shiffman - assessment prior to...
TRANSCRIPT
Mitchell L. Shiffman, MD, FACG
ASSESSMENT PRIOR TO TREATMENTDO WE NEED IL28B TESTING?DO WE NEED LIVER BIOPSY?DO WE NEED LIVER BIOPSY?
Mitchell L Shiffman, MDDirector
Liver Institute of VirginiaBon Secours Health System
Liver Institute of VirginiaEducation, Research and Treatment for Patients with Liver Disease
IVerBon SecoursHealth System
Bon Secours Health SystemRichmond and Newport News, VA
INTERFERONMECHANISMS OF ACTION
ISG
2,5 OASPKRMX
Immunologic Effects:Cell surface antigenNK cellsCytotoxic T cellsMacrophageImmunoglobulins
INFINF
MXAnti-viral effect:Entry, uncoatingmRNA & protein
synthesis
InterleukinsTNF
Samuel CE.Clin Microbiol Rev. 2001; 14:778-809.
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Mitchell L. Shiffman, MD, FACG
TREATMENT OF CHRONIC HCVPHASES OF VIROLOGIC RESPONSE
Phase1:Direct anti-viral effect of INF
Phase 2:Immune effects of INF
E Herman et al.Antivir Ther 2000; 5:85-90.
VIROLOGIC RESPONSEPATTERNS
2-log decline
Peginterferon/Ribavirin
Li it f d t ti
SVR
Limit of detection
A Sethi and ML ShifmanClin Liver Dis 2005; 9:453-471.
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Mitchell L. Shiffman, MD, FACG
SUSTAINED VIROLOGIC RESPONSEBASIS FOR HOST GENETIC EFFECT
• SVR rates are highly variable among various racial• SVR rates are highly variable among various racial groups:• Asians – highest• African Americans – lowest
• Variable response patterns during treatment even with the same viral genotype
• Not explained by host phenotypic factors alone:
IVer
• Cirrhosis• Body weight• Insulin resistance• Liver transaminases
IL28B POLYMORPHISMTHE INTERFERON SWITCH
• Host gene• Modulates the interferon response• Chromosome 19• SNP at loci rs12979860• CC haplotype (cure):
• Highly interferon sensitive• High rates of spontaneous resolution• Hi h t f RVR
CC-ON
IVer
• High rates of RVR• High rates of virologic response• High rates of SVR
D Ge et al.Nature 2009; 461:399-401.
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Mitchell L. Shiffman, MD, FACG
IL28B POLYMORPHISMTHE INTERFERON SWITCH
• Host gene• Modulates the interferon response• Chromosome 19• SNP at loci rs12979860• TT haplotype (terrible):
• Minimally interferon sensitive• No spontaneous resolution• L t f RVR
IVer
• Low rates of RVR• Low rates of virologic response• Low rates of SVR
TT-OFF
D Ge et al.Nature 2009; 461:399-401.
IL28B POLYMORPHISMTHE INTERFERON SWITCH
• Host gene• Modulates the interferon response• Chromosome 19• SNP at loci rs12979860• CT halotype:
• Lower interferon sensitivity• Low rates of spontaneous resolution• L t f RVR
CTMIDDLE
IVer
• Low rates of RVR• Low rates of virologic response• Low rates of SVR
D Ge et al.Nature 2009; 461:399-401.
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Mitchell L. Shiffman, MD, FACG
IL28 B POLYMORPHISM AND SVRIMPACT OF RACE AND ETHNICITY
Hispanics
Caucasians
Asians
African Americans
D Ge et al.Nature 2009; 461:399-401.
IL28 B POLYMORPHISMIMPACT OF RESPONSE AND RACE
C i Af i A iCaucasian African American
CC Non-CC CC Non-CC
RVR 28% 5% 15% 2%
cEVR 87% 33% 50% 22%
ETR 92% 54% 70% 26%
SVR 69% 30% 48% 14%
IVer
SVR 69% 30% 48% 14%
Relapse 14% 34% 23% 36%
A Thompson et al.Gastroenterology 2010; 139:120-129.
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Mitchell L. Shiffman, MD, FACG
PHASES OF VIROLOGIC RESPONSEIMPACT OF INF SENSITIVITY
Highly Interferon Sensitive – CCModerate Interferon Sensitivity – CT
Poorly Interferon Sensitive - TT
IVerE Herman et al.Antivir Ther 2000; 5:85-90.
TREATMENT OF HCV
INTERFERON RESPONSIVENESS
E ith t i hibit hi i SVR i till• Even with a protease inhibitor achieving SVR is still dependent upon the ability to respond to interferon
• Can be assessed by a lead-in response• Can be assessed by prior treatment response Null response – poorly responsive Relapse – highly responsive
• Interferon responsiveness is genetically mediated
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• Interferon responsiveness is genetically mediated IL28B genotype CC – highly responsive IL28B genotype TT – poorly responsive
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Mitchell L. Shiffman, MD, FACG
SIMEPREVIR-PEGINF-RIBAVIRINTREATMENT NAIVE
IVerM Manns et al. EASL 2013.
TELAPREVIRIL28B AND RAPID RESPONSE
witheRVR
AllPatients
withouteRVR
IM Jacobson et al.EASL 2011
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Mitchell L. Shiffman, MD, FACG
TELAPREVIR-PEGINF-RIBAVIRIN12 WEEKS OF TREATMENT
IL28B genotype CCNo cirrhosisNo cirrhosisRandomized if eRVR to:
PEGINF/RBV 12 weeks 24 weeks
TPV-BID 12 weeks 12 weeks
N 107 52
SVR 87% 97%
IVerDR Nelson et al. EASL 2013
SVR 87% 97%
HB<10 51% 44%
HB<8.5 13% 15%
IL28B GENOTYPE AND SVRSOFOSBUVIR
SOF/RBVGT 2-3
SOF/RBVFailed PEGINFGenotypes 2-3
RBVSOFGT1
RBVGT 2-3
E Lawitz et al. N Engl J Med 2013; 368:1878-1887.IM Jacobson et al. N Engl J Med 2013; 368:1867-77
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Mitchell L. Shiffman, MD, FACG
IL28B GENOTYPEWILL IT STILL BE USEFUL
• As cure rates exceed 90% the need for a test to predict who will respond does not exist.
• This assumes that everyone will be treated with these newer therapies
• This assumes that everyone can afford all oral therapies
• IL28B ill ll th h i i i i
IVer
• IL28B will allow the physician, insurance carrier, government the ability to identify which patients can be cured with a less costly therapy.
IS LIVER HISTOLOGY USEFULYES
• SVR is lower in patients with advanced fibrosis and cirrhosis regardless of the treatment utilized
• If advanced fibrosis or cirrhosis is present: Should treat for 48 weeks More complications during treatment
• If cirrhosis is present: must screen for HCC even after achieve SVR
• If mild disease the patient might prefer not to
IVer
• If mild disease the patient might prefer not to treat
• Histology can be utilized to predict the rate of fibrosis progression
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Mitchell L. Shiffman, MD, FACG
IMPACT OF CIRRHOSIS ON SVRTREATMENT NAIVE
NoNoCirrhosis
Cirrhosis
Genotype 1
PEGINF/RBV 47% 33%
Telaprevir + PEGINF/RBV 78% 62%
Boceprevir + PEGINF/RBV 67% 52
Simeprevir + PEGINF/RBV 83% 65%
IVer
Simeprevir + PEGINF/RBV 83% 65%
Faldaprevir + PEGINF/RBV 80% 56%
Sofosbuvir + PEGINF/RBV 92% 80%
Multiple DAA oral therapy 95% 85% ?
RE-TREATMENT WITH TELAPREVIR
IMPACT OF LIVER HISTOLOGY
IVer
PRIOR RESPONSE
S Zeuzem et al. N Eng J Med 2011; 364:2417-2428.
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Mitchell L. Shiffman, MD, FACG
IMPACT OF CIRRHOSIS ON SVR
TREATMENT NAIVE
NoCirrhosis
Cirrhosis
Genotype 2
PEGINF/RBV 82% 62%
Sofosbuvir + RBV 98% 91%
Genotype 3
IVer
PEGINF/RBV 71% 30%
Sofosbuvir + RBV 61% 34%
CHRONIC HCV INFECTIONPROGRESSION TO CIRRHOSIS
Initial fibrosis:
20
40
60
80
100
RR
HO
SIS
(%
)
Bridging
Portal
None
0
20
0 5 10 15 20
CI
YEARS
M Yano et al.Hepatology 1996; 23:1334-1340.
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Mitchell L. Shiffman, MD, FACG
PREDICTING FIBROSIS PROGRESSIONEFFECT OF INFLAMMATION
MG Ghany et al. Gastroenterol 2003; 124:97-104.
CHRONIC HCV
FIBROSIS PROGRESSION
Mild
Cirrhosis C
Cirrhosis A
Severe
Moderate
Mild
15-25%
25-33%
ML ShiffmanViral Hepatitis Rev 1999; 5:27-43.
0 10 20 30 40 50
HCC
YEARS
25 33%
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Mitchell L. Shiffman, MD, FACG
TREATMENT OF CHRONIC HCV
LIVER HISTOLOGY IS NOT USEFUL
• Liver biopsy is invasive• Complications can occur• Most patients with cirrhosis can be identified
without a liver biopsy• Non-invasive assessment of liver histology is
good enough
IVer
• Since treatment is more effective we should treat all patients regardless of histology
BIOCHEMICAL MARKER OF CIRRHOSISAST/ALT RATIO
ML Shiffman et al.Hepatology 1994; 19:933-940
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Mitchell L. Shiffman, MD, FACG
MARKERS OF ADVANCED FIBROSISAST AND PLATELET COUNT
0--
----
----
----
-x
100
CT Wai et al.Hepatology 2003; 38:518-526.
NON-INVASIVE MARKERS OF FIBROSISFIBROTEST
Utilizes 5 serum biochemical markers to predict fibrosis
Alpha-2 macroglobulin
Haptoglobin
Gamma glutamyl transpeptidase
IVer
Total bilirubin
Apolipoprotein A1
Markers of inflammation NOT fibrosis
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Mitchell L. Shiffman, MD, FACG
NON-INVASIVE MARKERS OF FIBROSISFIBROTEST
Fibrosis score ranges from 0 1
1F4
Cirrhosis0.9 Fibrosis score ranges from 0-1
Fibrotest is reliable at identifying patients with: No fibrosis – score under 0.10 Cirrhosis – score of over 0.75
It is not reliable in predicting between stages 1-3
Cirrhosis0.8
0.7F3
0.6
0.5F2
0.4
IVer
Patients with bridging fibrosis may not be recognized
0.3F1
0.2
0.1No fibrosis
0T Poynard et al.Clin Chem 2007; 53:1615-1622.
ASSESSMENT OF LIVER HISTOLOGYSERUM TESTS
T Poynard et al
Hepatology 2003; 38:481-492.
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Mitchell L. Shiffman, MD, FACG
NON-INVASIVE MARKERS OF FIBROSIS
FIBROSCAN
Transient elastrography:
• Ultrasound waves enter liver
• Bounce off fibrosis
IVer
• Return to transducer
• The greater the degree of fibrosis the faster the sound waves return to the transducer
NON-INVASIVE MARKERS OF FIBROSIS
FIBROSCAN
IVer
The impact of obesity?
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Mitchell L. Shiffman, MD, FACG
NON-INVASIVE MARKERS OF FIBROSISCOMPARISON OF TESTS
All noninvasive markers of All noninvasive markers of fibrosis provide similar information
All separate mild disease from advanced fibrosis
None of these tests can differentiate between mild and advanced fibrosisand advanced fibrosis
None of these tests can predict which patients will develop progressive fibrosis
L Castera et al.
Gastroenterology 2005;128:343-350.
TREATMENT OF CHRONIC HCVASSESSMENT OF SVR
Likelihood of SVR
>95% Increase chance for SVR:• IL28B genotype CC• Mild fibrosis• Prior relapse• Low viral load (< 200,000 IU)
75% Start point
D h f SVR
IVer
~15%
Decrease chance for SVR:• IL28B genotype TT• Bridging fibrosis or cirrhosis• Prior non-response
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Mitchell L. Shiffman, MD, FACG
IL28B GENOTYPE AND LIVER BIOPSY
SUMMARY
• Both IL28B genotype and knowledge of liver histologyBoth IL28B genotype and knowledge of liver histology are useful for: Assessing the need for treatment Assessing the likelihood that interferon based
treatment will be successful• Non-invasive tests of liver fibrosis can accurately
predict patients with cirrhosis but cannot reliably
IVer
p p ydifferentiate mild from advanced fibrosis AST/ALT ratio Platelet count
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