social media

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) Always2) Very Often3) Sometimes4) Rarely5) Never

ARS Question: How likely are you to use social media to help increase public

awareness of chronic hepatitis C?1) Very likely2) Likely3) Maybe4) Probably not5) 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?


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?


ARS Question: Among your genotype 1 patients, how

frequently will you be incorporating novel agents once they are approved?


How Will Social Media Impact Your Practice?

Bryan S. Vartabedian, MD, FAAPAssistant Professor of Pediatrics

Section of Gastroenterology, Hepatology, & NutritionBaylor College of Medicine

Houston, Texas

How Health Information Was Shared

MD

Patient

Graphic courtesy of Dr. Bryan Vartabedian.

Now Patients find each other

2000sInformation finds patients

1990sPatients find information

Long agoPatients depend on what they’re told

Evolution of Social Health


4: Individuals – email lists3: Closed networks – MySpace, Facebook2: Open networks – blogs, feeds, YouTube1: 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.

• Patient to patient• Crowdsourced data• “Clinical trials”

CureTogether

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

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.

61%

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.

The Social Media RevolutionHow Is Its Use in Adults Growing?

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?

Number of Pediatricians in the AAP

60,000

KevinMD.com. Available at: http://www.kevinmd.com/blog/2009/08/delayed-vaccine-schedule-dangerous.html. Accessed on: April 13, 2010.

Number of Members in the SSAT

2500

Number of Membersin the AASLD

3000Number of Members

in the AGA

16,000

Number of Members in the ASGE

10,000

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.

DDW’s 4 Sponsoring Societies

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


Blog


Left graphic: Kaplan Publishing. Spring 2009 Catalog. Available at: http://www.kaptest.com/pdf_files/publishing/seasonal-catalogs/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.

Visibility in Action

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, MPHProfessor of Medicine

Chief, Section of Gastroenterology and HepatologyBaylor College of Medicine

Michael E. DeBakey VA Medical CenterHouston, Texas

Infected 20+ years

Overall prevalence

Past and Future US Incidenceand Prevalence of HCV Infection

Armstrong GL, et al. Hepatology. 2000;31:777-782. Graphic courtesy of the CDC.

Decline among IDUs

Overall incidence

Histologic Fibrosis Stage by YearN

umbe

r of P

erso

ns

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)

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.

Category SVR (%)

Overall 54–561,2

Genotype 1 42–461,2

Genotype 2/3 76–821,2

Genotype 4 58–772–4

African American 285

Cirrhosis 43–441,2

TolerabilityAdherenceProvider experienceSupportive medical team

Treatment Factors

Host FactorsIL28B gene polymorphismNot African AmericanImmunocompetentLean, non-diabetic, insulin sensitiveYoung, good renal function, minimal comorbid illness

Virus FactorsGenotype 2/3Low viral loadRapid virologic response

HCV Patients Most Likely to Achieve SVR

El-Serag HB. Gastroenterology. 2007;132:8-10.

Treatment of HCV

Efficacy x Access x Correct Diagnosis x Recommendation x

Acceptance x Adherence

Efficacy in clinical trials and research centers

Effectiveness in community

practice

Efficacy and EffectivenessA Demonstration of the Multiplicative

Effect of Factors

Efficacy of Rx “X”

60%

Access x 80%

Correct diagnosis

x 85%

Recommend x 85%

Acceptance x 85%

Adherence x 70%

Effectiveness of Rx “X”

= 21%

El-Serag HB. Gastroenterology. 2007;132:8-10.

Efficacy of Rx “Y”

80%

Access x 80%

Correct diagnosis

x 85%

Recommend x 85%

Acceptance x 85%

Adherence x 70%

Effectiveness of Rx “Y”

= 28%

Efficacy of Rx “X”

60%

Access x 90%

Correct diagnosis

x 90%

Recommend x 90%

Acceptance x 90%

Adherence x 80%

Effectiveness of Rx “X” modified

= 32%

Example 1: Rx “X”

Example 2: Rx “Y”

Example 3: Rx “X” Modified

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.

Receipt of Treatment

Predictors of Treatment

DemographicsGenotype, viral loadCirrhosis diagnosis

ALT, Hct, Plt, WBC, CrComorbidity

HIV diagnosisInsurance

Patient factors

Provider specialtyHCV experience Continuity

Facility factors

Provider factors

Graphic courtesy of Dr. Hashem El-Serag.

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 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. 2005;100:1772-1779.

Treatment Outcomes Retrospective Observational Cohort

Completed treatment

Achieved SVR

48-week treatment for genotype 1, 24-week treatment for genotype 2/3.

Backus LI, et al. Hepatology. 2007;46:37-47.

N = 5944

Antiviral Therapy for HCV per Year Actual, 2002–2007

Projected, Through 2014

Volk ML, et al. Hepatology. 2009;50:1750-1755.

ActualProjected

Underutilization and Disparity

Clinical appropriateness and patient preferences

Healthcare system: access, legal, and regulatory issues

Discrimination, bias, uncertainty

Under-utilization

and DisparityP

erce

nt

Graphic courtesy of Dr. Hashem El-Serag.

Sur

vey

Res

pons

es

Refused treatment

Did not f/u with clinician

Received treatment

Clinician did not recommend treatment

Unaware of diagnosis

Reasons for Lack of Treatment Among Respondents to the NHANES Hepatitis C

Follow-Up QuestionnaireN = 133

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


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

Healthcare and social service

providersAt-risk populations

Policy makers and

the public

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

Institute of Medicine Report Consequences

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


Institute of Medicine Report Recommendations


Viral Hepatitis Services

Federally funded health insurance programs (eg, Medicare) should: Incorporate guidelines for risk-factor screening as required component of preventive care

Surveillance

The CDC should:Evaluate national HCV public health surveillance systemDevelop agreements with state health departments to support core HCV surveillanceSupport targeted surveillance

Knowledge & Awareness

The CDC should work with key stakeholders to:Develop HCV educational programs for providersDevelop and evaluate innovative and effective outreach programs to 1) target at-risk populations, and 2) increase public awareness

ARS Question: How likely are you to use social media to help increase public

awareness of chronic hepatitis C?1) Very likely2) Likely3) Maybe4) Probably not5) 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?


Optimization of Interferon-Based Therapies in

Current HCV Patients–Can We Do Better?

Donald M. Jensen, MDProfessor of Medicine

Director, Center for Liver DiseasesUniversity 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 SVRPercentage SVR by Genotype of rs12979860

0 20 40 60 80 100

C/C

T/C

T/T

SVR

Combined

European Americans

African AmericansHispanics

N = 1,137

P = 1.37 x 10-28 vs T/T

Ge D, et al. Nature. 2009;461:399-401.

n = 70n = 14n = 102

n = 91n = 35n = 433

n = 186

n = 559

n = 392n = 30

n = 336n = 26

rs12

9798

60 C

-alle

le F

requ

ency

SVR (%)

African Americans(n = 61)

Hispanics(n = 16)

European Americans(n = 271)

East Asians(n = 107)

IL28B Genetic Variation and Genotype 1 Response

Ge D, et al. Nature. 2009;461:399-401.

PEG IFN + RBV THERAPY

Treatment of Chronic HCVGenotype 1 Response Rate

Detection limit (50 IU/mL)

01

23

45

67

89

10

-6 0 4 8 12 16 20 24 28 32 36 40 44 48 72

Weeks

Log

HC

V R

NA

(IU

/mL)

Null

88%–91%

68%–72%

27%–43%

2%–5%

SVR

Partial~29%

Stopping Rules

1

cEVRRVR~20%

2

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.

pEVR

51%

Abbreviations: EVR, early virologic response; cEVR, complete EVR; pEVR, partial EVR; RVR, rapid virologic response.

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. 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 InterferonInduction IFN dosing

leads to a greater number of early

responders.However, standard

dosing catches up after induction ends.

0 12 24 36 48

HC

V R

NA

neg

(%)

Induction IFN

Std IFN

Weeks

Proportions of Patients with Undetectable HCV RNA After Starting Combination Therapy1

There is no overall SVR benefit to

induction dosing

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

0

20

40

60

80

100

5 9 13 17 21

SVR

(%)

RBV Dose (mg/kg)

P = .015

aP = .569; bP = .019. 1. Manns MP, et al. Lancet. 2001;358:958-965. 2. Jacobson IM, et al. Hepatology. 2007;46:971-981.

WIN-R Trial2

Genotype 1

Weight-baseda

Flat-dosingb

Importance of RBV AdherenceAdherence messages

• Maintain RBV dose >60% 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. 2009;50:402-411. 2. Reau N, et al. Am J Gastroenterol. 2008;103:1981-1988. 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.

Effect of RBV Exposure on Relapse Rate1

0

Cumulative Ribavirin Dose

10

20

30

40

50

60

70

80

Rel

apse

Rat

e (%

) >97% (n = 37)

5419 22 32

80%–97% (n = 14)60%–80% (n = 18)

>97% (n = 37)

0%–60% (n = 13)

Extending Duration Genotype 1 with Early Virologic Response

48 weeks72 weeks

12Week

Berg1

G1 onlyRBV 800 mg

48 724 0

29 21

Relapse

53 54

SVR

48 weeks72 weeks

Berg1

G1 onlyRBV 800 mg

HCV RNA pos at week 12; neg at week 24

64 4017 29

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.

48 weeks72 weeks

Pearlman2 G1RBV 800/1400 mg

18 38 59 20

HCV RNA pos at week 12; neg at week 24 P = .03 P = .004

P = .04

All patient analysis

Can We Shorten Therapy Based on an RVR

to Improve Adherence and Minimize Side Effects?

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. 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.

89

16

73

35

0

20

40

60

SVR

(%)

Patients with an RVR at wk 4

88

80

23

44

100

Patients without an RVR at wk 4

n = 18 33 40 56 81 84 208 210

PEG IFN -2a/RBV2

9124 wk + RBV 800

48 wk + RBV 80048 wk + RBV 1000/1200

24 wk + RBV 1000/1200

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. 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.

79 78 8085 85 85

0

20

40

60

80

100

16-wk Regimen

SVR

(%)

P = .02

Any genotypeGenotype 2

Accelerate Trial1

SVR Rates in Patients with RVR

Genotype 3

24-wk Regimen

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

Nonresponders

PEG IFN/RBV Nonresponder Clinical Trials

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.

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 + RBV 1000–1200 mg/d x 48 or 72 wk

SVR: 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.

Maintenance Therapy

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.

Maintenance PEG IFN in Nonresponders3 Randomized Controlled Trials

HALT-C COPILOT Bruix, et alNo difference

in clinical outcomes1

Subgroup with >4-log reduction in

HCV RNA had reduced

outcomes2

Subjects with baseline

portal hypertension had reduced

outcomes (variceal

bleeding) with PEG IFN3

In primary analysis,

maintenance was not

superior to observational

control in preventing

occurrence of clinical events4

Treat Now or Wait Until STAT-C?

• 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

Treat Now May Consider Waiting

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?


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

Ira M. Jacobson, MDVincent Astor Professor of Medicine

Chief, Division of Gastroenterology and HepatologyMedical Director of the Center for the Study of Hepatitis C

Weill Medical College of Cornell UniversityNew York, New York

Phases in the Evolution of 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

SpecificallyTargetedAntiviral Therapyfor HCV

(STAT-C)

The Final

Phase:Small

Molecule Combinations

???

The Refinement

Phase•Optimal dosing•Viral kinetics•Challengingpopulations

•Nonresponders

Emerging Anti-HCV Therapies

Genome Sequence-Based

EnzymeInhibitors 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

Specifically Targeted Antiviral Therapy for HCV (STAT-C)

Abbreviations: HCV, hepatitis C virus; IFN, interferon; PEG IFN, peginterferon; RBV, ribavirin.Graphic courtesy of Dr. Ira Jacobson.

Protease

Polymerase

NS5A

RNA Interference

Antisense

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.

Core E1 E2 P7

NS2 NS3 NS4A NS4B NS5A NS5B

Targets for Anti-HCV Drugs in Beyond Phase I Clinical Trials

5– –3

TelaprevirBoceprevirRG7227TMC 435350MK7009BI-201335BMS-650032ABT-450

BMS-790052

Active site (nucleosides)

RG7128IDX184PSI-7851

Nonnucleosides GS 9190FilibuvirABT-333ABT-072ANA598VX-222

Protease inhibitors Polymerase inhibitors

CyclophilinAntagonists

Debio 025SCY-635

NS5Ainhibitors

Not all-inclusive

Abbreviations: PEG IFN, peginterferon; RBV, ribavirin; TVR, telaprevir.With permission from Kieffer TL, et al. Hepatology. 2007;46:631-639.

-6

-5

-4

-3

-2

-1

0

1

1 2 3 4 5 6 7 8 9 10 11 12 13 14Study Time (days)

HC

V R

NA

Cha

nge

from

Bas

elin

e (L

og10

IU/m

L)

Telaprevir n = 8

PEG IFN -2a + Placebo n = 4

Baseline

15

• 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

Early Data with Telaprevir Potency, Resistance, and Interaction with IFN

Telaprevir + PEG IFN -2a n = 8

Sequence Analysis

Placebo + P + R P + R Follow-up

T + P + R Follow-up

T + P + R P + R Follow-up


McHutchison J, et al. N Engl J Med. 2009;360:1827-1838.

Abbreviations: R, ribavirin 1000–1200 mg/d; P, peginterferon -2a 180 µg/wk; T, telaprevir 1250 on day 1 then 750 mg q8h.

PROVE1—Telaprevir Phase IIb Study DesignUS, Genotype 1, Treatment-Naive

T12/PR24(n = 79)

T12/PR48(n = 79)

PR48 (control)(n = 75)

T12/PR12(n = 17)

240 48 7212 6036

240 48 7212 6036

Weeks

Weeks

PROVE 1—Telaprevir + PEG IFN/RBVSVR, Intent-to-Treat Analysis, Phase II

0

20

40

60

80

100

SVR

Rat

e (%

)

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

Graphic Courtesy of Dr. John McHutchison. McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.

n =

P = .02 P = .002

PROVE 1—Relapse Rates

0

10

20

30

40

50

Rel

apse

Rat

e (%

)

23

8/35

33

3/92

6

3/51PR 48 wk(Control)

T 12 wk +PR 12 wk

T 12 wk + PR 24 wk

T 12 wk +PR 48 wk

Denominator = number of subjects with undetectable HCV RNA at completion of assigned treatment duration. aIncludes subjects who met the 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.

1/41

TVR drives high rates of RVR and low rates of relapse

n =

a a

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)

PROVE1—Safety Data

Other TVR-related AEs: anemia, GI effects

McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838. Graphic courtesy of Dr. Ira Jacobson.Abbreviations: AE, adverse event; D/C, discontinuation; GI, gastrointestinal; TVR, telaprevir.

Hezode C, et al. N Engl J Med. 2009;360:1839-1850. Graphic courtesy of Dr. Ira Jacobson.

PROVE2—SVR European, Genotype 1, Treatment-Naive

aP = .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.

c

38/82 49/82 56/81 28/78

a b

n =

Higher relapse ratewith 12 vs 24 weeks

Impaired response, more breakthroughand more relapse

w/out RBV

C208 Study—Telaprevir 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. 2010;52(suppl 1):S26. Graphic courtesy of Dr. Ira Jacobson.

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

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 + P Follow-up

Placebo + P + R P + R Follow-up

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.

T24/P24(n = 111)

PR48(n = 114)

T12/P24(n = 115)

T24/PR48(n = 113)

240 48 7212 6036

240 48 7212 6036

Weeks

Weeks

PROVE3—Study DesignPrior Treatment Failures

PROVE3—SVR by Prior Response and Treatment Group (ITT)

aP <.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.

Prior RelapsersPrior Nonresponders

39 38

11 9

69

42

76

0

10

20

30

40

50

60

70

80

90

100

SVR

(%)

20

• SVR durable at 1 year• Equivalent efficacy in cirrhotics

n = 26/66 24/64 7/62 6/68 29/42 31/41 16/38 8/41

T12/PR24T24/PR48T24/P24 (no RBV)PR48

a a a ab b

Rollover Study (107) in Treatment Failures From Control Arms of PROVE 1/2/3

Berg T, et al. 45th EASL;April 14-18, 2010. Abstract 108.

T12/PR24T12/PR48

49/8118/34 4/24 15/27 15/25 24/25 3/3 6/7 0/10/3

P + R (n = 104) Follow-up

PR P + R + B (n = 103) Follow-upPR P + R + B (n = 103) Follow-up

P + R + B (n = 107) Follow-upP + R + B (n = 103) Follow-up

P + R (n = 16) Follow-upP + R-LD (n = 59) Follow-up

No Lead-in

R-LD

Control

Lead-in

Sprint 1—Boceprevir + PEG IFN -2b + RBV International, Phase II, Treatment-Naive, Geno 1

280 48 7212a 6036Weeks 4

Part

1Pa

rt 2

b

aInterim 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.

SPRINT 1—SVR 24 Rates

38

56

75

54

67

0

20

40

60

80

100

SVR

(%)

PRB Lead-In(n = 103)

PRBNo Lead-In(n = 103)

PRBLead-In(n = 103)


PRControl(n = 104)

Tx 28 Weeks Tx 48 Weeks

50

36

PR Control(n = 16)

PR-LD(n = 59)

Part 2Part 1

aP = 0.005; bP = 0.013; cP <.0001, compared with PR Control. Kwo P, et al. J Hepatol. 2009;50:S4.

a b c c

0

24

7

30

4

24

12

75

3

0

10

20

30

40

Breakthrough Relapse

Perc

ent

PR48PRB28PR4-PRB24PRB48PR4-PRB44

Relapse and Breakthrough in SPRINT 1Reduction with Lead-in

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

82

94

7484

0

20

40

60

80

100

SVR

(%)

PRControl(n = 104)

PRB Lead-In(n = 103)


PRBLead-In(n = 103)


Tx 28 Weeks Tx 48 WeeksKwo P, et al. J Hepatol. 2009;50:S4. Graphic courtesy of Dr. Paul Kwo.

32/3862/6632/4354/668/8

SPRINT 1—Null Responders to PEG/RBV Can Have SVR with a Protease Inhibitor

Kwo PY, et al. Hepatology. 2009;50(4 Suppl):331A.

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.

Log10 Viral Load Decrease After 4-Wk PR Lead-in

ab

PR4/PRB24PR4/PRB44

2/7 5/21 3/10 8/11 14/21 10/12 11/11 3/34/9 8/13 11/17 8/10 11/14 14/17 11/12 9/9

<0.5 0.5–<1.0 1.0–<1.5 1.5–<2.0 2.0–<3.0 3.0–<4.0 ≥4.0 Undetect-able

With permission from Bressanelli S, et al. J Virol. 2002;76:3482-3492.

HCV RNA PolymeraseNucleosides and Non-Nucleoside Inhibition

Thumbinhibitors

NNI

Catalytic siteNucleoside

analogs

NNI

Palm

FingersThumb

Allosteric GTP-binding sites

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

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 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. 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 2010Protease Inhibitors

• Good activity for telaprevir against genotype 21

– 3.7-log decline with 2 weeks of telaprevir monotherapy

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.

• 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%

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

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.

• 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

Highlights from EASL 2010NonSTAT-C Drugs

• Intravenous silibin for partial responders1

1. Biermer M, et al. 45th EASL;April 14-18, 2010. Abstract 142. 2. Jacobson I, et al. 45th EASL;April 14-18, 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.

• 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)

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.

A B C

Prevention of emergent resistance

(pre-existing or de novo)

+ +A

Profound suppression

of broad range ofviral variants,

including pre-existing

• 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.

The Goal of IFN-Free Combination Regimens

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?

ARS Question: Among your genotype 1 patients, how

frequently will you be incorporating novel agents once they are approved?


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