Overview: Treatment of HCV Infection Jürgen Rockstroh Department of Medicine I, University of Bonn,...
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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
ICVH Baltimore 20114/22/2011
Source: WHO 2002
4/22/2011 ICVH Baltimore 2011
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.
4/22/2011 ICVH Baltimore 2011
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
Week 12HCV-RNA-determination
Treatment discontinuatio
n
HCV-RNA< 12-15 IU/ml
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
Week 24HCV-RNA-determination
Z Gastroenterol 2010; 48:289–351
Treatment startHCV-RNA-level
Standard therapy in HCV genotyp 1/4
Week 4HCV-RNA-determination
Week 12HCV-RNA-determination
Week 24HCV-RNA-determination
Treatment discontinuatio
n
HCV-RNA< 12-15 IU/ml
HCV-RNA< 12-15 IU/ml
HCV-RNA< 12-15 IU/ml
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%
Z Gastroenterol 2010; 48:289–351
Treatment startHCV-RNA-level
Standard therapy in HCV genotyp 2/3
Week 4HCV-RNA-determination
Week 12HCV-RNA-determination
Treatment discontinuatio
n
HCV-RNA< 12-15 IU/ml
HCV-RNA< 12-15 IU/ml
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
Z Gastroenterol 2010; 48:289–351
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.
ICVH Baltimore 20114/22/2011
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
Sulkowski M, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 115.
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
Sulkowski M, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 115.
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]
4/22/2011 ICVH Baltimore 2011
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
4/22/2011 ICVH Baltimore 2011
4/22/2011 ICVH Baltimore 2011
Thank you !!!!