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Overview: Treatment of HCVInfection

Jrgen RockstrohDepartment of Medicine I, University of Bonn,Germany

ICVH Baltimore 20114/22/2011


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Discovery of Hepatitis C

4/22/2011 ICVH Baltimore 2011


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Treatment of HCV

Epidemiology Natural history Staging of liver disease and

indications for therapy Predictors of treatment success Treatment recommendations Shift in treatment paradigms



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Source: WHO 2002


Estimated 180 Million individuals infected with HCV worldwide

www.who.int/immunization/topics/hepatitis_c/en/.


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Worldwide Distribution of HCV Genotypes

Zein N. Clin Microbiol Rev. 2000;13:223-235. Reproduced with permission.http://cmr.asm.org/cgi/content/full/13/2/223?view=long&pmid=10755999.

1a1b234

567-8-9Others
http://cmr.asm.org/cgi/content/full/13/2/223?view=long&pmid=10755999http://cmr.asm.org/cgi/content/full/13/2/223?view=long&pmid=10755999


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Natural History of HCV Liver Disease

~55-85%

25-30 yrs

2 - 4% / yr

Liver

failure(2 5% / yr)


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VirusViral load?

HCV genotype?

EnvironmentAlcohol or drugs

HBV co-infectionHIV co-infectionSteatosis

IronNASH

Factors That May Influence theProgression of HCV Infection

HostSexAge

RaceGenetics

Immune responseDuration of infection

Alberti A, et al. J Hepatol. 1999;31(suppl 1):17-24.


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HIV-HCVAlcoholHBVHaemochromatosisHCVSteatosis BMI>252PBC

0.00

0.17

0.33

0.50

0.67

0.83

1.00

0 20 40 60 80

d function

4682

patients

Poynard, T. et al., (2003) A comparison of fibrosis progression in chronic liver disease. Journal of Hepatology38:257-265Age in years

Progression tocirrhosis


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Utility of the Liver Biopsy and NoninvasiveTests of Fibrosis

There are three primary reasons for performing a

liver biopsy:1. it provides helpful information on the current status of the

liver injury,2. it identifies features useful in the decision to embark on

therapy,

3.and it may reveal advanced fibrosis or cirrhosis thatnecessitates surveillance for hepatocellular carcinoma (HCC)and/or screening for varices.



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Definition No FibrosisFibrous

Portal Expansion Few Bridges or SeptaNumerous Bridges or

Septa Cirrhosis

IASL No FibrosisMild

FibrosisModerateFibrosis

Severe Fibrosis Cirrhosis

Metavir F0 F1 F2 F3 F4

Staging of fibrosis in chronic viralhepatitis

Goodman Z et al. J Hepatol 2007;47:598-607


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Non-invasive tests

Painless Frequent sampling possible Accurate at separating mild fibrosis from cirrhosis ?enough degree of separation to show progressive

changes

Fibrosis stage assessment is more important than which test ortechnique you use ..


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Who to treat ?

4/22/2011 ICVH Baltimore 2011 Ghany MG et al. AASLD Practice guidelines; Hepatology 2009


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Lindsay KL. Hepatology. 2002;36(suppl 1):S114-S120.

Goals of HCV Therapy

Primary goal of treatment is to eradicate the virus Additional goals

Slow disease progressionMinimize risk of liver cancerImprove liver damageEnhance quality of lifePrevent transmission of virusReduce extra-hepatic manifestations


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Chronic Hepatitis C:Improvement by trial anderror

0%

20%

40%

60%

80%

1988 1990 1992 1994 1996

IFN 24 weeks

IFN 48 weeks

Sustained virological responseOptimization of dose and duration


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IFN &Ribavirin48 weeks

0%

20%

40%

60%

80%

1988 1990 1992 1994 1996 1998

IFN 24 weeks

IFN 48 weeks

ained virological response

One unspecific drug plus another unspecific drug= highly effective therapy

O N

OHHO

HO

N

N

H2N

O

Chronic Hepatitis C:Improvement by trial and error


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IFN &Ribavirin48 weeks

0%

20%

40%

60%

80%

1988 1990 1992 1994 1996 1998

IFN 24 weeks

IFN 48 weeks

ained virological response

>50% cure of chronicHepatitis C

2001

PEG IFN &

Ribavirin

PEG- IFN 48 weeks

40 kDa PEG-- IFN alfa - 2a

12 kDa PEG- IFN alfa --2b


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More than 50% of patients with chronichepatitis C can be cured


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PegIFN/RBV

SVRRVR cEVR

Virologic Responses

Slow virologic response

0

12

3

4

56

7

8

EVR 2 log10 decline

Limit of detection

Weeks

0 4 12 18 24 30 36 42 48 54 60 66 728 78

V RNA (log10 IU/mL)


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Nullresponse

Suboptimal VirologicResponses

Relapse

Breakthrough

PegIFN/RBV

Partialresponse 2 log10 decline

Limit of detection

Weeks

0 4 12 18 24 30 36 42 48 54 60 66 728 78

V RNA (log10 IU/mL)

0

1

2

3

4

56

7

8


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Treatment startHCV-RNA-level

Standard therapy in HCV genotyp1/4

Week 4HCV-RNA-determination


Treatmentdiscontinuatio

n

HCV-RNA< 12-15 IU/ml


HCV RNA> 2 log or

> 3x104 IU/ml

InitialHCV-RNA *< 6-8x 105

IU/ml

+

24 weeks

of therapy

48 weeksof therapy

RVR cEV

* 6x105 IU/ml pegIFN 2b8x105 IU/ml pegIFN 2aNo shortened duration for F3/F4Metabolic syndromeNo data fror normaltransaminases


Z Gastroenterol 2010; 48:289351


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n




HCV RNA> 2 log or

> 3x104 IU/ml

HCV RNA pos

InitialHCV-RNA *< 6-8x 105

IU/ml

+

24 weeks

of therapy

48 weeksof therapy

72 weeksof therapy

RVR cEV Slow

* 6x105 IU/ml pegIFN 2b8x105 IU/ml pegIFN 2aNo shortened duration for F3/F4Metabolic SyndromNo data for normaltransaminases

Consensus:98%



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n



HCV-RNA> 12-15 IU/ml

HCV RNA*< 2 log

InitialHCV-RNA< 8x 105

IU/ml

+

16 weeks

of therapy

24 weeks

of therapy

48 weeksof therapy

Consensus:100%

No shortened duration for F3/F4Metabolic SyndromNo data for n ormaltransaminases

*extended therapy in case ofslowresponse is currently studied



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Ge D et al. Nature2009; 461(7262):399-401

IL 28B P l hi i th St t


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IL-28B Polymorphism is the StrongestBaseline Predictor of SVR Using Peginterferon/Ribavirin

Covariates - rs12979860 (2-level), ethnicity (4-level), age ( 40), gender, BMI (< 30), VL ( 600,000), ALT ( ULN),fasting glucose (< 5.6), hepatic steatosis (N/Y[>0%]), fibrosis (METAVIR F012), RBV (>13 mg/kg/d)Thompson AJ, et al Gastroenterology 2010 (139) p120-129

P


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RVR is Stronger than All BaselinePredictors of SVR Using Peginterferon/Ribavirin

P


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First DAAs under review

FDA Panel to Review Merck, Vertex Hepatitis Drugs in Late April

NEW YORK - A U.S. Food and Drug Administration panel will review two hepatitis C drugs indevelopment from Vertex Pharmaceuticals Inc. (VRTX) and Merck & Co. Inc. (MRK) in late April,as the companies race to compete against each other in a potentially lucrative market.

The agency's Antiviral Drugs Advisory Committee will review boceprevir on April 27 andtelaprevir on April 28. The widely expected reviews will have outside experts recommendwhether the agency should allow the drugs on the market.

Both drugs have shown success in increasing the cure rates of the liver disease when added tocurrent treatments.

They are expected to come to the market at similar times and be widely used, creating a marketshare battle. Merck said in early January that it was granted a six-month review; Vertex isgetting a similar review and expects a decision by May 23.

Both the Merck and Vertex drugs are known as protease inhibitors, which are designed to blockan enzyme that helps the hepatitis C virus replicate. Standard treatment is a combination of thedrug pegylated interferon and ribavirin, but adding the new drugs may improve cure rates andshorten the duration of treatment.


SPRINT 2 B i i HCV M


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TW 8-24 HCV-RNA Undetectable

TW 8-24 HCV-RNA Detectable

PR + Placebo Follow-up

Follow-up

BOCRGT

(N=368)

PR + BoceprevirPR

lead-in

BOC/PR48(N=366)

PR + Boceprevir Follow-upPR

lead-in

SPRINT 2: Boceprevir in HCV Mono-infected Patients

Week 4 Week 48

PR + Placebo Follow-upPR

lead-in

Week 28 Week 72

Control48 P/R

(N=363)

Sulkowski M, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 115.

SPRINT S i d Vi l i R


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p < 0.0001

p


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48 PR BOC RGT BOC/PR48

Median treatment duration (days) 203 197 335

Deaths (N) 4 1 1

Serious AEs 9% 11% 12%

Discontinued due to AEs 16% 12% 16%

Dose modification due to AEs 26% 40% 35%

Hematologic parameters

Neutrophil count(


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ADVANCE: Telaprevir in Combination with PegIFN/RBV inGenotype 1 HCV Treatment-Nave Patients

240 48 72

Weeks

128 36

Follow-upPR48SVR

Pbo + PR PR

T12PR TVR + PR

Follow-upSVR

eRVR- PR

eRVR+ Follow-up

SVR

PR

Follow-upSVR

TVR+

PRT8PR

eRVR- PR

Pbo +PR

Follow-up SVReRVR+PR

72 weeksassessment

Follow-up

Follow-up

Jacobson IM, et al. 61st AASLD; Boston, MA; October 29-November 2, 2010; Abst. 211.Jacobson IM, et al. AASLD 2010: Abstract 211.


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ADVANCE: Overall SVR rates

Jacobson IM, et al. 61st AASLD; Boston, MA; October 29-November 2, 2010; Abst. 211.

75%69%

44%of Patients with SVR

0

1020

30

40

50

60

70

80

90

100

T12PR

T8PR

PR

T12PR and T8PR vs. PR: P


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Tolerability

Discontinuation rates higher in PI arms Telaprevir

o Pruritus, nausea, rash, anemia, and diarrheao Severe rash in 3-6% (1% PEG/RBV)o 5-7% stop TVR; 1% stop treatmento Hgb


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Remaining challenges

Unclear how to use in special patient populations

with highest risk of disease progression Need for defining stopping rules to prevent

resistance emergence High compliance requirement Drug-drug interactions In whom to start and in whom to wait



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Thank you

!!!!

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