Transcript Jacobson - Projects In Knowledge

Social Media
“The use of web-based
technology to facilitate
interaction with others.”
ARS Question:
With the exception of e-mail, how often do
you interact with peers online through social
networking sites like Facebook & Twitter?
1)
Always
2)
Very Often
3)
Sometimes
4)
Rarely
5)
Never
ARS Question:
How likely are you to use social
media to help increase public
awareness of chronic hepatitis C?
1)
Very likely
2)
Likely
3)
Maybe
4)
Probably not
5)
Never
ARS Question:
In patients who present with non liver
related complaints, how often do you
evaluate a patient’s risk factors for
chronic hepatitis C infection?
1)
Always
2)
Very Often
3)
Sometimes
4)
Rarely
5)
Never
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?
1)
Always
2)
Very Often
3)
Sometimes
4)
Rarely
5)
Never
ARS Question:
Among your genotype 1 patients, how
frequently will you be incorporating novel
agents once they are approved?
1)
Always
2)
Very Often
3)
Sometimes
4)
Rarely
5)
Never
How Will Social Media
Impact Your Practice?
Bryan S. Vartabedian, MD, FAAP
Assistant Professor of Pediatrics
Section of Gastroenterology, Hepatology, & Nutrition
Baylor College of Medicine
Houston, Texas
How Health Information Was Shared
MD
Patient
Graphic courtesy of Dr. Bryan Vartabedian.
Evolution of Social Health
Now
Patients find each other
2000s
Information finds patients
1990s
Patients find information
Long ago
Patients depend on what they’re told
Graphic courtesy of Dr. Bryan Vartabedian.
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.
“You don’t need to go any
further doctor. Just spell
‘eosinophil’ if you would.”
CureTogether
Available at: http://www.curetogether.com. Accessed on: April 13, 2010.
CureTogether
• Patient to patient
• Crowdsourced data
• “Clinical trials”
Available at: http://www.curetogether.com/Irritable-Bowel-Syndrome/treatments/.
Accessed on: April 13, 2010.
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
patient’s quest to understand what’s
wrong with them
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
With permission from Solis B, et al. The conversation prism. Available at: http://www.theconversationprism.com.
Accessed on: April 13, 2010.
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/~/media//Files/Reports/2009/PIP_Health_2009.pdf. Accessed on:
April 13, 2010.
The Social Media Revolution
How 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/Reports/2009/Adults-and-Social-Network-Websites.aspx. Accessed on:
April 13, 2010.
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.
Where Are the Doctors?
The Absence of MDs in Social Media Space
• Late adopters
• Time/impatience
• Concerns over privacy, liability, and image
What Can You Do on
Social Networks?
• Educate patients
• Influence behavior
• Promote awareness of yourself or
your hospital
• Build relationships
• Filter information
Armano D. Human feed. Available at: http://darmano.typepad.com. Accessed on: April 13, 2010.
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-scheduledangerous.html. Accessed on: April 13, 2010.
DDW’s 4 Sponsoring Societies
16,000
3000
Number of Members
in the AGA
Number of Members
in the AASLD
10,000
2500
Number of Members
in the ASGE
Number of Members
in the SSAT
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.
How Should Physicians Handle
Patient Encounters in the
Social Media Space?
They Shouldn’t
Staying Safe on Social Networks
• Never discuss patients
• Patients, boss, future employer
will read everything you write
• Be nice
• Don’t be anonymous
Blog
Put a stake in the ground
Graphic courtesy of Dr. Bryan Vartabedian.
Blog
Graphic courtesy of Dr. Bryan Vartabedian.
Visibility in Action
Left graphic: Kaplan Publishing. Spring 2009 Catalog. Available at: http://www.kaptest.com/pdf_files/publishing/seasonalcatalogs/KPSpring09Catalog.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.
Armano D. Conversion. Available at: http://darmano.typepad.com. Accessed on: April 13, 2010.
The Low Rates of Chronic HCV
Diagnosis and Treatment:
Why and What Can We Do?
Hashem B. El-Serag, MD, MPH
Professor of Medicine
Chief, Section of Gastroenterology and Hepatology
Baylor College of Medicine
Michael E. DeBakey VA Medical Center
Houston, Texas
Past and Future US Incidence
and Prevalence of HCV Infection
Decline among IDUs
Overall incidence
Overall prevalence
Infected 20+ years
Armstrong GL, et al. Hepatology. 2000;31:777-782. Graphic courtesy of the CDC.
Number of Persons
Histologic Fibrosis Stage by Year
Year
Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings L . Gastroenterology 2010
Slide Not
Available
Hepatitis C—Age-Adjusted Rates of Ambulatory Care
Visits and Hospital Discharges with All-Listed
Diagnoses in the United States, 1979–2004
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.
Efficacy of Peginterferon + Ribavirin in
Achieving Sustained Virologic Response (SVR)
Category
SVR (%)
Overall
54–561,2
Genotype 1
42–461,2
Genotype 2/3
76–821,2
Genotype 4
58–772–4
African American
Cirrhosis
285
43–441,2
1. Manns M, et al. Lancet. 2001;358:958-965. 2. Fried M, et al. N Engl J Med. 2002;347:975-982.
3. Kamal SM, et al. Hepatology. 2007;46:1732-1740. 4. Khuroo MS, et al. Aliment Pharmacol Ther.
2004;20:931-938. 5. Conjeevaram H, et al. Gastroenterology. 2006;131:470-477.
HCV Patients Most Likely to Achieve SVR
Virus Factors
Treatment Factors
Genotype 2/3
Tolerability
Low viral load
Adherence
Rapid virologic response
Provider experience
Supportive medical team
Host Factors
IL28B gene polymorphism
Not African American
Immunocompetent
Lean, non-diabetic, insulin sensitive
Young, good renal function, minimal
comorbid illness
Treatment of HCV
Efficacy in
clinical trials and
research centers
Effectiveness in
community
practice
Efficacy x Access x
Correct Diagnosis x
Recommendation x
Acceptance x Adherence
El-Serag HB. Gastroenterology. 2007;132:8-10.
Efficacy and Effectiveness
A Demonstration of the Multiplicative
Effect of Factors
Example 1:
Rx “X”
Efficacy of Rx
“X”
Example 2:
Rx “Y”
60%
Efficacy of Rx
“Y”
80%
Example 3:
Rx “X” Modified
Efficacy of Rx
“X”
60%
Access
x 80%
Access
x 80%
Access
x 90%
Correct
diagnosis
x 85%
Correct
diagnosis
x 85%
Correct
diagnosis
x 90%
Recommend
x 85%
Recommend
x 85%
Recommend
x 90%
Acceptance
x 85%
Acceptance
x 85%
Acceptance
x 90%
Adherence
x 70%
Adherence
x 70%
Adherence
x 80%
Effectiveness
of Rx “X”
= 21%
Effectiveness
of Rx “Y”
= 28%
Effectiveness
of Rx “X”
modified
= 32%
El-Serag HB. Gastroenterology. 2007;132:8-10.
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.
Predictors of Treatment
Provider
factors
Patient
factors
Demographics
Genotype, viral load
Cirrhosis diagnosis
ALT, Hct, Plt, WBC, Cr
Comorbidity
HIV diagnosis
Insurance
Receipt of
Treatment
Facility
factors
Graphic courtesy of Dr. Hashem El-Serag.
Provider specialty
HCV experience
Continuity
Eligibility and Acceptability of
HCV Treatment
•
4084 HCV+ patients in VA Multicenter Study 12/99–12/00
•
Eligibility – 32% by standard criteria, 41% by treating physician
–
Predictors of noneligibility




•
OR 17.68
OR 9.62
OR 9.45
OR 8.43
Acceptability – 76% of eligible patients
–
Reasons for nonacceptance


•
Ongoing substance abuse
Comorbid medical disease
Psychiatric disease
Advanced liver disease
Defer Rx until better therapies
Concerns regarding side effects
50%
22%
Treatment completion rates
–
~50% of those treated (~8% of all patients)
Bini E, et al. Am J Gastroenterol. 2005;100:1772-1779.
Treatment Outcomes
Retrospective Observational Cohort
Completed treatment
N = 5944
Achieved SVR
48-week treatment for genotype 1, 24-week treatment for genotype 2/3.
Backus LI, et al. Hepatology. 2007;46:37-47.
Antiviral Therapy for HCV per Year
Actual, 2002–2007
Projected, Through 2014
Actual
Projected
Volk ML, et al. Hepatology. 2009;50:1750-1755.
Underutilization and Disparity
Percent
Clinical appropriateness
and patient preferences
Graphic courtesy of Dr. Hashem El-Serag.
Healthcare system:
access, legal, and
regulatory issues
Discrimination, bias,
uncertainty
Underutilization
and
Disparity
Reasons for Lack of Treatment Among
Respondents to the NHANES Hepatitis C
Follow-Up Questionnaire
Survey Responses
N = 133
Refused treatment
Did not f/u with clinician
Received treatment
Clinician did not recommend treatment
Unaware of diagnosis
Abbreviation: NHANES, National Health and Nutrition Evaluation Survey.
Volk ML, et al. Hepatology. 2009;50:1750-1755.
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 10–15 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
Summary
•
Clinical effectiveness is dependent on
several factors in addition to clinical efficacy
– HCV diagnosis
– Referral to specialists
– Treatment of comorbidities
– Adherence to treatment
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.
Institute of Medicine Report
Consequences
Inadequate
surveillance systems
underreport acute and
chronic infections
At-risk people do not
know they are at risk
or how to avoid being
infected
At-risk people may
not have access to
preventive services
People with chronic
HCV infection do not
know they are
infected
Many clinicians do not
know how to screen
people for risk factors or
manage those who are
infected
HCV-infected people
often have inadequate
access to testing, social
support, and medical
management services
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.
Institute of Medicine Report
Recommendations
Surveillance
The CDC should:
Evaluate national
HCV public health
surveillance system
Develop agreements
with state health
departments to
support core HCV
surveillance
Support targeted
surveillance
Knowledge &
Awareness
The CDC should work
with key stakeholders
to:
Develop HCV
educational programs
for providers
Develop and
evaluate innovative
and effective outreach
programs to 1) target
at-risk populations,
and 2) increase public
awareness
Viral Hepatitis
Services
Federally funded
health insurance
programs (eg,
Medicare) should:
Incorporate
guidelines for riskfactor screening as
required component of
preventive care
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.
ARS Question:
How likely are you to use social
media to help increase public
awareness of chronic hepatitis C?
1)
Very likely
2)
Likely
3)
Maybe
4)
Probably not
5)
Never
ARS Question:
In patients who present with non liver
related complaints, how often do you
evaluate a patient’s risk factors for
chronic hepatitis C infection?
1)
Always
2)
Very Often
3)
Sometimes
4)
Rarely
5)
Never
Optimization of InterferonBased Therapies in
Current HCV Patients–
Can We Do Better?
Donald M. Jensen, MD
Professor of Medicine
Director, Center for Liver Diseases
University of Chicago Medical Center
Chicago, Illinois
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. 2009;50:412-420.
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. 2009;461:399-401.
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. 2009;461:399-401.
C Allele is Associated with SVR
Percentage SVR by Genotype of rs12979860
T/T
n = 186
n = 70
n = 14
n = 102
T/C
n = 559
n = 91
n = 35
n = 433
C/C
n = 392
n = 30
n = 26
n = 336
0
Combined
African Americans
Hispanics
European Americans
N = 1,137
P = 1.37 x 10-28 vs T/T
20
40
60
SVR
Ge D, et al. Nature. 2009;461:399-401.
80
100
rs12979860 C-allele Frequency
IL28B Genetic Variation and
Genotype 1 Response
European Americans
(n = 271)
Hispanics
(n = 16)
African Americans
(n = 61)
SVR (%)
Ge D, et al. Nature. 2009;461:399-401.
East Asians
(n = 107)
Treatment of Chronic HCV
Log HCV RNA (IU/mL)
Genotype 1 Response Rate
10
9
SVR
PEG IFN + RBV THERAPY
8
1
7
2
Stopping
Rules
6
2%–5%
Null
5
~29%
4
27%–43%
Partial
3
2
cEVR
RVR
~20%
1
0
-6
0
4
8
51%
12 16
pEVR
68%–72%
88%–91%
20
24
Weeks
28
32
36
40
44
48
72
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. 2006;43:954-960. 2. Ghany MG, et al. Hepatology. 2009;49:1335-1374. 3. Fried MW, et al.
N Engl J Med. 2002;347:975-982. 4. Manns MP, et al. Lancet. 2001;358:958-965. 5. Davis GL, et al. Hepatology.
2003;38:645-652. Graphic courtesy of Dr. Donald Jensen.
Improving Current Therapy
2 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. 2005;9:329-346. 2. Shiratori Y, et al. Ann Intern Med. 2005;142:105-114.
3. Shiratori Y, et al. Ann Intern Med. 2000;132:517-524. 4. Poynard T, et al. Gastroenterology.
2002;122:1303-1313. 5. Foster GR, et al. J Viral Hepat. 2009;16:605-611.
Goal—Increase SVR Rate
Current options
• Increase interferon and/or ribavirin dose
• Increase adherence
• Increase treatment duration
Is there evidence that these work?
Induction Dosing of Interferon
HCV RNA neg (%)
Induction IFN dosing
leads to a greater
number of early
responders.
However, standard
dosing catches up after
induction ends.
Proportions of Patients with Undetectable
HCV RNA After Starting Combination Therapy1
Induction IFN
Std IFN
0
12
There is no overall
SVR benefit to
induction dosing
24
36
48
Weeks
Abbreviations: CR, conventional; HR, high-dose induction. 1. Upper right graphic with permission from Kim
TH, et al. Intervirology. 2005;48:230-238. Lower left graphic courtesy of Dr. Donald M. Jensen.
Evidence for Increased RBV Dosing
PEG IFN -2b/RBV Registration Trial1
All genotypes
100
WIN-R Trial2
Genotype 1
80
60
P = .015
Weight-baseda
Flat-dosingb
40
20
0
5
9
13
17
21
RBV Dose (mg/kg)
aP
= .569; bP = .019.
1. Manns MP, et al. Lancet. 2001;358:958-965. 2. Jacobson IM, et al. Hepatology. 2007;46:971-981.
Importance of RBV Adherence
Effect of RBV Exposure on Relapse Rate1
Relapse Rate (%)
80
Adherence messages
Cumulative Ribavirin
Dose
70
>97% (n = 37)
80%–97% (n = 14)
60%–80% (n = 18)
0%–60% (n = 13)
60
50
40
30
20
• Maintain RBV dose
>60% over entire
treatment1,2
• Use 200 mg dose
reduction steps1,2
• For anemia, use
erythropoiesisstimulating agents
sparingly (black box
warning)3-5
10
19
22 32 54
0
1. Reddy KR, et al. J Hepatol. 2009;50:402-411. 2. Reau N, et al. Am J Gastroenterol. 2008;103:19811988. 3. Sulkowski MS, et al. J Viral Hepat. 2004;11:243-250. 4. Afdhal NH, et al. Gastroenterology.
2004;126:1302-1311. 5. US FDA. News release. March 9, 2007.
Extending Duration
Genotype 1 with Early Virologic Response
Week
0 4
12
48
72
SVR
Relapse
All patient analysis
Berg1
G1 only
RBV 800 mg
Berg1
G1 only
RBV 800 mg
48 weeks
72 weeks
HCV RNA pos at week 12; neg at week 24
48 weeks
72 weeks
Pearlman2 HCV RNA pos at week 12; neg at week 24
G1
48 weeks
RBV 800/
72 weeks
1400 mg
53
54
29
21
64
40
P = .04
17
29
P = .03
18
38
1. Berg T, et al. Gastroenterology. 2006;130:1086-1097. 2. Pearlman BL, et al. Hepatology.
2007;46:1688-1694. Graphic courtesy of Dr. Donald M. Jensen.
P = .004
59
20
Can We Shorten Therapy
Based on an RVR
to Improve Adherence and
Minimize Side Effects?
Utilizing RVR to Shorten Therapy in
Genotype 1
PEG IFN -2a/RBV2
24 wk + RBV 800
100
91
89 88
24 wk + RBV 1000/1200
48 wk + RBV 800
80
73
SVR (%)
48 wk + RBV 1000/1200
60
44
40
35
23
20
0
16
n = 18
33
40
56
Patients with
an RVR at wk 4
81
84
208 210
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
Patients without
an RVR at wk 4
1. Zeuzem S, et al. J Hepatol. 2006;44:97-103. 2. Graphic with permission from Jensen DM, et al.
Hepatology. 2006;43:954-960. 3. Ferenci P, et al. Gastroenterology. 2008;135:451-458. 4. Yu ML, et al.
Hepatology. 2008;47:1884-1893. 5. Zeuzem S, et al. J Viral Hepat. 2009;16:75-90. 6. Nelson DR, et al.
Clin Gastroenterol Hepatol. 2009;7:397-414.
Utilizing RVR to Shorten Therapy in
Genotypes 2 and 3
Accelerate Trial1
SVR Rates in Patients with RVR
P = .02
SVR (%)
100
80
79
78
80
Any genotype
Genotype 2
Genotype 3
85 85 85
60
40
20
For genotype 2 or 3,
conflicting clinical
trials data, but largest
study to date suggests
shortening therapy
may lead to greater
relapse rates1-7
0
16-wk Regimen
24-wk Regimen
1. Shiffman ML, et al. N Engl J Med. 2007;357:124-134. 2. von Wagner M, et al. Gastroenterology.
2005;129:522-527. 3. Mangia A, et al. N Engl J Med. 2005;352:2609-2617. 4. Lagging M, et al.
Hepatology. 2008;47:1837-1845. 5. Dalgard O, et al. Hepatology. 2008;47:35-42. 6. Andriulli A, et al.
Dig Liver Dis. 2006;38:741-748. 7. Nelson DR, et al. Clin Gastroenterol Hepatol. 2009;7:397-414.
Response-Guided Therapy
A New Paradigm?
Individualized treatment based on viral
kinetic measurements should….
• Improve overall cost-benefit
• Improve tolerability for those with RVR
• Decrease relapse rate
Nonresponders
PEG IFN/RBV Nonresponder
Clinical Trials
EPIC31
476
NRs
PEG IFN -2b 1.5 mcg/kg + RBV
800–1400 mg/d x 48 wk
SVR:
6% overall
4% geno-1
REPEAT2
942
Geno-1 NRs
PEG IFN -2a 180 or 360/180 g/wk + SVR:
RBV 1000–1200 mg/d x 48 or 72 wk
7%–16%
DIRECT3
659
Geno-1 NRs
cIFN 9 or 15 g/d + RBV 1000–1200
x 48 weeks
SVR:
7%–11%
Abbreviation: cIFN, consensus interferon.
1. Poynard T, et al. Gastroenterology. 2009;136:1618-1628. 2. Jensen DM, et al. Ann Intern Med.
2009;150:528-540. 3. Bacon BR, et al. Hepatology. 2009;49:1838-1846.
Maintenance Therapy
Maintenance PEG IFN in Nonresponders
3 Randomized Controlled Trials
HALT-C
COPILOT
Bruix, et al
No difference
in clinical
outcomes1
Subjects with
In primary
baseline
analysis,
portal
maintenance
hypertension
was not
had reduced
superior to
Subgroup
outcomes
observational
with >4-log
(variceal
control in
reduction in
bleeding)
preventing
HCV RNA had with PEG IFN3 occurrence of
reduced
clinical
2
outcomes
events4
1. Di Bisceglie AM, et al. Hepatology. 2007;46:LB1. 2. Shiffman ML, et al. J Hepatol. 2008;48:S62.
3. Afdhal NH, et al. J Hepatol. 2008;48:S4. 4. Bruix J, et al. J Hepatol. 2009;50(suppl 1):S22.
Treat Now or Wait Until STAT-C?
Treat Now
•
Advanced fibrosis
•
Symptomatic
•
Genotype 2, 3, or 4
•
IL28B C/C genotype (?)
May Consider Waiting
•
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
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
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?
1)
Always
2)
Very Often
3)
Sometimes
4)
Rarely
5)
Never
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
Phases in the Evolution
of Anti-HCV Therapy
The
Empiric
Phase
The
Refinement
Phase
• Optimal dosing
• Viral kinetics
• Challenging
populations
• Nonresponders
The Phase
of
Specifically
Targeted
Antiviral
Therapy
for HCV
(STAT-C)
The
Final
Phase:
Small
Molecule
Combinations
???
Weisberg IW, et al. Current Hepatitis Reports. 2007;6:75-82. Graphic courtesy of Dr. Ira Jacobson.
Emerging Anti-HCV Therapies
Specifically Targeted Antiviral Therapy for HCV
(STAT-C)
Enzyme
Inhibitors
Protease
Polymerase
Genome
Sequence-Based
RNA
Interference
Antisense
NS5A
Abbreviations: HCV, hepatitis C virus; IFN, interferon; PEG IFN,
peginterferon; RBV, ribavirin.
Graphic courtesy of Dr. Ira Jacobson.
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
Hepatitis C Virus Life Cycle
With permission from Tellinghuisen TL, et al. J Virol. 2007;81:8853-8867.
HCV Genome
With permission from Tellinghuisen TL, et al. J Virol. 2007;81:8853-8867.
Targets for Anti-HCV Drugs in
Beyond Phase I Clinical Trials
5–
Core
E1
E2
P
7
NS2
NS3
Protease inhibitors
Cyclophilin
Antagonists
Debio 025
SCY-635
Not all-inclusive
Telaprevir
Boceprevir
RG7227
TMC 435350
MK7009
BI-201335
BMS-650032
ABT-450
NS4A
NS4B
NS5A
NS5A
inhibitors
NS5B
–3
Polymerase
inhibitors
BMS-790052
Active site
(nucleosides)
RG7128
IDX184
PSI-7851
Nonnucleosides
GS 9190
Filibuvir
ABT-333
ABT-072
ANA598
VX-222
HCV RNA Change from Baseline
(Log10 IU/mL)
Early Data with Telaprevir
Potency, Resistance, and Interaction with IFN
1
Sequence
Analysis
0
Baseline
PEG IFN -2a +
Placebo n = 4
-1
-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
-4
Telaprevir n = 8
-5
-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. 2007;46:631-639.
Telaprevir +
PEG IFN -2a
n=8
PROVE1—Telaprevir Phase IIb Study Design
US, Genotype 1, Treatment-Naive
Weeks
0
PR48
(control)
(n = 75)
12
24
Placebo +
P+R
48
P+R
T12/PR12
T+P+R
(n = 17)
60
72
Follow-up
Follow-up
T12/PR24
T+P+R
(n = 79)
P+R
Follow-up
T12/PR48
T+P+R
(n = 79)
Weeks 0
36
P+R
12
24
Follow-up
36
48
60
72
Abbreviations: R, ribavirin 1000–1200 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. 2009;360:1827-1838.
PROVE 1—Telaprevir + PEG IFN/RBV
SVR, Intent-to-Treat Analysis, Phase II
SVR Rate (%)
100
80
61
67
60
41
40
P = .02
P = .002
35
20
0
n=
31/75
6/17
48/79
53/79
PR 48 wk
(Control)
T 12 wk +
PR 12 wk
T 12 wk +
PR 24 wk
T 12 wk +
PR 48 wk
Graphic Courtesy of Dr. John McHutchison. McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.
PROVE 1—Relapse Rates
Relapse Rate (%)
50
40
33
30
23
TVR drives high rates of RVR
and low rates of relapse
20
10
0
6
n=
2
8/35
PR 48 wk
(Control)
3/9
T 12 wk +
a
PR 12 wk
1/41
3/51
T 12 wk +
a
PR 24 wk
T 12 wk +
PR 48 wk
Denominator = number of subjects with undetectable HCV RNA at completion of assigned treatment duration.
aIncludes subjects who met the 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. 2009;360:1827-1838.
PROVE 1—Viral 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. 2009;360:1827-1838.
PROVE1—Safety 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. 2009;360:1827-1838. Graphic courtesy of Dr. Ira Jacobson.
PROVE2—SVR
European, Genotype 1, Treatment-Naive
Higher relapse rate
with 12 vs 24 weeks
Impaired response,
more breakthrough
and more relapse
w/out RBV
n = 38/82
49/82
56/81
a
28/78
b
c
= .004 vs control; bP = .12 vs control; cP = .003 vs control. Abbreviations: P, peginterferon -2a 180
µg/wk; R, ribavirin 1000–1200 mg/d; T, telaprevir 1250 mg on day 1 then 750 mg q8h.
Hezode C, et al. N Engl J Med. 2009;360:1839-1850. Graphic courtesy of Dr. Ira Jacobson.
aP
C208 Study—Telaprevir q8h vs q12h and
PEG IFN alfa-2a vs 2b + RBV (N = 161)
Response-Guided Therapy
T 1125 mg q12h +
P -2a 180 µg/wk +
R 1000–1200 mg/d
T 1125 mg q12h +
P -2b 1.5 µg/kg/wk +
R 800–1200 mg/d
T 750 mg q8h +
P -2a 180 µg/wk +
R 1000–1200 mg/d
T 750 mg q8h +
P -2b 1.5 µg/kg/wk +
R 800–1200 mg/d
Abbreviations: P, peginterferon; R, ribavirin; T, telapravir.
Forns X, et al. Journal of Hepatology. 2010;52(suppl 1):S26. Graphic courtesy of Dr. Ira Jacobson.
PROVE3—Study Design
Prior Treatment Failures
Weeks
0
12
T12/P24
T+P+R
(n = 115)
24
P+R
36
T+P+R
P+R
T24/P24
(n = 111)
T+P
Follow-up
PR48
(n = 114)
Placebo + P + R
P+R
12
60
72
Follow-up
T24/PR48
(n = 113)
Weeks 0
48
24
36
Follow-up
Follow-up
48
60
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 1000–1200 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. 2010;362:1292-1303.
72
PROVE3—SVR by Prior Response and
Treatment Group (ITT)
100
90
T12/PR24
T24/PR48
• SVR durable at 1 year
• Equivalent efficacy in cirrhotics
76
80
SVR (%)
T24/P24 (no RBV)
PR48
69
70
60
50
40
39
42
38
30
20
20
10
0
11
a
n = 26/66
a
24/64
9
b
7/62
6/68
Prior Nonresponders
aP
a
29/42
a
31/41
b
16/38
8/41
Prior Relapsers
<.001; bP = .02, all vs PR48 control group.
Graphic Courtesy of Dr. John McHutchison. McHutchison JG, et al. N Engl J Med. 2010;362:1292-1303.
Rollover Study (107) in Treatment Failures
From Control Arms of PROVE 1/2/3
T12/PR24
T12/PR48
49/8118/34
4/24 15/27
15/25 0/3
Berg T, et al. 45th EASL;April 14-18, 2010. Abstract 108.
24/25 3/3
6/7
0/1
Sprint 1—Boceprevir + PEG IFN -2b + RBV
International, Phase II, Treatment-Naive, Geno 1
P + R (n = 104)
Part 1
Control
Lead-in
PR
P + R + B (n = 103)
PR
Part 2b
No
Lead-in
aInterim
Follow-up
P + R + B (n = 103)
P + R + B (n = 107)
R-LD
Weeks 0
Follow-up
4
12a
Follow-up
Follow-up
P + R + B (n = 103)
Follow-up
P + R (n = 16)
Follow-up
P + R-LD (n = 59)
Follow-up
28
36
48
60
analysis; bPart 2 consisted of 75 patients in 10 US sites, 1:4 randomization.
Abbreviations: B, boceprevir 800 mg TID; P, PEG IFN -2b 1.5 µg/kg/wk; R, ribavirin 800–1400 mg/d;
R-LD, low-dose ribavirin 400–1000 mg/d.
Kwo P, et al. J Hepatol. 2009;50:S4.
72
SPRINT 1—SVR 24 Rates
100
Part 1
Part 2
80
75
SVR (%)
67
60
40
56
54
50
38
36
20
0
PR
Control
(n = 104)
PRB a
PRBb
PRB c
PRBc
Lead-In No Lead-In Lead-In No Lead-In
(n = 103) (n = 107) (n = 103) (n = 103)
Tx 28 Weeks
aP
= 0.005; bP = 0.013; cP <.0001, compared with PR Control.
Kwo P, et al. J Hepatol. 2009;50:S4.
PR
Control
(n = 16)
Tx 48 Weeks
PR-LD
(n = 59)
Relapse and Breakthrough in SPRINT 1
Reduction with Lead-in
40
30
30
Percent
PR48
PRB28
PR4-PRB24
PRB48
PR4-PRB44
24
24
20
12
10
7
4
0
7
5
3
0
Breakthrough
Relapse
Kwo P, et al. J Hepatol. 2009;50:S4. Graphic courtesy of Dr. Ira Jacobson.
SPRINT 1—SVR 24 in Those Who
Achieved RVR
100
100
94
84
82
74
SVR (%)
80
60
40
20
0
8/8
PR
Control
(n = 104)
54/66
32/43
PRB
PRB
Lead-In No Lead-In
(n = 103) (n = 107)
Tx 28 Weeks
Kwo P, et al. J Hepatol. 2009;50:S4.
Graphic courtesy of Dr. Paul Kwo.
62/66
32/38
PRB
PRB
Lead-In No Lead-In
(n = 103) (n = 103)
Tx 48 Weeks
SPRINT 1—Null Responders to PEG/RBV
Can Have SVR with a Protease Inhibitor
PR4/PRB24
PR4/PRB44
a
2/7
5/21
4/9
<0.5
3/10
8/11
8/13
11/17
8/10
0.5–<1.0
1.0–<1.5
1.5–<2.0
b
14/21
10/12
11/14
14/17
2.0–<3.0
3.0–<4.0
11/11
11/12
≥4.0
Log10 Viral Load Decrease After 4-Wk PR Lead-in
a1
3/3
9/9
Undetectable
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. 2009;50(4 Suppl):331A.
HCV RNA Polymerase
Nucleosides and Non-Nucleoside Inhibition
Allosteric
GTP-binding sites
Thumb
Fingers
NNI
Thumb
inhibitors
Catalytic site
Nucleoside
analogs
NNI
Palm
With permission from Bressanelli S, et al. J Virol. 2002;76:3482-3492.
NS5B Polymerase Inhibitor Overview
Efficacy



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
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 (40%–75%) vs SOC2,3
1. Lalezari J, et al. J Hepatol. 2008;48:S29. 2. Jacobson I, et al. J Hepatol. 2009;48:S382-S383.
3. Rodriguez-Torres M, et al. Hepatology. 2009;50(4 suppl):LB6.
NS5B Polymerase Inhibitor Overview
Resistance and Adverse Effects
•
Differences in genetic barrier to resistance class:
nucleosides have high barrier
•
Resistance can be minimized by combining with
PEG 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. 2008;52:675-683. 2. Lawitz E, et al. J Hepatol. 2009;50(suppl 1):S37.
3. Nelson D, et al. J Hepatol. 2008;48:S371. 4. McCown MF, et al. Antimicrob Agents Chemother. 2008;52:1604-1612.
5. Lalezari J, et al. J Hepatol. 2008;48:S29. 6. Bavisotto L, et al. Hepatology. 2007;46 (suppl 1):255A. 7. Cooper C, et al.
Hepatology. 2007;46(suppl 1):LB11.
Highlights from EASL 2010
Protease 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 62%–69% with 240 mg QD or BID, with or without 3-day
lead-in
– Viral rebound at 12 weeks 16%–22%
1. Foster GR, et al. 45th EASL;April 14-18, 2010. Abstract 206. 2. Gane E, et al. 45th EASL;April 14-18,
2010. Abstract 144. 3. Carroll S, et al. 45th EASL;April 14-18, 2010. Abstract 128. 4. Sulkowski M, et al.
45th EASL;April 14-18, 2010. Abstract 298.
Highlights from EASL 2010
NS5B 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
– >3-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 EASL;April 14-18, 2010. Abstract 143. 2. Rodriguez-Torres M, et al. 45th EASL;April
14-18, 2010. Abstract 137. 3. Jacobson I, et al. 45th EASL;April 14-18, 2010. Abstract 5.
4. Pol S, et al. 45th EASL;April 14-18, 2010. Abstract 297.
Highlights from EASL 2010
NonSTAT-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 EASL;April 14-18, 2010. Abstract 142. 2. Jacobson I, et al. 45th EASL;April 1418, 2010. Abstract 6. 3. Muir A, et al. 45th EASL;April 14-18, 2010. Abstract 138. 4. Mouch SA, et al.
45th EASL;April 14-18, 2010. Abstract 204. 5. Shiffman ML, et al. 45th EASL;April 14-18, 2010. Abstract
296.
INFORM-1 Study—Median Change
from Baseline Cohorts B–G
Abbreviation: TF, treatment failure.
With permission from Gane EJ, et al. Hepatology. 2009;50(4 suppl):394A-395A.
The Goal of IFN-Free Combination Regimens
AA
+
Profound
suppression
of broad range of
viral variants,
including pre-existing
B
+
C
Prevention of
emergent
resistance
(pre-existing or
de novo)
•
Different drugs may contribute variably to each of these goals
•
Not all components have to be STAT-C agents
Graphic courtesy of Dr. Ira Jacobson.
New Anti-HCV Therapies
Anticipated 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?
ARS Question:
Among your genotype 1 patients, how
frequently will you be incorporating novel
agents once they are approved?
1)
Always
2)
Very Often
3)
Sometimes
4)
Rarely
5)
Never