N 5944
48-week treatment for genotype 1, 24-week
treatment for genotype 2/3. Backus LI, et al.
Hepatology. 20074637-47.
45
Antiviral Therapy for HCV per Year Actual,
20022007Projected, Through 2014
Volk ML, et al. Hepatology. 2009501750-1755.
46
Underutilization and Disparity
Clinical appropriateness and patient preferences
Healthcare system access, legal, and regulatory
issues
Under- utilization and Disparity
Percent
Discrimination, bias, uncertainty
Graphic courtesy of Dr. Hashem El-Serag.
47
Reasons for Lack of Treatment Among Respondents
to the NHANES Hepatitis C Follow-Up Questionnaire
N 133
Abbreviation NHANES, National Health and
Nutrition Evaluation Survey.Volk ML, et al.
Hepatology. 2009501750-1755.
48
Summary

• HCV prevalence peaked in 2001 at 3.6 million
  persons
• Number and proportion of HCV patients with
  cirrhosis, decompensation, and HCC will increase
  for at least another 1015 years
• Age of persons with complications will rise
• Will antiviral therapy change the future?
• Eradication of HCV stops progression, eliminates
  the risk of liver failure, and reduces HCC risk
• Requires therapeutic intervention before onset of
  advanced fibrosis
• Requires identification of infected cases

49
Summary

• Clinical effectiveness is dependent on several
  factors in addition to clinical efficacy
• HCV diagnosis
• Referral to specialists
• Treatment of comorbidities
• Adherence to treatment

50
Institute of Medicine Report Underlying Factors

• Lack of knowledge and awareness about chronic
  viral hepatitis among

Healthcare and social service providers
At-risk populations
Policy makers and the public

• Insufficient understanding about the extent and
  seriousness of this public health problem

Colvin HM, Mitchell AE, eds. Hepatitis and liver
cancer a national strategy for prevention and
control of hepatitis B and C. Institute of
Medicine. Washington, DC The National Academies
Press, 2009.
51
Institute of Medicine Report Consequences
Colvin HM, Mitchell AE, eds. Hepatitis and liver
cancer a national strategy for prevention and
control of hepatitis B and C. Institute of
Medicine. Washington, DC The National Academies
Press, 2009.
52
Institute of Medicine Report Recommendations
Colvin HM, Mitchell AE, eds. Hepatitis and liver
cancer a national strategy for prevention and
control of hepatitis B and C. Institute of
Medicine. Washington, DC The National Academies
Press, 2009.
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ARS Question How likely are you to use social
media to help increase public awareness of
chronic hepatitis C?

• Very likely
• Likely
• Maybe
• Probably not
• Never

56
ARS Question In patients who present with non
liver related complaints, how often do you
evaluate a patients risk factors for chronic
hepatitis C infection?

• Always
• Very Often
• Sometimes
• Rarely
• Never

57
Optimization of Interferon-Based Therapies in
Current HCV PatientsCan We Do Better?

• Donald M. Jensen, MD
• Professor of MedicineDirector, Center for Liver
  DiseasesUniversity of Chicago Medical Center
• Chicago, Illinois

58
Why Do Current Drugs Fail?

• Viral factors1
• Viral protein products as inhibitors of innate
  immunity
• Viral proteins as inhibitors of adaptive
  responses
• Host factors
• Fixed race, genetics, age, gender
• Modifiable body mass index, insulin resistance,
  steatosis1
• Treatment factors
• Dose, duration, adherence, tolerability

1. Tai AW, et al. J Hepatol. 200950412-420.
59
Baseline Predictors

• Host genetic makeup
• IL28B polymorphism1
• Allele on chromosome 19, rs12979860
• Resides 3 kilobases upstream from the IL28B gene
  encoding IFN-gamma-3
• Strongly associated with rate of sustained
  virologic response
• Other racial and genetic factors
• Viral factors
• Genotype
• Viral load

1. Ge D, et al. Nature. 2009461399-401.
60
Importance of IL28B Polymorphisms

• C/C genotype is more common in racial groups with
  a higher sustained virologic response (SVR)
• C/C genotype is associated with a higher SVR
  compared with T/C or T/T
• IL28B polymorphisms may partially explain racial
  differences in antiviral response and may be a
  useful pretherapy tool

Ge D, et al. Nature. 2009461399-401.
61
C Allele is Associated with SVRPercentage SVR by
Genotype of rs12979860
n 186
Combined
n 70
T/T
African Americans
n 14
n 102
Hispanics
European Americans
n 559
n 91
T/C
N 1,137
n 35
n 433
n 392
n 30
C/C
n 26
P 1.37 x 10-28 vs T/T
n 336
0
20
40
60
80
100
SVR
Ge D, et al. Nature. 2009461399-401.
62
IL28B Genetic Variation and Genotype 1 Response
European Americans (n 271)
East Asians (n 107)
Hispanics (n 16)
rs12979860 C-allele Frequency
African Americans (n 61)
SVR ()
Ge D, et al. Nature. 2009461399-401.
63
Treatment of Chronic HCVGenotype 1 Response Rate
10
9
SVR
8
1
2
Stopping Rules
7
25
6
Log HCV RNA (IU/mL)
Null
5
29
2743
4
Partial
3
6872
pEVR
cEVR
2
RVR 20
1
8891
51
0
-6
0
4
8
12
16
20
24
28
32
36
40
44
48
72
Weeks
Detection limit (50 IU/mL)
Abbreviations EVR, early virologic response
cEVR, complete EVR pEVR, partial EVR RVR, rapid
virologic response.
1. Jensen DM, et al. Hepatology. 200643954-960.
2. Ghany MG, et al. Hepatology.
2009491335-1374. 3. Fried MW, et al. N Engl J
Med. 2002347975-982. 4. Manns MP, et al.
Lancet. 2001358958-965. 5. Davis GL, et al.
Hepatology. 200338645-652. Graphic courtesy of
Dr. Donald Jensen.
64
Improving Current Therapy2 Goals

• Increase SVR rate
• Decrease risk of hepatocellular carcinoma
  (HCC)1,2
• Decrease risk of decompensation3,4
• Improve fibrosis/reversal of cirrhosis4
• Improve quality of life5
• Improve adherence and tolerability
• Shorten treatment duration if RVR
• Minimize treatment-related adverse events

1. Craxi A, et al. Clin Liver Dis.
20059329-346. 2. Shiratori Y, et al. Ann Intern
Med. 2005142105-114. 3. Shiratori Y, et al.
Ann Intern Med. 2000132517-524. 4. Poynard T,
et al. Gastroenterology. 20021221303-1313. 5.
Foster GR, et al. J Viral Hepat. 200916605-611.
65
GoalIncrease SVR Rate

• Current options
• Increase interferon and/or ribavirin dose
• Increase adherence
• Increase treatment duration
• Is there evidence that these work?

66
Induction Dosing of Interferon
Induction IFN dosing leads to a greater number of
early responders. However, standard dosing
catches up after induction ends.
There is no overall SVR benefit to induction
dosing
Weeks
Abbreviations CR, conventional HR, high-dose
induction. 1. Upper right graphic with permission
from Kim TH, et al. Intervirology.
200548230-238. Lower left graphic courtesy of
Dr. Donald M. Jensen.
67
Evidence for Increased RBV Dosing
PEG IFN ?-2b/RBV Registration Trial1All genotypes
WIN-R Trial2Genotype 1
Weight-baseda
Flat-dosingb
aP .569 bP .019. 1. Manns MP, et al.
Lancet. 2001358958-965. 2. Jacobson IM, et al.
Hepatology. 200746971-981.
68
Importance of RBV Adherence
Effect of RBV Exposure on Relapse Rate1

• Adherence messages
• Maintain RBV dose gt60 over entire treatment1,2
• Use 200 mg dose reduction steps1,2
• For anemia, use erythropoiesis-stimulating agents
  sparingly (black box warning)3-5

1. Reddy KR, et al. J Hepatol. 200950402-411.
2. Reau N, et al. Am J Gastroenterol.
20081031981-1988. 3. Sulkowski MS, et al. J
Viral Hepat. 200411243-250. 4. Afdhal NH, et
al. Gastroenterology. 20041261302-1311. 5. US
FDA. News release. March 9, 2007.
69
Extending Duration Genotype 1 with Early
Virologic Response
12
48
72
4
0
Week
Relapse
SVR
All patient analysis
Berg1 G1 only RBV 800 mg
48 weeks
53
54
72 weeks
29
21
HCV RNA pos at week 12 neg at week 24
P .04
Berg1 G1 only RBV 800 mg
64
48 weeks
40
29
72 weeks
17
P .03
P .004
HCV RNA pos at week 12 neg at week 24
Pearlman2 G1 RBV 800/ 1400 mg
59
48 weeks
38
20
72 weeks
18
1. Berg T, et al. Gastroenterology.
20061301086-1097. 2. Pearlman BL, et al.
Hepatology. 2007461688-1694. Graphic courtesy
of Dr. Donald M. Jensen.
70
Can We Shorten Therapy Based on an RVR to
Improve Adherence and Minimize Side Effects?
71
Utilizing RVR to Shorten Therapy in Genotype 1

• For genotype 1, retrospective and prospective
  data suggest 24 weeks of therapy may be adequate
  when RVR is achieved (particularly those with low
  baseline HCV RNA)1-6

1. Zeuzem S, et al. J Hepatol. 20064497-103. 2.
Graphic with permission from Jensen DM, et al.
Hepatology. 200643954-960. 3. Ferenci P, et al.
Gastroenterology. 2008135451-458. 4. Yu ML, et
al. Hepatology. 2008471884-1893. 5. Zeuzem S,
et al. J Viral Hepat. 20091675-90. 6. Nelson
DR, et al. Clin Gastroenterol Hepatol.
20097397-414.
72
Utilizing RVR to Shorten Therapy in Genotypes 2
and 3

• For genotype 2 or 3, conflicting clinical trials
  data, but largest study to date suggests
  shortening therapy may lead to greater relapse
  rates1-7

1. Shiffman ML, et al. N Engl J Med.
2007357124-134. 2. von Wagner M, et al.
Gastroenterology. 2005129522-527. 3. Mangia A,
et al. N Engl J Med. 20053522609-2617. 4.
Lagging M, et al. Hepatology. 2008471837-1845.
5. Dalgard O, et al. Hepatology. 20084735-42.
6. Andriulli A, et al. Dig Liver Dis.
200638741-748. 7. Nelson DR, et al. Clin
Gastroenterol Hepatol. 20097397-414.
73
Response-Guided TherapyA New Paradigm?

• Individualized treatment based on viral kinetic
  measurements should.
• Improve overall cost-benefit
• Improve tolerability for those with RVR
• Decrease relapse rate

74
Nonresponders
75
PEG IFN/RBV Nonresponder Clinical Trials
Abbreviation cIFN, consensus interferon.
1. Poynard T, et al. Gastroenterology.
20091361618-1628. 2. Jensen DM, et al. Ann
Intern Med. 2009150528-540. 3. Bacon BR, et al.
Hepatology. 2009491838-1846.
76
Maintenance Therapy
77
Maintenance PEG IFN in Nonresponders3 Randomized
Controlled Trials
1. Di Bisceglie AM, et al. Hepatology.
200746LB1. 2. Shiffman ML, et al. J Hepatol.
200848S62. 3. Afdhal NH, et al. J Hepatol.
200848S4. 4. Bruix J, et al. J Hepatol.
200950(suppl 1)S22.
78
Treat Now or Wait Until STAT-C?
Treat Now
May Consider Waiting

• Advanced fibrosis
• Symptomatic
• Genotype 2, 3, or 4
• IL28B C/C genotype (?)

• Genotype 1 with mild histology
• PEG IFN/RBV prior nonresponders
• IL28B T/T or T/C genotype

Interferon and ribavirin will be required in
combination with all new STAT-C agents for
several years
79
Conclusions

• Response-guided therapy is important theme now
  for optimizing existing interferon/ribavirin-based
  therapies
• Improvements in current standard of care can be
  demonstrated by
• Identifying likely responder populations
• Shortening treatment duration in patients with
  RVR and poor tolerability
• Extending treatment duration in patients with
  slow partial response

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81
ARS Question Among all your genotype 1
patients who are eligible for current therapy,
how often are you withholding therapy while
waiting for novel drugs?

• Always
• Very Often
• Sometimes
• Rarely
• Never

82
How Will STAT-C Therapies Affect Future Anti-HCV
Treatment Paradigms?

• 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 Medical College of Cornell University
• New York, New York

83
Phases in the Evolution of Anti-HCV Therapy
Weisberg IW, et al. Current Hepatitis Reports.
2007675-82. Graphic courtesy of Dr. Ira
Jacobson.
84
Emerging Anti-HCV Therapies
Specifically Targeted Antiviral Therapy for HCV
(STAT-C)
Enzyme Inhibitors
Genome Sequence-Based
Other

• IFN and RBV modifications
• Albinterferon
• PEG IFN lambda (IL-29)
• Other IFN formulations
• Taribavirin (viramidine)

• Immune approaches
• Therapeutic vaccines
• Toll-like receptor agonists
• Hepatitis C immune globulin
• Monoclonal antibodies

• Targeting cellular factors
• Cyclophilin antagonists
• Nitazoxanide
• mIR-122 inhibitors
• Entry inhibitors

Abbreviations HCV, hepatitis C virus IFN,
interferon PEG IFN, peginterferon RBV,
ribavirin.Graphic courtesy of Dr. Ira Jacobson.
85
Hepatitis C Virus Life Cycle
With permission from Tellinghuisen TL, et al. J
Virol. 2007818853-8867.
86
HCV Genome
With permission from Tellinghuisen TL, et al. J
Virol. 2007818853-8867.
87
Targets for Anti-HCV Drugs in Beyond Phase I
Clinical Trials
Polymerase inhibitors
NS5Ainhibitors
Protease inhibitors
Not all-inclusive
88
Early Data with Telaprevir Potency, Resistance,
and Interaction with IFN
Sequence Analysis
1
Baseline
0
PEG IFN ?-2a Placebo n 4
-1
HCV RNA Change from Baseline (Log10 IU/mL)
-2

• More resistant variants emerged with TVR
  monotherapy
• Patients went on to receive 24 wk PEG IFN RBV
• Resistant variants were suppressed by PEG IFN
  RBV

-3
Telaprevir n 8
-4
-5
Telaprevir PEG IFN ?-2a n 8
-6
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Study Time (days)
Abbreviations PEG IFN, peginterferon RBV,
ribavirin TVR, telaprevir. With permission from
Kieffer TL, et al. Hepatology. 200746631-639.
89
PROVE1Telaprevir Phase IIb Study DesignUS,
Genotype 1, Treatment-Naive
PR48 (control)(n 75)
T12/PR12(n 17)
T12/PR24(n 79)
T12/PR48(n 79)
Abbreviations R, ribavirin 10001200 mg/d P,
peginterferon ?-2a 180 µg/wk T, telaprevir 1250
on day 1 then 750 mg q8h.
McHutchison J, et al. N Engl J Med.
20093601827-1838.
90
PROVE 1Telaprevir PEG IFN/RBVSVR,
Intent-to-Treat Analysis, Phase II
100
80
67
61
SVR Rate ()
60
P .02
P .002
41
35
40
20
31/75
6/17
48/79
53/79
n
0
PR 48 wk(Control)
T 12 wk PR 12 wk
T 12 wk PR 24 wk
T 12 wk PR 48 wk
Graphic Courtesy of Dr. John McHutchison.
McHutchison JG, et al. N Engl J Med.
20093601827-1838.
91
PROVE 1Relapse Rates
50
40
33
30
Relapse Rate ()
23
TVR drives high rates of RVR and low rates of
relapse
20
10
6
2
n
8/35
3/9
3/51
1/41
0
PR 48 wk(Control)
T 12 wk PR 12 wk
T 12 wk PR 24 wk
T 12 wk PR 48 wk
a
a
Denominator number of subjects with
undetectable HCV RNA at completion of assigned
treatment duration. aIncludes subjects who met
the RVR criterion and stopped at 12 or 24 total
weeks of treatment. Graphic Courtesy of Dr. John
McHutchison. McHutchison JG, et al. N Engl J
Med. 20093601827-1838.
92
PROVE 1Viral Breakthrough by Week 12

• 12/175 (7) of telaprevir-treated patients had
  breakthrough
• 9/12 occurred in first 4 weeks
• 3/12 occurred between weeks 5 and 12
• Only 2 breakthroughs occurred in subjects after
  HCV RNA became undetectable
• Telaprevir-resistant viral variants
• V36M and R155K (10 patients with genotype 1a)
• A156T (1 patient with genotype 1b)
• Wild type (1 patient who missed several days)

McHutchison JG, et al. N Engl J Med.
20093601827-1838.
93
PROVE1Safety Data
Other TVR-related AEs anemia, GI effects
Abbreviations AE, adverse event D/C,
discontinuation GI, gastrointestinal TVR,
telaprevir.
McHutchison JG, et al. N Engl J Med.
20093601827-1838. Graphic courtesy of Dr. Ira
Jacobson.
94
PROVE2SVR European, Genotype 1, Treatment-Naive
n
38/82
49/82
56/81
28/78
c
a
b
aP .004 vs control bP .12 vs control cP
.003 vs control. Abbreviations P, peginterferon
?-2a 180 µg/wk R, ribavirin 10001200 mg/d T,
telaprevir 1250 mg on day 1 then 750 mg q8h.
Hezode C, et al. N Engl J Med. 20093601839-1850.
Graphic courtesy of Dr. Ira Jacobson.
95
C208 StudyTelaprevir q8h vs q12h and PEG
IFN alfa-2a vs 2b RBV (N 161)Response-Guided
Therapy
Abbreviations P, peginterferon R, ribavirin T,
telapravir. Forns X, et al. Journal of
Hepatology. 201052(suppl 1)S26. Graphic
courtesy of Dr. Ira Jacobson.
96
PROVE3Study DesignPrior Treatment Failures
T12/P24(n 115)
T24/PR48(n 113)
T24/P24(n 111)
PR48(n 114)
Patients who failed previous treatment with at
least 1 adequate course of PEG IFN combination
with RBV defined as at least 12 weeks of
therapy. Abbreviations R, ribavirin 10001200
mg/d P, peginterferon ?-2a 180 µg/wk T,
telaprevir 1125 mg day 1 then 750 mg
q8h.McHutchison JG, et al. N Engl J Med.
20103621292-1303.
97
PROVE3SVR by Prior Response and Treatment Group
(ITT)

• SVR durable at 1 year
• Equivalent efficacy in cirrhotics

100
90
76
80
69
70
60
SVR ()
50
39
38
40
30
20
20
11
9
a
a
b
10
a
a
b
n
0
Prior Relapsers
Prior Nonresponders
aP lt.001 bP .02, all vs PR48 control
group.Graphic Courtesy of Dr. John McHutchison.
McHutchison JG, et al. N Engl J Med.
20103621292-1303.
98
Rollover Study (107) in Treatment Failures From
Control Arms of PROVE 1/2/3
T12/PR24
T12/PR48
Berg T, et al. 45th EASLApril 14-18, 2010.
Abstract 108.
99
Sprint 1Boceprevir PEG IFN ?-2b RBV
International, Phase II, Treatment-Naive, Geno 1
Control
Part 1
Lead-in
No Lead-in
R-LD
Part 2b
aInterim analysis bPart 2 consisted of 75
patients in 10 US sites, 14 randomization.
Abbreviations B, boceprevir 800 mg TID P, PEG
IFN ?-2b 1.5 µg/kg/wk R, ribavirin 8001400
mg/d R-LD, low-dose ribavirin 4001000
mg/d.Kwo P, et al. J Hepatol. 200950S4.
100
SPRINT 1SVR 24 Rates
100
Part 1
80
75
67
60
56
54
SVR ()
38
40
20
0
a
b
c
c
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
aP 0.005 bP 0.013 cP lt.0001, compared with
PR Control. Kwo P, et al. J Hepatol. 200950S4.
101
Relapse and Breakthrough in SPRINT 1Reduction
with Lead-in
40
PR48
PRB28
30
PR4-PRB24
30
PRB48
24
24
PR4-PRB44
Percent
20
12
10
7
7
5
4
3
0
0
Breakthrough
Relapse
Kwo P, et al. J Hepatol. 200950S4. Graphic
courtesy of Dr. Ira Jacobson.
102
SPRINT 1SVR 24 in Those Who Achieved RVR
100
94
100
84
82
74
80
60
SVR ()
40
20
32/38
62/66
32/43
54/66
8/8
0
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. 200950S4. Graphic
courtesy of Dr. Paul Kwo.
103
SPRINT 1Null Responders to PEG/RBV Can Have SVR
with a Protease Inhibitor
PR4/PRB24
PR4/PRB44
b
a
Log10 Viral Load Decrease After 4-Wk PR Lead-in
a1 patient who was positive at wk 24 became
undetectable at wk 30 onwards b2 patients were
missing PCR at wk 24, but later had undetectable
PCR.
Kwo PY, et al. Hepatology. 200950(4 Suppl)331A.
104
HCV RNA PolymeraseNucleosides and Non-Nucleoside
Inhibition
With permission from Bressanelli S, et al. J
Virol. 2002763482-3492.
105
NS5B Polymerase Inhibitor OverviewEfficacy

• Many agents with antiviral activity, increased
  with PEG IFN RBV
• Nucleosides appear active across genotypes
• Some non-nucleosides have potency gradient across
  genotypes and even G1 subtypes

106
NS5B Polymerase Inhibitor Overview Efficacy

• Phase II trials
• Nucleos(t)ide polymerase inhibitors (RG7128 PEG
  FN alfa RBV)
• RVR in 85 with RG7128 SOC vs 10 with SOC
  alone1
• Nonnucleos(t)ide polymerase inhibitors
  (filibuvir, ANA598, GS 9190, ABT-333) PEG IFN
  alfa RBV
• Higher rates of RVR (4075) vs SOC2,3

1. Lalezari J, et al. J Hepatol. 200848S29. 2.
Jacobson I, et al. J Hepatol. 200948S382-S383. 3
. Rodriguez-Torres M, et al. Hepatology.
200950(4 suppl)LB6.
107
NS5B Polymerase Inhibitor OverviewResistance and
Adverse Effects

• Differences in genetic barrier to resistance
  class nucleosides have high barrier
• Resistance can be minimized by combining withPEG
  IFN RBV
• Different resistance mutation patterns suggest
  potential for combinations of polymerase
  inhibitors
• Toxicity issues with earlier agents GI effects,
  hepatotoxicity, hematologic toxicity, and visual
  disturbance

1. Shi ST, et al. Antimicrob Agents Chemother.
200852675-683. 2. Lawitz E, et al. J Hepatol.
200950(suppl 1)S37. 3. Nelson D, et al. J
Hepatol. 200848S371. 4. McCown MF, et al.
Antimicrob Agents Chemother. 2008521604-1612.
5. Lalezari J, et al. J Hepatol. 200848S29. 6.
Bavisotto L, et al. Hepatology. 200746 (suppl
1)255A. 7. Cooper C, et al. Hepatology.
200746(suppl 1)LB11.
108
Highlights from EASL 2010Protease Inhibitors

• Good activity for telaprevir against genotype 21
• 3.7-log decline with 2 weeks of telaprevir
  monotherapy

• Ritonavir boosting lowers dose needed for RG7227,
  a protease inhibitor2

• Development of a protease inhibitor (MK-5172)
  with in vitro activity against resistant variants
  R155K, A156T, D168V3

• Excellent activity of a protease inhibitor (BI
  201335) in nonresponders to PEG IFN RBV with
  low breakthrough rates4
• RVR 6269 with 240 mg QD or BID, with or
  without 3-day lead-in
• Viral rebound at 12 weeks 1622

1. Foster GR, et al. 45th EASLApril 14-18, 2010.
Abstract 206. 2. Gane E, et al. 45th EASLApril
14-18, 2010. Abstract 144. 3. Carroll S, et al.
45th EASLApril 14-18, 2010. Abstract 128. 4.
Sulkowski M, et al. 45th EASLApril 14-18, 2010.
Abstract 298.
109
Highlights from EASL 2010NS5B and NS5A Inhibitors

• SVR data for a nucleoside (RG7128) in genotypes
  2,31
• 13/20 (65) prior treatment failures had SVR

• Robust nonnucleoside with high barrier to
  resistance(VX-222)2
• gt3-log decline in HCV RNA with 3 days of dosing

• Promise for NS5A inhibitors4
• Up to 92 RVR with BMS-790052 in dose ranging
  study with Peg IFN RBV

1. Gane EJ, et al. 45th EASLApril 14-18, 2010.
Abstract 143. 2. Rodriguez-Torres M, et al. 45th
EASLApril 14-18, 2010. Abstract 137. 3. Jacobson
I, et al. 45th EASLApril 14-18, 2010. Abstract
5. 4. Pol S, et al. 45th EASLApril 14-18, 2010.
Abstract 297.
110
Highlights from EASL 2010NonSTAT-C Drugs

• Intravenous silibin for partial responders1

• Potential role for immune stimulation (GI5005,
  TLR-9 agonist)2,3

• Increased SVR with vitamin D (86 vs 41, n 27)4

• Nitazoxanide in nonresponders (SVR 7)5

• Cyclophilin Inhibitor Debio 025 can induce SVR
  Peg IFN after a four week course (four patients)

1. Biermer M, et al. 45th EASLApril 14-18, 2010.
Abstract 142. 2. Jacobson I, et al. 45th
EASLApril 14-18, 2010. Abstract 6. 3. Muir A, et
al. 45th EASLApril 14-18, 2010. Abstract 138. 4.
Mouch SA, et al. 45th EASLApril 14-18, 2010.
Abstract 204. 5. Shiffman ML, et al. 45th
EASLApril 14-18, 2010. Abstract 296.
111
INFORM-1 StudyMedian Change from Baseline
Cohorts BG
Abbreviation TF, treatment failure. With
permission from Gane EJ, et al. Hepatology.
200950(4 suppl)394A-395A.
112
The Goal of IFN-Free Combination Regimens


A

• 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.
113
New Anti-HCV TherapiesAnticipated Developments

• Approval of telaprevir/boceprevir seems likely in
  2011
• Other direct antivirals and compounds with novel
  mechanisms of action in development
• Response-guided therapy
• Incorporation of genetic testing
• Accelerated development of interferon-free
  combinations
• The question for clinicians to wait or not to
  wait?

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117
ARS Question Among your genotype 1 patients,
how frequently will you be incorporating novel
agents once they are approved?

• Always
• Very Often
• Sometimes
• Rarely
• Never