New York State

HCV Provider Webinar Series

Overview of Fibrosis Staging,

Child’s Pugh, MELD Scores

Objectives

• Discuss the rationale to assess fibrosis in HCV

infected patients

• Review prevalence of advanced fibrosis in US HCV

infected patients

• Discuss techniques to assess fibrosis

– Lab testing

– Non-invasive imaging

– Liver Biopsy

• Review Childs-Pugh Score and MELD related to

predicting patient outcomes

• Analyze treatment response rates in HCV infected

patients with cirrhosis

What is the Prevalence of Cirrhosis

in US Patients Infected with HCV?

0

5

10

15

20

25 1988-1995

1996-2006

2007-2012

Advanced Fibrosis (FIB-4)

Cirrhosis (APRI >2 [Ishak 5-

6])

Prevalence of Cirrhosis or Advanced Fibrosis Among US

Residents With HCV

HC

V S

urv

ey

Pa

rtic

ipan

ts (

%)

7%

16%

9%

8%

17%

10%

Rates of Fibrosis are Increasing as the Patient Population Ages

• An estimated 370,500

Americans with cirrhosis and

347,800 with advanced fibrosis

(2007-2012)

– Nearly one in five US adults

with HCV infection have

cirrhosis

• During 2007-2012

– Cirrhosis was associated with

• Increasing age (OR: 1.04)

• Diabetes (OR: 2.33)

• Obesity (OR: 2.96)

– Advanced fibrosis was

associated with

• Increasing age (OR: 1.08)

• Diabetes (OR: 3.37)

NHANES: Prevalence of Cirrhosis and

Advanced Fibrosis Among US Adults With HCV

(1988-1994 and 1999-2012)

Udompap P, et al. J Hepatol. 2016;64;1027-1032.

Rationale to Assess Fibrosis

in Patients with HCV

• Presence of cirrhosis:

– Triggers routine cirrhosis care

• Evaluation for esophageal and/or gastric varices

• Surveillance for hepatocellular carcinoma

– May effect rate of SVR

– May affect treatment duration

– May require use of ribavirin

• Does not require liver biopsy!

– Non invasive tests

– APRI/Fib-4/elastography/MRI/Fibroscan/Fibrosure

• All patients with liver disease should undergo an

assessment of fibrosis

Compensated vs.

Decompensated Cirrhosis

• Patients with Decompensated Cirrhosis have

portal hypertension and/or one or more of the

following complications

– Ascites (Hepato-renal Syndrome, hepatic

hydrothorax)

– Hepatic Encephalopathy

– Varices (esophageal,gastric)

– Portal Hypertensive Gastropathy

– Hepatocellular Carcinoma

Su

rviv

al

Pro

ba

bil

ity (

%)

Months

00

384A

Patients at risk

Compensated HCV cirrhosis

HCV cirrhosis with

a complication

65 39 21 11 7 4 4 3 3 2 1B376 342 288 236 165 126 79 52 39 25

12 24 36 48 60 72 84 96 108 120

20

40

60

80

100

e.g. Decompensated Cirrhosis

Patients with HCC at time zero were excluded

Poor Survival Rates in Patients with

Decompensated Cirrhosis

Fattovich, et al. Gastro. 1997:112:463-72.

Tools to Assess:

Fibrosis/Cirrhosis/Portal Hypertension

• Physical Exam

– Nodular liver, splenomegaly

– Presence of spider angiomata, palmar erythema, gynecomastia,

caput medusa

• Caveat: findings are specific for cirrhosis and/or portal HTN, but are

not sensitive

• Radiology

– Helpful if studies reveal:

• Nodular liver

• Enlarged caudate lobe

• Enlarged Spleen

• Reversal of flow in portal vein or the presence of

portal vein collaterals

Lab Tests to Assess Fibrosis

• Liver Enzymes ( AST/ALT) may be normal

or elevated in patients with advanced fibrosis

or cirrhosis

• Normal ALT does not mean “inactive HCV”

• Liver Tests including bilirubin, albumin, INR may

be normal until patients have advanced cirrhosis

• Liver tests that suggest advanced fibrosis/

cirrhosis include:

– Platelet count < 150 K

– AST:ALT ration > 1

– Elevated globulins

Noninvasive Methods to

Assess Hepatic Fibrosis

Serum Tests

• AST to platelet ratio

(APRI)

• FIB4: Age, AST,

ALT, platelets

• Fibrosure

(Fibrotest in Europe)

• Other lab techniques:

– ELF

– Forns

– Hepascore

Measurement of

liver stiffness

• Transient elastography

• Acoustic radiation force

impulse imaging

• Magnetic resonance

elastography

Castera L. Gastroenterology. 2012;142:1293-1302.

> 1.0 specificity 72% for F4 fibrosis < 1.45 = F0-F1 fibrosis

> 3.25 = F3-F4 fibrosis

APRI and FIB-4 Calculation

Zhu X. Dig Dis Sci. 2011:56: 2742-29.

Results Result METAVIR

0.75-1.00 F4

0.73-0.74 F3-F4

0.59-0.72 F3

0.49-0.58 F2

0.32-0.48 F1-F2

0.28-0.31 F1

0.22-0.27 F0-F1

0.00-0.21 F0

Fibrosure

• Fibrosure ( available in US)

• Fibrotest ( available in Europe)

• Components of these tests:

– Age

– Gender

– serum y-glutamyl

transferase (GGT)

– total bilirubin (TB)

– a-2 macroglobulin

– Haptoglobin

– apolipoprotein A1

– alanine aminotransferase (ALT)

if also assessing inflammation

• Good for mild vs advanced fibrosis

• Cheap, noninvasive

• Best validated in hepatitis C

Benefits of Non-Invasive Fibrosis Testing

0.0

0.2

0.4

0.6

0.8

0.8 15.0

10.0

5.0

0.0

-5.0

0 1 2 3 40 1 2 3 40 1 2 3 4

0 1 2 3 4 0 1 2 3 4 0 1 2 3 4

0.6

0.4

0.2

0.0

1.0

0.0 0.0

2.0

4.0

6.0

8.0

10.0

12.0

0.0

2.0

4.0

6.0

8.0

10.0

12.0

0.2

0.4

0.6

0.8

1.0

Fib

rote

st

MP

3

Fib

rom

ete

r

Hep

as

co

re

Fo

rn’s

Sco

re

AP

RI

• Significant overlap across stages

• May be influenced by other factors

• Caveat: may not be so sensitive

for F2-F3

Fib

rosu

re

Leroy. J Hepatol. 2007;775-82.

How Accurate are

Non-Invasive Tests of Fibrosis?

Systematic Review of 172 Studies

Chou and Wasson. Ann Int Med. 2013;158:807-820.

Test Sensitivity Specificity AUROC

Platelet < 140 0.56 0.91 0.71

APRI > 0.5

APRI > 1.5

0.81

0.37

0.55

0.95

0.71

AST/ALT > 1 0.35 0.77 0.59

ELF > 8.75 0.85 0.70 0.81

FIB-4 > 1.45

FIB-4 > 3.25

0.64

0.50

0.68

0.79

0.74

Fibrotest > 0.1

Fibrotest > 0.7

0.92

0.22

0.38

0.96

0.79

Forns > 4.2

Forns > 6.9

0.88

0.36

0.52

0.94

0.76

Hepascore > 0.46 0.6 0.79 0.79

Liver Stiffness by Transient Elastography

• Ultrasound-based technique

• Determines liver “stiffness”

• Correlates well with fibrosis

• No ceiling, ie, increases

with worsening

cirrhosis→predicts complications

(eg, varices)

• Simple to use – minimal training

• Other methods in development

– Shear wave elastography

Caveats: Fails in up to 20%

(especially in obese patients) –

improved with XL probe.

Influenced by inflammation – it falsely

elevates measurements

• Very good for minimal fibrosis (F0-2) vs cirrhosis (F4)

• Lots of overlap in the middle

• Becoming more widely available

P < 0.001

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0 100

63

40

25

16

10

6.3

4.0

2.50

n = 15 n = 49 n = 26 n = 14 n = 65

1 2 3 4

Lo

gari

thm

of

Tra

ns

ien

t E

las

tom

etr

y

Meas

ure

men

t (l

og

kP

a)

Tra

nsie

nt

Ela

sto

metr

y M

eas

ure

me

nt

(lo

g k

Pa

)

Fibrosis Stage

Liver Stiffness by Transient Elastography

Boursier J, et al. Am J Gastroenterol. 2011;106:1255-63.

Correlation Between Liver Stiffness (kPA)

& Fibrosis Stage

*Gastroentérol Clin Biol. 2008;32,58-67; **J Hepatol. 2009;49:1062-68. Aliment Pharmacol Ther. 2008;28:1188-98;

***Hepatology. 2010;51:454-62. Gastroentérol Clin Biol. 2008;32:58-67.

F1: Patient with F1 liver fibrosis, exhibiting mean elasticity values of 6.8

kPa. Standard deviation of 0,7 kPa demonstrate tissue homogeneity

Shearwave Elastography allows

Ultrasound and Assessment of Fibrosis

to be performed Simultaneously

Liver Biopsy

was required to

assess fibrosis

infrequently

and only when

Fibroscan and

Fibrotest results

did not concur

Combining Fibroscan and Fibrotest/Fibrosure

May Increase Accuracy of Fibrosis Assessment

and Decrease Requirement for Liver Biopsy

Castera L. J Hepatology. 2010;52:191-198.

HCV patients

(n=302)

FIBROSCAN + FIBROTEST

(n=302)

Disagree FS failure

(n=8) Agree

FS ≥ 7.1 kPa

and

FT ≤ 0.48

(n=49)

FS < 7.1 kPa

and

FT > 0.48

(n=29)

FS < 7.1 kPa

and

FT ≤ 0.48

(n=87)

FS ≥ 7.1 kPa

and

FT > 0.48

(n=129)

LIVER BIOPSY NEEDED

(n=86)

Significant fibrosis absent or present

No need for liver biopsy

(n=216)

0.00.0

0.2

0.4

0.6

0.8

1.0

0

P<.0001 P<.0001

20 40 60 0 20 40 60

>.95

>.90

>.85

>.80>.75

≤.75

80

0.2

0.4

0.6

0.8

1.0

Follow-up (Months) Follow-up (Months)

Ov

era

ll S

urv

ival

(%)

Ov

era

ll S

urv

ival

(%)

B C

>50 kPa

>40 kPa

>20 kPa>30 kPa

>9.5 kPa

≤9.5 kPa

Fibroscan and Fibrosure Results Predict

Overall 5 Year Patient Survival in HCV Infection

Verginol, et al. Gastroenterology. 2011;140:1970.

Yin M, et al. Radiology. 201727:160622.

• Measures stiffness

of liver by

introducing shear

waves via MRI.

• Older MRI units

can be “upgraded”

to perform MRE

• Software Upgrade

allows assessment

of Liver Stiffness

Liver Biopsy

Pros

• Gold standard for intermediate fibrosis stages

• Assess activity (inflammation)

• Other diagnoses

– Fatty liver

– Autoimmune

Cons

• Invasive

• Complications*

• Sampling error

• Expensive

• Requires experts

– Biopsy

– Pathology

*Complications include:

Pain, bleeding, hollow viscus

perforation – mortality in 0.005%

Indications for Liver Biopsy

Documented HCV infection

(HCV RNA positive) plus:

• Inconclusive, unreliable, or unavailable non-

invasive tests

• Diagnostic uncertainty

– Concern about concomitant condition • Fatty liver

• Alcohol

• Autoimmune hepatitis

• Drug-induced liver injury

• Other i.e, unexplained lab results

(AMA, ANA, Ceruloplasmin, Alpha 1 AT, Ferritin)

liver liver

deflated

balloon Inflated

balloon

Free hepatic

Vein pressure Wedged Hepatic

Vein pressure to assess

Portal pressure

Options for Liver Biopsy in Patients Unable to

Undergo Transcutaneous Liver Biopsy

• In patients who are coagulapathic and/or have significant ascites,

transcutaneous liver biopsy may not be possible

• Transjugular liver biopsy with hepatic and portal pressure

measurements can provide liver tissue and assess if the patient

has portal HTN

– Portal pressure – free hepatic vein pressure > 10 mmHG = clinically

significant portal HTN, when ascites, varices, encephalopathy may occur

Liver Biopsy Appearance and

Categories of Fibrosis

1. Brunt EM. Hepatology. 2000;31:241-246; 2.Standish R, et al. Gut. 2006;55:569-578; 3. Knodell RG, et al. Hepatology. 1981;1:431-435;

4. Bedossa P, Poynard T. Hepatology. 1996;24:289-293.

Methods to Predict Outcomes in

Patients with Liver Disease

CTP has better

prognostic utility

in predicting

outcomes after

Surgical Procedures

https://www.mdcalc.com/child-pugh-score-cirrhosis-mortality

Points*

1 2 3

Encephalopathy None Grade 1-2

(or precipitant-induced)

Grade 3-4

(or chronic)

Ascites None Mild/Moderate

(diuretic-responsive)

Severe

(diuretic-refractory)

Bilirubin (mg/dL) <2 2-3 >3

Albumin (g/dL) >3.5 2.8-3.5 <2.8

PT (sec

prolonged) or INR

<4

<1.7

4-6

1.7-2.3

>6

>2.3

Child-Turcotte-Pugh (CTP) Calculator

This calculator is used for the classification of the severity of cirrhosis

*CTP score is obtained by adding the score for each parameter.

CTP class:

A= 5-6 points

B= 7-9 points

C= 10-15 points

Surgical Outcomes

Number of patients (percentages) shown.

Ascites=ascites present on physical examination and/or imaging

studies; emergent=emergency surgery performed;

morbidity=postoperative complications or death within 30 days.

Causey, et al. American Journal of Surgery. 2012;203:589-593.

Total (n=64) Morbidity

(n=28)

Mortality at

3 mo (n=7)

Mortality at

1 y (n=17)

CTP class A 23 7 (30) 0 (0) 2 (9)

CTP class B 31 13 (42) 3 (10) 8 (26)

CTP class C 10 8 (80) 4 (40) 7 (70)

Emergent 10 9 (90) 2 (20) 6 (60)

Ascites 34 21 (62) 6 (18) 14 (41)

MELD and MELD Sodium are

useful to predict survival in

patients with cirrhosis

http://www.mayoclinic.org/medical-professionals/model-end-stage-liver-disease/meld-model

MELD=Model for End Stage Liver Disease

0

0 6 12 18 24

P<0.0001

30 36

20

40

60

80

100100

92

78

Time (Months)

Cu

mu

lati

ve W

ait

ing

Lis

t S

urv

ival

(%)

As MELD rises,

survival

decreases

MELD and Prognosis

Kamath P, et al. Hepatology. 2001;33(2):464-70.

0

0 6 12 18 24

P<0.0001

30 36

20

40

60

80

100100

92

78

Time (Months)

Cu

mu

lati

ve W

ait

ing

Lis

t S

urv

ival

(%)

<10

As MELD rises,

survival

decreases

MELD and Prognosis

Kamath P, et al. Hepatology. 2001;33(2):464-70.

0

0 6 12 18 24

P<0.0001

30 36

20

40

60

80

100100

92

78

Time (Months)

Cu

mu

lati

ve W

ait

ing

Lis

t S

urv

ival

(%)

<10

11-18 As MELD rises,

survival

decreases

MELD and Prognosis

Kamath P, et al. Hepatology. 2001;33(2):464-70.

0

0 6 12 18 24

P<0.0001

30 36

20

40

60

80

100100

92

78

Time (Months)

Cu

mu

lati

ve W

ait

ing

Lis

t S

urv

ival

(%)

<10

11-18

19-25

As MELD rises,

survival

decreases

MELD and Prognosis

Kamath P, et al. Hepatology. 2001;33(2):464-70.

0

0 6 12 18 24

P<0.0001

30 36

20

40

60

80

100100

92

78

Time (Months)

Cu

mu

lati

ve W

ait

ing

Lis

t S

urv

ival

(%)

<10

11-18

19-25 26-35

As MELD rises,

survival

decreases

MELD and Prognosis

Kamath P, et al. Hepatology. 2001;33(2):464-70.

0

0 6 12 18 24

P<0.0001

30 36

20

40

60

80

100100

92

78

Time (Months)

Cu

mu

lati

ve W

ait

ing

Lis

t S

urv

ival

(%)

<10

11-18

19-25 26-35

>35

As MELD rises,

survival

decreases

MELD and Prognosis

Kamath P, et al. Hepatology. 2001;33(2):464-70.

7

6

5

4

3

2

1

0

Hazard

Rati

o

MELD

Hazard Ratio 3.64 2.35 1.21 0.62 0.38 0.22 0.18 0.07 0.04

p-values <0.001 <0.001 0.41 <0.01 <0.001 <0.001 <0.001 <0.001 <0.001

6-11 12-14 15-17 18-20 21-23 24-26 27-29 30-39 ≥40

Any MELD > 15 predicted better outcomes

IF PATIENT WAS TRANSPLANTED vs

Remaining on waiting list

MELD PREDICTS PRE- & POST-

TRANSPLANT OUTCOMES

7

6

5

4

3

2

1

0

Hazard

Rati

o

MELD

Hazard Ratio 3.64 2.35 1.21 0.62 0.38 0.22 0.18 0.07 0.04

p-values <0.001 <0.001 0.41 <0.01 <0.001 <0.001 <0.001 <0.001 <0.001

6-11 12-14 15-17 18-20 21-23 24-26 27-29 30-39 ≥40

Mortality risk transplanted vs waitlist Merion, et al. AJT. 2005;2:307-313xt

Any MELD > 15 predicted better outcomes

IF PATIENT WAS TRANSPLANTED vs

Remaining on waiting list

MELD PREDICTS PRE- & POST-

TRANSPLANT OUTCOMES

100

90

80

70

60

50

40

30

0% 0% 0% 0%1.5% 3.5%

17%

36%

66%

50%

100%

25%

Normal serum sodium

Hyponatremia

20

10

0< 10

(n=15)

10-14

(n=70)

15-19

(n=63)20-24

(n=25)

25-29

(n=14)

≥30

(n=7)

Mo

rta

lity

(%

)

MELD Score Categories

At any MELD score

> 10, patients with

serum Na+ < 136

had higher death

rates when compared

to patients with

normal serum Na+

Kim R, et al. NEJM. 2008;359:1018-1026, Biggins S, et al. Gastro. 2006;130:1652-1660.

MELD- Na Model

As of January 2016,

MELD-Na is used by UNOS

for organ allocation

What is the One Year Survival in

Patients With and Without Various

Manifestations of Portal HTN?

ASCITES

VARICES

BLEEDING

ASCITES

DEATH

Stage 1

Stage 2

Stage 3

Stage 4

Co

mp

en

sate

d

Deco

mp

en

sate

d

1%

3.4%

20%

57%

4.4% 7%

6.6% 4%

7.6%

Patients without

portal HTN have low

death rates and low

rates of developing

manifestations of

portal HTN.

However, as pts

develop varices

and/or ascites,

death rates increase

Baveno IV International Consensus

Workshop Staging System for Cirrhosis:

1-Year Outcome Probabilities

D’Amico G, et al. J Hepatol. 2006;44:217-231.

VARICES

NO ASCITES

NO VARICES

NO ASCITES

Non Invasive Evaluation of Liver Tissue Fibrosis (Staging)

APRI

Fib-4

Fibrosure

Plat < 150K

CT, MRI

Consider hepatic vein catheterization

with Hepatic Vein and Portal Vein

Pressure Measurements with

Transjugular liver biopsy to Assess for

Portal Hypertension

Summary

Algorithm to Assess Severity of Liver Disease

Complications of cirrhosis

(variceal hemorrhage,

ascites, encephalopathy)

• Plt < 100,000/µl + AST > ALT

• Cirrhotic liver on imaging

Patient has cirrhosis

Screen for Liver Cancer

Assess for Liver Transplantation

• CBC

• Liver profile

• Ultrasound

Fibrosis assessment with

transient elastography

and/or fibrosis serum panel

Disagree, unreliable, unavailable,

or diagnostic uncertainty

Reliable/Agree

History + physical exam

HCV-RNA positive

Manage HCV

according to fibrosis stage Liver Biopsy

OR

Baseline factors

significantly associated

with all-cause mortality:

• Older age

• GT 3 (2-fold

increase in mortality

and HCC)

• Higher Ishak

fibrosis score

• Diabetes

• Severe alcohol use

SVR patients Non-SVR patients

10

-ye

ar

Cu

mu

lati

ve

Occu

rren

ce R

ate

(%

)

8.9

26.0

1.9

27.4

5.1

21.8

2.1

29.9

25

20

15

10

5

0

30

All-cause mortality

Liver-related mortality or

liver transplant

HCC Liver failure

530 patients followed for a median of 8.4 years

SVR Decreases Mortality in Patients

with Advanced Fibrosis

Van der Meer A, et al. JAMA. 2012; 308:2584‒2593.

Improved No change Worsen

0

20

40

60

80

100

Pati

en

ts (

%)

60%

34%

55%

F3-F4 (n=35)

Cirrhosis (n=65)

Baseline

Overall (n=100)

6%

Change in Fibrosis by FibroScan

69%

14% 17%

45%

0%

Regression of Advanced Fibrosis or

Cirrhosis by FibroScan Post SVR

• Retrospective chart review of SVR12

and prospective FibroScan, biopsy,

and/or clinical assessment after SVR12

(n=100)

– Cirrhosis/F3-F4 (65%/35%)

• Regimens

– Sofosbuvir-based (45%), telaprevir +

PR (29%), PR (16%), clinical

trial/other (10%)

• Overall median time to improvement:

2.5 years after SVR

– Cirrhosis versus F3-F4: 3.0 versus

2.5 years

• Predictor of regression in F3-F4 at

baseline: APRI (P<0.05)

• Surrogate marker of improvement

of baseline cirrhosis: decrease in

ALT (P=0.03)

Crissien AM, et al. Hepatology. 2015;62(suppl S1):264A-265A. Abstract 108.

100

80

60

40

20

00 2 4 6 8 10 12

100

80

60

40

20

00 2 4 6 8 10 12

SVRSVR

Non-SVRNon-SVR

P<.001

P<.001

HCC

(n=307)

Liver-Related Complications*

(n=307)

Cu

mu

lati

ve I

ncid

en

ce (

%)

Follow-Up (years)

Cu

mu

lati

ve I

ncid

en

ce (

%)

Follow-Up (years)

SVR to HCV Therapy Reduced HCC and Liver-

Related Complications in Patients With

Bridging Fibrosis or Cirrhosis

*Ascites, variceal bleeding.

Cardoso A-C, et al. J Hepatol. 2010;52:652-657.

100

80

60

40

20

00 2 4 6 8 10 12

100

80

60

40

20

00 2 4 6 8 10 12

SVRSVR

Non-SVRNon-SVR

P<.001

P<.001

HCC

(n=307)

Liver-Related Complications*

(n=307)

Cu

mu

lati

ve I

ncid

en

ce (

%)

Follow-Up (years)

Cu

mu

lati

ve I

ncid

en

ce (

%)

Follow-Up (years)

Therapy: Interferon and Ribavirin: SVR 33%

SVR to HCV Therapy Reduced HCC and Liver-

Related Complications in Patients With

Bridging Fibrosis or Cirrhosis

*Ascites, variceal bleeding.

Cardoso A-C, et al. J Hepatol. 2010;52:652-657.

100

80

60

40

20

00 2 4 6 8 10 12

100

80

60

40

20

00 2 4 6 8 10 12

SVRSVR

Non-SVRNon-SVR

P<.001

P<.001

HCC

(n=307)

Liver-Related Complications*

(n=307)

Cu

mu

lati

ve I

ncid

en

ce (

%)

Follow-Up (years)

Cu

mu

lati

ve I

ncid

en

ce (

%)

Follow-Up (years)

Therapy: Interferon and Ribavirin: SVR 33%

SVR to HCV Therapy Reduced HCC and Liver-

Related Complications in Patients With

Bridging Fibrosis or Cirrhosis

*Ascites, variceal bleeding.

Cardoso A-C, et al. J Hepatol. 2010;52:652-657.

80

94 94100 100

60

40

20

0

100

99 97 98 99

0

20

40

60

80

100

SV

R12 (

%)

179/

180

178/

184

181/

184

179/

181

12 Weeks 24 Weeks

LDV/SOF

+ RBV

LDV/SOF

+ RBV

LDV/S

OF

LDV/S

OF

Non-Cirrhotic

32/

34

34/

34

31/

33

36/

36

LDV/SOF

+ RBV LDV/SOF

+ RBV

LDV/S

OF LDV/SO

F

12 Weeks 24 Weeks

SV

R12 (

%)

Cirrhotic

LDV/SOF ± RBV for 12 vs 24 Weeks:

SVR12 in GT 1 Treatment-naïve Patients

Afdhal, et al. N Eng J Med. 2014;370:1889-98.

No cirrhosis

Cirrhosis

83/

87

19/

22

89/

89

18/

22

86/

87

22/

22

88/

89

22/

22

12 Weeks 24 Weeks

LDV/SOF + RBV LDV/SOF + RBV LDV/SOF LDV/SOF

SV

R12 (

%)

100

80

60

40

20

0

95 86 100 82

100 99 100 99

LDV/SOF ± RBV for 12 vs 24 Weeks:

SVR12 in GT 1 Treatment-experienced Patients

Afdhal, EASL. Abst O109. N Engl J Med. 2014 Apr 17;370(16):1483-93.

Pts with previous IFN,

riba, boceprevir,

telaprevir, simeprevir,

or faldaprevir failure

12 wks of LDV/SOF + RBV

100

80

60

40

20

0

N =

24 wks of LDV/SOF

SV

R12 (

%)

77

97 96

77

Effect of Tx Duration and RBV in Cirrhotic,

PI-Experienced, GT1 Pts (LDV/SOF)

Bourlière M, et al. Lancet Infect Dis. 2015;15:397-404.

99 100 100

86

100 100 100 100 100 100

0

10

20

30

40

50

60

70

80

90

100

Overall Treatmentnaive

Relapse Partialresponse

Nullresponse

SV

R12 (

%)

Treatment-

experienced

67

/68

51

/51 22

/22

18

/18

14

/14

10

/10 6

/7

3

/3

25

/25

20

/20

12 Weeks 24 Weeks

SVR12 in GT 1b Cirrhotic Patients Treated with

PTV/RTV/OMV + DSV + RBV for 12 vs 24 Weeks

• Pooled analysis of Phase 3 trials

• All treated with RBV

Colombo M, et al. AASLD 2014, Boston. #1931.

SVR12

0

20

40

60

80

100

SV

R1

2 (

%)

Compensated Cirrhosis

(n=60)

100%

Ombitasvir/Paritaprevir/r + Dasabuvir in

HCV Genotype 1b With Cirrhosis

Feld JJ, et al. J Hepatol. 2016;64:301-307.

• Phase 3, open-label study (n=60)

– Treatment-naïve (n=27) or pegIFN-

experienced (n=33), genotype 1b

– HCV RNA >1000 IU/mL

– Compensated cirrhosis (Child-Pugh A),

no history of decompensation

– Creatinine clearance >30 mL/min

• Ombitasvir/paritaprevir/r + dasabuvir

for 12 weeks

• All patients achieved SVR12

• Safety

– No discontinuations due to

adverse events

– No grade 3/4 hemoglobin declines

SVR12

0

20

40

60

80

100

SV

R1

2 (

%)

Compensated Cirrhosis

(n=60)

100%

NO

Riba!!

Ombitasvir/Paritaprevir/r + Dasabuvir in

HCV Genotype 1b With Cirrhosis

Feld JJ, et al. J Hepatol. 2016;64:301-307.

• Phase 3, open-label study (n=60)

– Treatment-naïve (n=27) or pegIFN-

experienced (n=33), genotype 1b

– HCV RNA >1000 IU/mL

– Compensated cirrhosis (Child-Pugh A),

no history of decompensation

– Creatinine clearance >30 mL/min

• Ombitasvir/paritaprevir/r + dasabuvir

for 12 weeks

• All patients achieved SVR12

• Safety

– No discontinuations due to

adverse events

– No grade 3/4 hemoglobin declines

0

10

20

30

40

50

60

70

80

90

100

Su

bje

cts

Ac

hie

vin

g S

VR

, %

GT1a GT1b

SVR by GT1 Subtype SVR by Cirrhosis Status Overall SVR

b

n

N

273

288

144

157

129

131 207

220 66

68

95% 98% 92% 94% 97%

Without

Cirrhosis

With

Compensated

Cirrhosis

SVR Rates for GT1 Subjects Receiving 12 Weeks of Therapy

Elbasvir and grazoprevir: Efficacy in

Treatment-Naive HCV GT1-Infected

• <1% (1/288) of subjects experienced on-treatment virologic failure

• 3% (10/288) of subjects relapsed after treatment

Kwo, et al. Gastroenterology. 2017;152:164-175.

99 99 99 99 99

0

20

40

60

80

100

SV

R12 (

%)

618/624 496/501 120/121 418/423

Non-

Cirrhotic

Treatment-

Naïve Treatment-

Experienced

200/201

Total Cirrhotic

Sofosbuvir/Velpatasvir for 12 Weeks

in GT 1, 2, 4, 5, 6 HCV-Infected Patients

N Engl J Med. 2015;373(27):2599-607.

Summary

• Prevalence of cirrhosis in patients with HCV is increasing

• Assessment of fibrosis is critical in all patients with HCV

– May affect therapy choice

– Requires surveillance for varices and liver cancer

• Non-invasive assessment of fibrosis is possible

– Plat count < 150

– APRI, Fib-4, Fibrosure

– Fibroscan, MRE

• Despite the presence of cirrhosis, SVR rates are high in

patients who undergo therapy