Shiffman - Assessment Prior to...

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.

ACG's Hepatitis School - Nashville, TN Copyright 2013 American College of Gastroenterology

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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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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:

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• 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

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• 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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• 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

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• Low rates of RVR• Low rates of virologic response• Low rates of SVR

TT-OFF

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


• 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

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• 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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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%

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SVR 69% 30% 48% 14%

Relapse 14% 34% 23% 36%

A Thompson et al.Gastroenterology 2010; 139:120-129.


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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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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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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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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

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• 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

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• 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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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%

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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

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PRIOR RESPONSE

S Zeuzem et al. N Eng J Med 2011; 364:2417-2428.


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IMPACT OF CIRRHOSIS ON SVR

TREATMENT NAIVE

NoCirrhosis

Cirrhosis

Genotype 2

PEGINF/RBV 82% 62%

Sofosbuvir + RBV 98% 91%

Genotype 3

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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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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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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

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• 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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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

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Total bilirubin

Apolipoprotein A1

Markers of inflammation NOT fibrosis


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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

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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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NON-INVASIVE MARKERS OF FIBROSIS

FIBROSCAN

Transient elastrography:

• Ultrasound waves enter liver

• Bounce off fibrosis

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• Return to transducer

• The greater the degree of fibrosis the faster the sound waves return to the transducer

NON-INVASIVE MARKERS OF FIBROSIS

FIBROSCAN

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The impact of obesity?


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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

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~15%

Decrease chance for SVR:• IL28B genotype TT• Bridging fibrosis or cirrhosis• Prior non-response


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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

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p p ydifferentiate mild from advanced fibrosis AST/ALT ratio Platelet count


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