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?
 Prevalence of Cirrhosis in the US

• Approximately 0.27% of the US population,

corresponding to 633,323 persons
• Sixty-nine percent reported that they were
unaware of having liver disease.
• Estimated 28.5% of HCV patients have cirrhosis

Gordon et al. AJG 2-15

 Epidemiologic Patterns of
HCV Infection in the US
Total HCV Infections (millions)

Ever infected
Chronic HCV
Acute HCV
Cirrhosis

Peak
Cirrhosis

1950 1960 1970 1980 1990 2000 2010 2020 2030

Year

Davis GL, et al. Gastroenterology. 2010;138:513-521.

 Importance of Assessing Fibrosis

• Determines urgency of therapy

• Selects patients in need of additional screening
– Varices
– Hepatocellular carcinoma
• Allows for selection of proper treatment plan
and duration of therapy
• Used by many payors as a way to restrict
access to therapy
 Rationale to Assess Fibrosis
in Patients with HCV
• Does not require liver biopsy!
– Non invasive tests
– APRI/Fib-4/elastography/MRI/Fibroscan/Fibrosure
• All patients with HCVshould 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
 Poor Survival Rates in Patients with
Decompensated Cirrhosis
100
Compensated HCV cirrhosis

80
Survival Probability (%)

60

40

HCV cirrhosis with

20 a complication

e.g. Decompensated Cirrhosis

0
0 12 24 36 48 60 72 84 96 108 120
Months
A 384 376 342 288 236 165 126 79 52 39 25
B 65 39 21 11 7 4 4 3 3 2 1
Patients at risk
Patients with HCC at time zero were excluded
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
 Assessing Fibrosis

Ø Liver biopsy
– Widely available
– In real life, it is not as good as advertised
Ø Vibration-controlled transient elastography – VCTE
– FDA approved, not yet widely available in in the U.S.
Ø MRI elastography
– Expensive, not readily available
Ø Serum tests and formulas:
– Fibrosure, APRI, AST/ALT ratio, Forns index, FIB-4, etc.
• Work well in cases of no fibrosis or established cirrhosis

No single test is accurate enough!

 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
 Noninvasive Methods to
Assess Hepatic Fibrosis
Serum Tests Measurement of
• AST to platelet ratio liver stiffness
(APRI) • Transient elastography
• FIB4: Age, AST, • Acoustic radiation force
ALT, platelets impulse imaging
• Fibrosure • Magnetic resonance
(Fibrotest in Europe) elastography
• Other lab techniques:
– ELF
– Forns
– Hepascore

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

 APRI and FIB-4 Calculation

< 1.45 = F0-F1 fibrosis

> 1.0 specificity 72% for F4 fibrosis > 3.25 = F3-F4 fibrosis

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

 Fibrosure

• Fibrosure ( available in US)

Result METAVIR Results
• Fibrotest ( available in Europe)
0.75-1.00 F4
• Components of these tests: 0.73-0.74 F3-F4
– Age
0.59-0.72 F3
– Gender
0.49-0.58 F2
– serum y-glutamyl
0.32-0.48 F1-F2
transferase (GGT)
0.28-0.31 F1
– total bilirubin (TB)
0.22-0.27 F0-F1
– a-2 macroglobulin
0.00-0.21 F0
– Haptoglobin
– apolipoprotein A1
– alanine aminotransferase (ALT)
if also assessing inflammation
 How Accurate are
Non-Invasive Tests of Fibrosis?
Systematic Review of 172 Studies
Test Sensitivity Specificity AUROC

Platelet < 140 0.56 0.91 0.71

APRI > 0.5 0.81 0.55 0.71
APRI > 1.5 0.37 0.95
AST/ALT > 1 0.35 0.77 0.59

ELF > 8.75 0.85 0.70 0.81

FIB-4 > 1.45 0.64 0.68 0.74
FIB-4 > 3.25 0.50 0.79
Fibrotest > 0.1 0.92 0.38 0.79
Fibrotest > 0.7 0.22 0.96
Forns > 4.2 0.88 0.52 0.76
Forns > 6.9 0.36 0.94
Hepascore > 0.46 0.6 0.79 0.79
Chou and Wasson. Ann Int Med. 2013;158:807-820.
 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
*Complications include:
– Biopsy
Pain, bleeding, hollow viscus
– Pathology
perforation – mortality in 0.005%
 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.
 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)
 How Good is Liver Biopsy?

§ Widely regarded as the “Gold Standard”

– Compared to what?
§ Published data may not represent real-life
results
§ What is an optimal liver biopsy?
 Liver Biopsy in HCV

§ Specimen size matters

– >11 portal tracts should be represented

Colloredo G, et al. J Hepatol 2003;39:239-244

 How Can You Get an Accurate Liver
Biopsy Interpretation?
• Size matters!
– Ideal specimen: >2cm, 16 or 14 gauge needle (1.4mm width)
– 93.7% of biopsies 2cm long had >11 portal tracts
• Pathologist matters!
§ 391 HCV patients underwent liver biopsies
§ 2 hepatopathologists read the biopsies, reading
compared to community pathologist
– Agreement among readings: 50%
– Community pathologists under-staged fibrosis in 73% of
cases
Colloredo G, et al. J Hepatol 2003;39:239-244
Robert M, et al. Clin Gastroenterol Hepatol 2009;7:335-338
 Interobserver Agreement Between
Hepatopathologists and Community
Pathologists

Kappa values: >0.75 = excellent; 0.4 to 0.74 = good; <0.4

= poor
Robert M, et al. Clin Gastroenterol Hepatol 2009;7:335-338
Liver Biopsy May Not be As Good As
Advertised

• How many of your biopsies:

– Are >2cm in length and a single intact
specimen?
– Obtained with a 14 or 16 gauge needle?
– Pathology report states the number of
portal tract present?
– Read
Liverbybiopsy
a hepatopathologist?
is one of several
components of fibrosis assessment
 Vibration-Controlled Transient
Elastography (VCTE)

• Non-invasive method to assess fibrosis

Tapper EB, et al. Clin Gastroenterol Hepatol 2015;13:27-36

Liver Stiffness by Transient Elastography

• Ultrasound-based technique Caveats: Fails in up to

• Determines liver “stiffness”
20%
• Correlates well with fibrosis
• No ceiling, ie, increases
(especially in obese
with worsening patients) – improved
cirrhosis→predicts with XL probe.
complications
(eg, varices) Influenced by
• Simple to use – minimal inflammation – it
training
falsely
• Other methods in development
– Shear wave elastography elevates
measurements
VCTE Analyzes a Larger Volume of Liver
Tissue
VCTE Liver Biopsy

~ 1 cm x 4 cm ~ 0.14 cm x 2-3
cm
 VCTE vs. Liver Biopsy

ADVANTAGES DISADVANTAGES
– Non-invasive • Test failure or unreliable
– Safer, less expensive
results
– BMI >30 kg/m2
– Can be used for serial – Inexperienced operator
assessment of fibrosis (<100 exams; best: >500)
• Best to differentiate
F0/F1 from F4
• Gives no information on
inflammation
•

HCV: >7.3 kPa suggests significant fibrosis; >12.5

kPa suggests cirrhosis
Tapper EB, et al. Clin Gastroenterol Hepatol 2015;13:27-36
 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.
 Fibroscan and Fibrosure Results Predict
Overall 5 Year Patient Survival in HCV Infection

B 1.0
≤9.5 kPa
C 1.0 ≤.75
>.75
>9.5 kPa >.80
0.8
0.8 >.85
Overall Survival (%)

Overall Survival (%)

>.90
>30 kPa
0.6 >20 kPa 0.6
>40 kPa
0.4 0.4

>50 kPa
0.2 0.2
>.95

P<.0001 P<.0001
0.0
0.0
0 20 40 60 80 0 20 40 60
Follow-up (Months) Follow-up (Months)

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

 Combining Fibroscan and Fibrotest/Fibrosure
May Increase Accuracy of Fibrosis Assessment
and Decrease Requirement for Liver Biopsy
HCV patients
(n=302)
Liver Biopsy
was required to
FIBROSCAN + FIBROTEST
(n=302) assess fibrosis
FS failure
infrequently
Disagree Agree
(n=8)
and only when
Fibroscan and
FS ≥ 7.1 kPa FS < 7.1 kPa FS < 7.1 kPa FS ≥ 7.1 kPa
and
FT ≤ 0.48
and
FT > 0.48
and
FT ≤ 0.48
and
FT > 0.48
Fibrotest results
(n=49) (n=29) (n=87) (n=129)
did not concur

LIVER BIOPSY NEEDED Significant fibrosis absent or present

No need for liver biopsy
(n=86) (n=216)

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

 Non-Invasive Assessment of Fibrosis

VCTE + serum markers

fibrosis

Discordant results Concordant results

Recheck Cirrhosis No
Cirrhosis

Still discordant
Cancer Disease-
and specific
Varices follow-up
Liver Biopsy Screen

Tapper EB, et al. Clin Gastroenterol Hepatol 2015;13:27-36

 • 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
• Not widely
available
• Expensive
Yin M, et al. Radiology. 201727:160622.
Take Home Message:
Use All Your Tools!

• Serum fibrosis tests

• AST/ALT ratio
– >1 suggests advanced fibrosis if no alcohol
• APRI
– AST/ULN divided by platelet count x 100; >2 suggests cirrhosis
• Platelet count
– <150,000 suggests portal hypertension
• Ultrasound
– Splenomegaly or PV diameter >13mm suggests portal
hypertension
• VTCE
– >7.3 kPa suggests advanced fibrosis
Methods to Predict Outcomes in
Patients with Liver Disease
 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.

Points*

1 2 3 Childs Class
Encephalopathy None
Grade 1-2
(or precipitant-induced)
Grade 3-4
(or chronic) A= 5-6 points
Ascites None
Mild/Moderate
(diuretic-responsive)
Severe
(diuretic-refractory)
B= 7-9 points
Bilirubin (mg/dL) <2 2-3 >3 C= 10-15 points
Albumin (g/dL) >3.5 2.8-3.5 <2.8

PT (sec <4 4-6 >6 CTP has better

prolonged) or INR <1.7 1.7-2.3 >2.3
prognostic utility
in predicting
outcomes after
https://www.mdcalc.com/child-pugh-score-cirrhosis-mortality
Surgical Procedures
 MELD=Model for End Stage Liver Disease

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 and Prognosis

100 <10
100
P<0.0001
Cumulative Waiting List Survival (%)

92
80 11-18 As MELD rises,
78 survival
decreases
60 26-35
19-25
40
>35
20

0
0 6 12 18 24 30 36
Time (Months)

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

 MELD PREDICTS PRE- & POST-
TRANSPLANT OUTCOMES
7

6 Mortality risk transplanted vs waitlist

Merion, et al. AJT. 2005;2:307-313xt
5
Hazard Ratio

4 Any MELD > 15 predicted better outcomes

IF PATIENT WAS TRANSPLANTED vs
3 Remaining on waiting list

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

100%
100 At any MELD score
90 Normal serum sodium > 10, patients with
80 serum Na+ < 136
Hyponatremia
70 66% had higher death
Mortality (%)

rates when compared

60
50% to patients with
50 normal serum Na+
40 36%

30 25%

20 17%

10 1.5% 0% 3.5%
0% 0% 0%
0
< 10 10-14 15-19 20-24 25-29 ≥30
(n=15) (n=70) (n=63) (n=25) (n=14) (n=7)
MELD Score Categories

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

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?
 Baveno IV International Consensus
Workshop Staging System for Cirrhosis:
1-Year Outcome Probabilities
NO VARICES 1%
Patients without

Compensated
Stage 1 NO ASCITES
portal HTN have low
death rates and low 7% 4.4%

rates of developing Stage 2 VARICES 3.4%

manifestations of NO ASCITES
portal HTN. 6.6% 4% DEATH
However, as pts
Decompensated

develop varices Stage 3 ASCITES ±

20%
VARICES
and/or ascites,
death rates increase 7.6%

Stage 4 BLEEDING
± 57%
ASCITES

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

Sample SVR rates in Compensated
Cirrhosis
 LDV/SOF ± RBV for 12 vs 24 Weeks:
SVR12 in GT 1 Treatment-naïve Patients
Non-Cirrhotic Cirrhotic
99 99
100 97 98 100 100
100 94 94

80
80
SVR12 (%)

SVR12 (%)
60
60

40 40

20 20
179/ 178/ 181/ 179/ 32/ 34/ 31/ 36/
180 184 184 181 34 34 33 36
0 0
LDV/S LDV/SOF LDV/S LDV/SOF LDV/S LDV/SOF LDV/SO LDV/SOF
OF + RBV OF + RBV OF + RBV F + RBV

12 Weeks 24 Weeks 12 Weeks 24 Weeks

Afdhal, et al. N Eng J Med. 2014;370:1889-98.
 Effect of Tx Duration and RBV in Cirrhotic,
PI-Experienced, GT1 Pts (LDV/SOF)

12 wks of LDV/SOF + RBV 24 wks of LDV/SOF

100 96 97
Pts with previous IFN,
80 riba, boceprevir,
telaprevir, simeprevir,
SVR12 (%)

60 or faldaprevir failure

40

20
N= 77 77
0

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

 Ombitasvir/Paritaprevir/r + Dasabuvir in
HCV Genotype 1b With Cirrhosis
• Phase 3, open-label study (n=60) SVR12
– Treatment-naïve (n=27) or pegIFN- 100%
experienced (n=33), genotype 1b 100

– HCV RNA >1000 IU/mL

80
– Compensated cirrhosis (Child-Pugh A), NO
no history of decompensation Riba!!

SVR12 (%)
– Creatinine clearance >30 mL/min 60

• 12 weeks of treatment
40
• Safety
– No discontinuations due to
20
adverse events

0
Compensated
Cirrhosis
(n=60)

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

 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
12 Weeks 24 Weeks
99 100 100 100 100 100 100 100 100
100
90 86
80
70
SVR12 (%)

60
50
40
30
20
67 51 22 18 14 10 6 3 25 20
10
/68 /51 /22 /18 /14 /10 /7 /3 /25 /20
0
Overall Treatment Relapse Partial Null
naive response response

Treatment-
Colombo M, et al. AASLD 2014, Boston. #1931. experienced
 Elbasvir and grazoprevir: Efficacy in
Treatment-Naive HCV GT1-Infected
SVR Rates for GT1 Subjects Receiving 12 Weeks of Therapy
Overall SVR SVR by GT1 Subtype SVR by Cirrhosis Status

95% 98% 94% 97%

100 92%
Subjects Achieving SVR, %

90
80
70
60
50
40
30
20 273 144 129 207 66
n 288 157 131 220 68
10
N
0 b
GT1a GT1b Without With
Cirrhosis Compensated
Cirrhosis
• <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.
 Sofosbuvir/Velpatasvir for 12 Weeks
in GT 1, 2, 4, 5, 6 HCV-Infected Patients

99 99 99 99 99
100

80
SVR12 (%)

60

40

20
618/624 496/501 120/121 418/423 200/201
0
Total Non- Cirrhotic Treatment- Treatment-
Cirrhotic Naïve Experienced

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

Benefits of SVR in HCV: The expected
and the unexpected
 Regression of Advanced Fibrosis or
Cirrhosis by FibroScan Post SVR
• Retrospective chart review of SVR12
Change in Fibrosis by FibroScan
and prospective FibroScan, biopsy,
and/or clinical assessment after SVR12 100
(n=100) Improved No change Worsen
– Cirrhosis/F3-F4 (65%/35%)
80
• Regimens 69%
– Sofosbuvir-based (45%), telaprevir +

Patients (%)
PR (29%), PR (16%), clinical 60%
60 55%
trial/other (10%)
• Overall median time to improvement: 45%

2.5 years after SVR 40 34%

– Cirrhosis versus F3-F4: 3.0 versus
2.5 years
20 17%
• Predictor of regression in F3-F4 at 14%
baseline: APRI (P<0.05) 6%
0%
• Surrogate marker of improvement 0
of baseline cirrhosis: decrease in Overall F3-F4 Cirrhosis
(n=100) (n=35) (n=65)
ALT (P=0.03)
Baseline
Crissien AM, et al. Hepatology. 2015;62(suppl S1):264A-265A. Abstract 108.
 SVR Decreases Mortality in Patients
with Advanced Fibrosis
530 patients followed for a median of 8.4 years
Baseline factors
SVR patients Non-SVR patients
significantly associated
with all-cause mortality: 29.9
30
27.4
• Older age 26.0

Occurrence Rate (%)

25
10-year Cumulative
• GT 3 (2-fold 21.8
increase in mortality
20
and HCC)
• Higher Ishak 15
fibrosis score
• Diabetes 10 8.9

• Severe alcohol use 5.1

5
2.1
1.9
0
All-cause Liver-related HCC Liver failure
mortality mortality or
liver transplant
Van der Meer A, et al. JAMA. 2012; 308:2584‒2593.
 SVR to HCV Therapy Reduced HCC and Liver-
Related Complications in Patients With
Bridging Fibrosis or Cirrhosis
HCC Liver-Related Complications*
(n=307) (n=307)

100 100
Therapy: Interferon and Ribavirin: SVR 33%

Cumulative Incidence (%)

Cumulative Incidence (%)

80 80

Non-SVR Non-SVR
60 60

P<.001
40 40

P<.001
20 20
SVR
SVR
0 0
0 2 4 6 8 10 12 0 2 4 6 8 10 12
Follow-Up (years) Follow-Up (years)

*Ascites, variceal bleeding.

Cardoso A-C, et al. J Hepatol. 2010;52:652-657.
The Expected: HCV Cure Decreases Risk
of Liver and Non-liver complications

• SVR associated with

–decreased incidence of HCC
–reduced risk of hepatic
decompensation
–reduced risk of cardiovascular
events
–reduced risk of bacterial infections
Nahon et al. Gastro 2017; 152:142-156.
 The Unexpected: Viral Reactivation after
SVR

• Hepatitis B reactivation1 • Herpesvirus2

– 24 reported cases, including 2 deaths – 10 reactivations
• Includes isolated HBc IgM • 7 cutaneous
– All patients initiating HCV DAA therapy • 2 ocular
should be assessed for HBV coinfection • 1 labialis
with HBsAg, anti-HBs and anti-HBc.
– For HBsAg+ patients who are not
already on HBV suppressive therapy,
• Monitoring of HBV DNA levels during and
immediately after DAA therapy for HCV is
recommended
• Antiviral treatment for HBV should be given
if treatment criteria for HBV are met.
– The FDA now requires a boxed
warning for all DAAs.

1. AASLD guidance document. Accessed 11-18-2016

2. 2. Perello et al. Clin Gastro and Hep 2016;14:1662-66
 Post-SVR Treatment Monitoring:
Recommendations
• Clinicians should evaluate patients with
persistent abnormal transaminase levels after
SVR for other causes of liver disease and
consult with a liver disease specialist.
• Clinicians should screen for hepatocellular
carcinoma (HCC) every 6 months.
• Clinicians should recommend EGD for screening
for esophageal varices every 2-3 years
 Summary

• It is critical to identify those HCV patients with bridging

fibrosis and cirrhosis
• Prevalence of cirrhosis in 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
• SVR rates are high in patients with bridging fibrosis and
cirrhosis