Overview: Treatment of HCV Infection Jürgen Rockstroh Department of Medicine I, University of Bonn, Germany ICVH Baltimore 20114/22/2011.

Overview: Treatment of HCV Infection

Jürgen RockstrohDepartment of Medicine I, University of Bonn,

Germany

ICVH Baltimore 20114/22/2011

Discovery of Hepatitis C

4/22/2011 ICVH Baltimore 2011

Treatment of HCV

• Epidemiology • Natural history• Staging of liver disease and

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


Source: WHO 2002


Estimated 180 Million individuals infected with HCV worldwide

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

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.

1a1b234567-8-9Others

Natural History of HCV Liver Disease

~55-85%

25-30 yrs

2 - 4% / yr

Liver failure

(2 – 5% / yr)

VirusViral load?

HCV genotype?

EnvironmentAlcohol or drugsHBV co-infectionHIV co-infection

SteatosisIron

NASH

Factors That May Influence the Progression of HCV Infection

HostSexAge

RaceGenetics

Immune responseDuration of infection

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

HIV-HCVAlcoholHBVHaemochromatosisHCV Steatosis BMI>252PBC

0.00

0.17

0.33

0.50

0.67

0.83

1.00

0 20 40 60 80

Hazard function

4682 patients

Poynard, T. et al., (2003) A comparison of fibrosis progression in chronic liver disease. Journal of Hepatology 38:257-265

Age in years

Progression to cirrhosis

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,• it identifies features useful in the decision to embark on

therapy, • and it may reveal advanced fibrosis or cirrhosis that

necessitates surveillance for hepatocellular carcinoma (HCC) and/or screening for varices.


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 viral hepatitis

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

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 or technique you use ………..

Who to treat ?

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

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 progression Minimize risk of liver cancer Improve liver damage Enhance quality of life Prevent transmission of virus Reduce extra-hepatic manifestations

Chronic Hepatitis C: Improvement by trial and error

0%

20%

40%

60%

80%

1988 1990 1992 1994 1996

IFN 24 weeks

IFN 48 weeks

Sustained virological responseOptimization of dose and duration

IFN & Ribavirin 48 weeks

0%

20%

40%

60%

80%

1988 1990 1992 1994 1996 1998

IFN 24 weeks

IFN 48 weeks

Sustained 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

IFN & Ribavirin 48 weeks

0%

20%

40%

60%

80%

1988 1990 1992 1994 1996 1998

IFN 24 weeks

IFN 48 weeks

Sustained virological response

>50% cure of chronic Hepatitis C

2001

PEG IFN & Ribavirin

PEG- IFN 48 weeks

40 kDa PEG-- IFN alfa-2a

12 kDa PEG-IFN alfa--2b

More than 50% of patients with chronic hepatitis C can be cured

PegIFN/RBV

SVRRVR cEVR

Virologic Responses

Slow virologic response

0

1

2

3

4

5

6

7

8

EVR 2 log10 decline

Limit of detection

Weeks

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

HCV RNA (log10 IU/mL)

Null response

Suboptimal Virologic Responses

Relapse

Breakthrough

PegIFN/RBV

Partial response 2 log10 decline

Limit of detection

Weeks

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

HCV RNA (log10 IU/mL)

0

1

2

3

4

5

6

7

8

Treatment startHCV-RNA-level

Standard therapy in HCV genotyp 1/4

Week 4HCV-RNA-determination


Treatment discontinuatio

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 weeks of therapy

RVR cEVR

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


Z Gastroenterol 2010; 48:289–351







n




HCV RNA > 2 log or

> 3x104 IU/ml

HCV RNA pos

InitialHCV-RNA *

< 6-8x 105 IU/ml

+

24 weeks of therapy

48 weeks of therapy

72 weeks of therapy

RVR

cEVR

Slow Responder

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

Consensus: 98%







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 weeks of therapy

Consensus: 100%

No shortened duration for F3/F4Metabolic SyndromNo data for n ormal transaminases*extended therapy in case of slowresponse is currently studied


Ge D et al. Nature 2009; 461(7262):399-401

IL-28B Polymorphism is the Strongest Baseline 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 <0.0001

P <0.0001

P <0.0001

P <0.0001

P <0.0001

P= 0.004

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

P <.001

P <.001

P = .0001

P = 0.0361

P <.001

P <.001

P <.001

Comparison of RVR vs no RVR + non-CC genotypeComparison of no-RVR + CC genotype vs no-RVR + non-CC genotypeCo-variates : RVR vs no RVR + CC genotype vs no RVR + non-CC genotype (3-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

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 in

development 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 and telaprevir on April 28. The widely expected reviews will have outside experts recommend whether 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 to current treatments.

• They are expected to come to the market at similar times and be widely used, creating a market share battle. Merck said in early January that it was granted a six-month review; Vertex is getting 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 block an enzyme that helps the hepatitis C virus replicate. Standard treatment is a combination of the drug pegylated interferon and ribavirin, but adding the new drugs may improve cure rates and shorten the duration of treatment.


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.

p < 0.0001

p <0.0001

Non-Black Patients

p = 0.044

p =0.004

Black Patients

SVR

SPRINT-2: Sustained Virologic Response and Relapse Rates (ITT)

Relapse Rate


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 (<750 to 500/mm3 / <500/mm3)

14% / 4% 24% / 6% 25% / 8%

Hemoglobin (<10 to 8.5 g/dL / <8.5 g/dL)Discontinuation due to anemiaDose reductions due to anemiaErythropoietin useMean (median) days of use

26% / 4%1%13%24%

121 (109)

45% / 5%2%

20%43%

94 (85)

41% / 9%2%21%43%

156 (149)

SPRINT-2: Safety Profile Over Entire Course of Therapy


ADVANCE: Telaprevir in Combination with PegIFN/RBV in Genotype 1 HCV Treatment-Naïve 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 + PR

T8PR

eRVR- PR

Pbo +PR

Follow-upSVReRVR

+PR

72 weeksassessme

nt

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.

ADVANCE: Overall SVR rates

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

75%69%

44%Percent of Patients with SVR

0

10

20

30

40

50

60

70

80

90

100

T12PR

T8PR

PR

T12PR and T8PR vs. PR: P<0.0001

Jacobson IM, et al. AASLD 2010: Abstract 211.

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 <10g/dl: 35-45% vs. 14% [ESA use not allowed]


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



Thank you !!!!

Overview: Treatment of HCV Infection Jürgen Rockstroh Department of Medicine I, University of Bonn, Germany ICVH Baltimore 20114/22/2011.

Documents

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hcv rna log

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hcv worldwide

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