Presentation at The 2015 Liver Summit

Cholangitis
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AbbVie, Bristol-Myers Squibb, Gilead, Intercept
Pharmaceuticals, and Merck
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Disclaimer
In accordance with the ACCME Standards for Commercial Support of CME,
the speakers for this course have been asked to disclose to participants the
existence of any financial interest and/or relationship(s) (e.g., paid speaker,
employee, paid consultant on a board and/or committee for a commercial
company) that would potentially affect the objectivity of his/her presentation
or whose products or services may be mentioned during their presentation.
The following disclosures were made:
Planning Committee Member
John Bayliss, VP, Business Development, Spouse
-Employee of Amgen, Inc
Lisa D. Pedicone, PhD
-No Relevant Relationships
Faculty
Robert Gish, MD
Medical Director, Professor
Hepatitis B Foundation, San Diego
and Stanford University
Catherine Frenette, MD
Medical Director of Liver Transplantation
Scripps Clinic
La Jolla, CA
Disclosures
Consultant/Speaker Bureau: Contravir, Genentech,
Janssen, MedImmune, Eiger, Novira, Presidio, Bayer,
Gilead Sciences, Inc., Onyx, Salix, AbbVie, Bristol-Myers
Squibb
Advisory Board Membership: AbbVie, Merck,
Arrowhead, Contravir, Novira, Isis, Presidio, Eiger Enyo,
Janssen, MedImmune
Stockholder: Kinex, Synageva, Arrowhead
Educational Objectives
Identify the risk factors and overall disease processes in chronic

liver diseases
Describe current and evolving treatment strategies for chronic liver

diseases in order to optimize patient outcomes
Effectively adhere to long-term surveillance recommendations

outlined in the AASLD guidelines
Primary Biliary Cholangitis (PBC)
What is PBC?
Chronic cholestatic disease with a progressive course
which may extend over many decades
Rate of progression varies greatly
Asymptomatic in early disease
Often leads to fatigue, pruritus and Sicca syndrome (dry
eyes and/or dry mouth)
Primary biliary cholangitis (PBC) affects about 1/1000
women age >40 years and is a leading indication for
liver transplantation1
1. Kumagi T, Heathcote EJ. Orphanet J Rare Dis. 2008;3:1.
Causes and Markers of PBC

Autoimmune disease thought to be due to a
combination of genetic predisposition and
environmental triggers
High degree of specificity for involvement of the
small intrahepatic bile ducts
Serologic hallmark of PBC is the AMA, a highly
disease-specific autoantibody found in 90-95% of
patients and less than 1% of controls.
AASLD Suggested Diagnostic Algorithm

for Patients With Suspected PBC
Elevated serum alkaline phosphatase (ALP) activity
Exclude other causes of liver disease including
alcohol and drugs
Cross sectional imaging of liver to exclude biliary
obstruction
AMA (Antimitrochondrial antibody), ANA (antinuclear
antibody), ASMA (anti-smooth muscle antibody)
Consider liver biopsy, especially if AST>5x ULN or AMA -
Ursodeoxycholic Acid (UDCA)

Orally administered nontoxic bile acid
Replaces the bile acids normally produced by the liver, which
are more toxic and can harm the liver
UDCA in a dose of 13-15 mg/kg/day is the only currently FDA
approved therapy for PBC
UDCA is initiated gradually and given BID
Improvement in liver tests will be seen within a few weeks and
90% of the improvement usually occurs within 6-9 months
AASLD Guidance Document

Safe, may improve clinical symptoms, delay
progression of disease and survival, and
improve QOL
However, up to 40% of PBC patients treated
with UDCA have a suboptimal response
Pares A, Gastroenterology, 2006; Marschall HU, Gastroenterology, 2005.
ALP <1.67 x ULN and Normal Bilirubin after 1 Year

of UDCA is Highly Predictive of Outcome
Global PBC Study Group (N=4845)
Responder
Non-Responder
Lammers, EASL, AASLD. 2013.
Backbone of therapy in PBC in the past 20 years

Early treatment provides the most benefit
Can improve the outcome but does not cure PBC
Up to 40% have a suboptimal response to URSO
defined by AP parameters
Obeticholic Acid (OCA): A Modified Bile Acid

and FXR Agonist
CDCA
OCA (6E-CDCA)
obeticholic acid
chenodeoxycholic acid
6- ethyl
substitution
FXR EC50 = 8.6 M
~100x increased potency
FXR EC50= 90 nM
Obeticholic Acid (OCA): A Modified Bile Acid

and FXR Agonist
OCA in Patients with PBC: POISE Study Design

If on UDCA: Continue UDCA
Randomization Strata
Subjects stratified 1:1:1 by:
1) ALP >3x ULN and/or AST >2x ULN and/or
total bilirubin >ULN (Paris I)
2) Not receiving UDCA treatment
Screening
Placebo (n=73)
OCA 10 mg (n=73)
Titrate to OCA 10 mg (n=33)
OCA 5 mg
W2
M3
Remain at OCA 5 mg (n=36)
M6
M9
M12
OCA Titration at 6 Months: Subjects in OCA

titration arm titrated from 5 mg to 10 mg at
Month 6 if they met any of the following
criteria at the Month 6 assessment:
1.
2.
The primary endpoint (ALP <1.67x ULN

or bilirubin ULN) was not achieved
No evidence of tolerability issues, e.g. pruritus
Primary Objective and Patient Population
To assess the proportion of patients achieving ALP <1.67 xULN and a

decrease of 15% and total bilirubin ULN
Inclusion
PBC diagnosis (EASL and AASLD guidelines)
ALP 1.67 xULN and/or total bilirubin >ULN to <2 xULN
Stable UDCA or unable to tolerate UDCA
Exclusion
Concomitant liver diseases, decompensation, severe pruritus requiring treatment
Randomization Strata
UDCA (yes/no)
Paris I1
1. Corpechot, Hepatology 2008.
Demographic and Baseline Characteristics

Placebo
(N=73)
OCA Titration
(N=70)
OCA 10 mg
(N=73)
55.5 10
55.8 11
56.2 11
68 (93)
65 (93)
63 (86)
White
66 (90)
67 (96)
70 (96)
Non-White
7 (10)
3 (4)
3 (4)
26.2 4
25.6 5
26.3 5
327 115
326 116
316 104
Bilirubin, umol/L
12 7
10 6
11 7
UDCA use, n (%)
68 (93)
65 (93)
67 (92)
Daily UDCA dose, mg/kg
15 4
17 5
16 5
Pretreatment Liver Biopsy Performed
7 (10)
13 (19)
9 (12)
Age at PBC diagnosis, y
47.3 9.3
47.6 11.7
47.1 10.6
Duration PBC, y
8.3 5.4
8.3 5.8
9.2 6.9
Age, y
Sex, Female, n (%)
Race/Ethnicity, n (%)
BMI (kg/m2)
ALP, U/L
Data are mean SD where applicable.
Disposition of OCA Titration Group

70 Subjects Randomized
to Titration
69 Completed
Month 6 Visit
32 Ineligible for Titration

Remained at 5 mg OCA
21 Reached
Primary Endpoint
8 Pruritus
Tolerability
3 Other/Other AE
37 Eligible for Titration to

10 mg OCA
33 Titrated from 5
mg to 10 mg OCA
4 Remained at 5
mg OCA
3 Reached Primary
Endpoint at Month 12
Percent Achieving Primary Endpoint

Responders (%)
60
*
40
Placebo (n=73)
Titration OCA (n=70)
10 mg OCA (n=73)
*p<0.0001 vs. placebo
20
0
6 months
12 months
Response:
Achieving ALP <1.67x ULN with bilirubin ULN and 15% reduction in ALP
p values obtained using Cochran-Mantel-Haenszel stratified by randomization strata factor

Titration OCA group: 5 mg OCA for 6months 10 mg OCA if well tolerated & ALP >1.67x ULN or bilirubin >ULN
OCA Treatment Significantly Reduced ALP

LS Mean (SE) Change in ALP (U/L)
Placebo (n=73)
10 mg OCA (n=73)
0
***
-50
***
-100
***
***
***
***
***
-150
***
***
***
-200
0
6
Time (Months)
12
***p<0.0001 vs. placebo for all post baseline values of Titration OCA and 10 mg OCA groups Baseline values (mean SE, U/L):
Placebo 327 13; Titrated OCA: 326 14; 10 mg OCA: 316 12; N=216
Titration OCA group: 5 mg OCA for 6 months then titrated to 10 mg OCA if tolerated & ALP 1.67x ULN or bilirubin >ULN
A Significantly Greater Proportion of OCA-treated

Subjects Had a 10, 20 or 40% ALP Reduction
10% Reduction
% of Subjects
100
80
20% Reduction
100
***
***
*** ***
60
40% Reduction
100
80
*** ***
60
80
60
***
***
40
40
20
0
40
20
Month 6
Month 12
Placebo (n=73)
*** ***
20
Month 6
Titration (n=70)
Month 12
Month 6
*** ***
Month 12
10 mg OCA (n=73)
***p<0.0001 vs. placebo; p values obtained using Cochran-Mantel-Haenszel stratified by randomization strata factor
OCA Treatment Resulted in Significant Decreases

in Markers of Hepatobiliary Damage
LS Mean (SE) Change from Baseline
GGT (U/L)
ALT (U/L)
AST (U/L)
-50
-10
-10
-100
***
***
-20
-150
***
***
-200
-250
***
-30
***
***
Month 6
Month 12
Placebo (n=73)
-40
***
Month 6
***
-20
***
***
***
Month 12
Titration (n=70)
-30
Month 6
10 mg OCA (n=73)
***p<0.001 vs. placebo

Month 12
OCA Treatment Decreased Bilirubin Over Time

Total Bilirubin
3
2
1
*
-1
*
-2
0
Time (Month)
*
12
LS Mean (SE) Change from Baseline ( m ol/L)
LS Mean (SE) Change from Baseline ( m ol/L)
Placebo (n=73)
10 mg OCA (n=73)
Direct Bilirubin
3
2
1
0
*
-1
-2
0
Time (Month)
*p<0.05 vs. placebo

Baseline Direct Bilirubin (mean SE, mol/L): Placebo 5.5 0.7; Titrated OCA: 4.5 0.5; 10 mg OCA: 4.9 0.5Baseline Total
Bilirubin (mean SE, mol/L): Placebo 11.8 0.9; Titration OCA: 10.3 0.7; 10 mg OCA: 11.3 0.8
12
Adverse Events
Pruritus, generally mild to moderate, was the
most common and dose related AE
Few subjects treated with OCA withdrew due
to pruritus (<6%)
The incidence of AEs other than pruritus was no

worse with OCA (Placebo, 90%, 5/10 mg OCA,
89%, 10 mg OCA, 86%)
Overall Findings
The effect of OCA was consistent independent of age at diagnosis,

duration of PBC and baseline ALP.
Titration from 5 to 10 mg based on clinical response improved
tolerance, minimized dropouts due to pruritus, and showed
comparable efficacy to 10 mg OCA after 1 year. Thus, starting
patients on OCA 5 mg with titration to 10 mg based on the clinical
response appears to be an appropriate dosing strategy.
OCA given to individuals with PBC with an inadequate response to
or unable to tolerate UDCA produced a significant clinically
meaningful improvement in liver biochemistry, which have been
shown to correlate strongly with clinical benefit.
Long-term Management of Patients

with PBC (AASLD Guidance)
Liver tests every 3-6 months

Thyroid status (TSH) annually
Bone mineral densitometry every 2-4 years
Vitamins A, D, K annually if bilirubin >2.0
Upper endoscopy every 1-3 years if cirrhotic or Mayo
risk score >4.1
Ultrasound AFP every 6 months in patients with known
or suspected cirrhosis
Nonalcoholic Fatty Liver Disease (NAFLD)

and Nonalcoholic Steatohepatitis (NASH)
Adult Obesity in America 2014

Percent of Obese Adults
(Body Mass Index of 30+)
20 - 24.9%
25 - 29.9%
30-34.9%
Adult Obesity in America 2011-12

35%+
34.9%
68.5%
Obese
Overweight or Obese
Childhood Obesity in America 2011-12
http://stateofobesity.org/adult-obesity/
16.9%
31.8%
Obese
Overweight or Obese
Diseases Associated with Visceral Obesity

NAFLD is Closely Associated with Visceral Obesity and Insulin Resistance
Visceral
Obesity
Dyslipidemia
Hypertension
Polycystic Ovarian
Syndrome
(PCOS)
Endothelial Dysfunction
Atherosclerosis
Coronary
Artery Disease
(CAD)
Insulin Resistance
Type 2 Diabetes
Non-alcoholic
Fatty Liver Disease
(NAFLD)
The Spectrum of NAFLD

NAFLD Spectrum
Normal
Simple Steatosis
or NAFL
NASH
Exclusion of liver diseases (HCV & ETOH)

Requires specific pathologic criteria for NASH
Important for prognosis
Ludwig 1980, Diehl 1988, Lee 1989, Powell 1990, Bacon 1994, Younossi 1997, Matteoni/Younossi 1999, Angulo 1999, Caldwell 1999, Ponawala 2000, Contos
2001, Ong/Younossi 2001, Bugianesi 2002, Ratziu 2002, Saddeh/Younossi 2002, Harrison 2003, Marchesini 2003, Younossi 2004, Gramlich/Younossi 2004,
Fassio 2004, Sanyal 2004, Ong/Younossi 2005, Adams 2005, Ong/Younossi 2008, Mishra/Younossi 2008, Rafiq/Younossi 2010, Hossain/Younossi 2009,
Kim/Younossi 2010, Stepanova/Younossi 2010, Hossain/Younossi 2010, Stepanova, Younossi 2012, Younossi 2012, Chalasani, Younossi 2012.
Prevalence of NAFLD & NASH

80
Prevalence
(%)
60
46
40
San Antonio, Texas

(Williams, et al.
Gastroenterology.
2011;140:124-31.)
58.3
45
30
20
0
Torres DM. Clin Gastro Hepatol. 2012;32:30-38.
44.4
33
35.1
24
29.9
12.2
Dallas Heart Study

Prevalence Numbers
(Browning, et al.
Hepatology.
2004;40:1387-95.)
Prevalence of NAFLD in Children

Using surrogate markers,
prevalence of NAFLD in
children is 2.6-17.3%
Autopsy study from
UCSD (N=742)
Prevalence: 9.6%, rates
increasing with age
More common in boys
Highest rate in Hispanics
Schwimmer JB 2006, Argo C 2009
Natural History of NAFLD

~70-75%
Isolated Fatty Liver

Fatty Liver with
Mild Inflammation
NAFLD
~20-25%
1.
2.
1.
2.
Possible sampling variability with

some risk of progression
NASH
risk of death compared with general population

1. Cardiovascular
2. Malignancy
3. Liver-related
NASH with fibrosis portends worse prognosis
1. Fibrosis progression a/w DM, severe IR,
weight gain >5kg, rising ALT, AST
None to very minimal progression

to fibrosis
No risk of death compared with
the general population
~7.2% over 6.5 years
HCC
~11% over 15 years, but

significant variability
NASH
Cirrhosis
19-45% over 7-10 years
Decompensation
Modified from Torres DM, et el. Features, diagnosis, and treatment of NAFLD. Clin Gastro Hepatol. 2012;10:837-858.
Summary of Outcomes of NASH

Annual
Incidence
2-3%
Overall
10-15%
NASH
Cirrhosis
HCC
Ludwig 1980, Diehl 1988, Lee 1989, Powell 1990, Bacon 1994, Matteoni 1999, Angulo 1999, Caldwell 1999, Ponawala 2000, Contos 2001, Ong 2001,
Bugianesi 2002, Ratziu 2002, Harrison 2003, Marchesini 2003, Younossi 2004, Fassio 2004, Sanyal 2004, Ong 2005, Adams 2005, Ong 2006, Rafiq
2008, Stepanova 2010, Younossi 2012.
Predicting Advanced Fibrosis

100%
(100)
33%
(33)
NAFLD
20%
(7)
Fibrosis
progression
Rapid Fibrosis
progression
Harrison SA. Clin Gastro Hepatol. 2014.
Progression from
stage 0 to stage
3-4 over a mean
of 5.9 years
NAFLD Patients With Components of Metabolic Syndrome

are at Highest Risk for Advanced Fibrosis
NAFLD with liver biopsy

(N=432)
In multivariate analysis,
elevated AST and ALT,
presence of diabetes
mellitus, male gender
and Caucasian ethnicity
were associated with
moderate to severe
fibrosis (p-value<0.0001)
Hossain N, et al. Gastro and Hepatology. 2009.
Positive
0.3
Negative
% with moderate to severe fibrosis
DM
HTN
DM+HTN
DM+HTN+
Visceral obesity*
Predicting Liver Related Mortality (LRM)

209 NAFLD patients with liver biopsy slides, clinical
data and mortality data were included
Median follow up = 146 months (max 342 months)
During follow-up, 31% of patients died with 9% dying of LRM
Regardless of the pathologic criteria used, NASH

patients had higher LRM than non-NASH NAFLD
(13.0% vs. 1.3% for Original NAFLD NASH, p = 0.0047)
On multivariate analysis, only significant fibrosis

(Stage > 2) was an independent predictor of LRM
Younossi Z, et al. Hepatology. 2011.
Long-term Outcomes of Diabetics with NAFLD

NAFLD & DM (n=44) vs. NAFLD alone (n=88)
Patients with NAFLD and DM have*:
Higher rate of cirrhosis (25% vs. 10.2%, p=0.04)
Higher liver-related mortality (RR=22.83, p=0.003)
Higher mortality (RR=3.3, p=0.002)
*Average follow up = 10 years

Younossi et al. Clin Gastro and Hepatology 2004
Liver Biopsy
&
Pathologic Protocols
Clinical Presentation
&
Routine
Laboratory Data
Routine
Radiologic Tests
(Ultrasound, CT, MRI)
Diagnostic &
Prognostic
Tests for NASH
New Biomarkers
(NASH or Fibrosis)
Predictive Panels
Based on Clinical
and Lab Data
New Radiologic
Modalities
(Transient Elastography,
LMS MRI/MRE)
NAFLD Guideline Recommendations

Non-invasive Assessment
NAFLD Fibrosis Score is a clinically useful tool

for identifying NAFLD patients with higher
likelihood of having bridging fibrosis and/or
cirrhosis (Strength - 1, Evidence - B)
Although serum/plasma CK18 is a promising
biomarker for identifying steatohepatitis, it is
premature to recommend in routine clinical
practice (Strength - 1, Evidence - B)

Role of Biopsy
Liver biopsy should be considered in patients with

NAFLD who are at increased risk to have
steatohepatitis and advanced fibrosis (Strength - 1,
Evidence - B)
Liver biopsy should be considered in patients with
suspected NAFLD in whom competing etiologies for
hepatic steatosis and co-existing chronic liver
diseases cannot be excluded without a liver biopsy
(Strength - 1, Evidence - B)
Who Would You Biopsy?
A Minority (39%) of Patients Have a Liver Biopsy to Confirm Their

Diagnosis of NASH; Hepatologists Performed the Greatest Percentage
of Biopsies vs. Other Specialties
Diagnosed NASH Patients Who Received a Liver Biopsy
70
%of NASH
Patients [95% Cl]
60
50
40
30
20
10
53
41
29
Compared with Hepatologists. *denotes p=0.027, **denotes p<0.001, Tukeys HSD

Harrison SA, Abstract AASLD. 2014.
31
39
Goals of Liver Biopsy

Identify NASH (ballooning, inflammation, etc)
Establish diagnosis
Clinical trials
Stage fibrosis
Rule out concomitant liver disease (iron loading, etc)
Prognosis
Red Flags for NASH
Age
Gender
Hispanic
HT
Obesity
Diabetes
ALT and AST level
AST/ALT ratio
Insulin level
PNPLA3
No lab test or imaging study

will be able to predict with
100% accuracy
The more risk factors the
more concern
Transient Elastography
Allows painless and simultaneous measurement of

two quantitative parameters:
Liver stiffness expressed in kPa
Correlated to liver fibrosis [1]
Controlled Attenuation Parameter (CAP)

expressed in dB/meter
Correlated to liver steatosis [2]
Both quantitative parameters are assessed on the

same volume of liver tissue
100 times bigger than liver biopsy
1. Friedrich Rust, et al. Gastroenterology. 2008; 2. Sasso, et al. Journal of Viral Hepatitis. 2011.
Transient Elastography
Measures velocity of a low-frequency (50 Hz) elastic shear wave propagating

through the liver
Normal liver: ~5.5 kPa
Good performance for excluding advanced stage disease (stage 3-4)
User-friendly, short procedure time
Problems still with severe obesity, ascites, operator experience
False positives: acute hepatitis, extrahepatic cholestasis and congestion
Fibroscan VCTE, one method of TE, has an XL probe: ~25% unreliable results;
cut-off concerns
****Not very good in our hands at predicting fibrosis in NAFLD patients****
Castera L. Nat Rev Gastroenterol Hepatol. 2013.
MRE Can Identify Advanced Fibrosis in NAFLD
5
4
2
2D MRE (kPa)
Stage 4
FIBROSIS STAGE
Loomba, et al. Abstract DDW, 2013.
A threshold of 3.63 Kpa

discriminates
advanced fibrosis
Multi-parametric MRI Stages Adult Patients

with Chronic Disease
cT1 vs Ishak stage for all subjects (n=84)
The first non-invasive

test to clearly identify
even early fibrosis
Sensitivity of cT1
cT1 (ms)
AUROC is 094 (95% CI 089

099) to detect any disease;
sensitivity 86%, specificity 93%
Journal of Hepatology Jan
2014 Normal Liver (HV +F0) vs F1-6
1 - Specificity
Ishak fibrosis stage (F0-6)
Iron (T2*)
Certified by:
Sponsored by:
Inflammation &
fibrosis (T1)
Endorsed by:
Fat
Comparison of NASH stage 0-2 Vs 3-4

ROC Analysis:
British study of
145 NAFLD
patients
Sensitivity
FIB-4: 0.86
AST/ALT:0.83
NAFLD Fib Score:0.81
BARD: 0.77
APRI:0.67
NPV:
1 - Specificity
McPherson S et al. Gut 2010;59:1265-1269.
FIB-4:95%
BARD:95%
AST/ALT:93%
NAFLD Fib Score:92%
APRI:84%
Treatment and Intervention
Weight Loss Pyramid

Weight Loss 10%1
Weight Loss 7%1
Weight Loss 5%1,2,3
Weight Loss 3%1,2,3,4
1. Vilar-Gomez. Gastroenterology 2015; 2. Promrat. Hepatology 2010; 3. Harrison. Hepatology 2009; 4. Wong. J Hepatol 2013
*Depending on degree of weight loss

Weight loss generally reduces hepatic steatosis, achieved
either by hypocaloric diet alone or in conjunction with
increased physical activity (Strength - 1, Evidence - A)
Loss of at least 3-5% of body weight appears necessary to
improve steatosis, but a greater weight loss (up to 10%) may
be needed to improve necroinflammation (Strength - 1,
Evidence - B)
Exercise alone in adults with NAFLD may reduce hepatic
steatosis but its ability to improve other aspects of liver
histology remains unknown (Strength - 1, Evidence - B)
Metformin has no significant effect on liver histology and is not

recommended as a specific treatment for liver disease in adults
with NASH. (Strength - 1, Evidence - A)
Pioglitazone can be (?) used to treat steatohepatitis in patients

with biopsy-proven NASH. (Strength - 1, Evidence - B)
However, the majority of patients who participated in clinical trials that
investigated pioglitazone for NASH were non-diabetic
Long term safety and efficacy of pioglitazone in patients with NASH is
not established
Treatment: Vitamin E
Therapy
Author
Design
Duration
(Months)
ALT Improve
Histo
Vitamin E
Lavine
11
Open
4-10
Yes
N/A
Vitamin E
Kawanaka
10
Open
Yes
N/A
Vitamin E
Sanyal
10
RCT
Yes
N/A
Vitamin E
Hasegawa
12
Open
12
Yes
Yes
Vitamin E
Vajro
14
RCT
No
N/A
Vitamin E
Bugianesi
25
RCT
No
N/A
Vitamin E/Ex
Kugelmas
Open
Yes
N/A
Vitamins E+C
Harrison
23
RCT
No
? Yes
Vitamins E+C
Ersoz
28
RCT
Yes
N/A
PIVENS
(Sanyal)
84
RCT
24
Yes
Yes
Vitamin E

Vitamin E (a-tocopherol) administered at daily dose of 800
IU/day improves liver histology in non-diabetic adults with
biopsy-proven NASH and therefore should be considered
as a first-line pharmacotherapy for this patient population.
(Strength - 1, Quality - B)
Until further data supporting its effectiveness become
available, vitamin E is not recommended to treat NASH in
diabetic patients, NAFLD without liver biopsy, NASH
cirrhosis, or cryptogenic cirrhosis (Strength - 1, Quality - C)
Competitive Landscape in NASH

Clinical development pipeline
Company
GENFIT
Product
GFT505
MoA
PPAR / agonist
Phase
Condition
NASH
Timeline
Endpoint
Beginning late 2015
Beginning 2015
Co=primary
1. Reversal of NASH
without worsening
of fibrosis
2. Improvement in
fibrosis without
worsening of
NASH
Liver fibrosis/NASH
Enrollment complete
Improvement of NAS
(by 2 points) and no
worsening of fibrosis
2b
Liver fibrosis/NASH
Enrollment complete
Change in
morphometric
quantitative collagen
FGF 19 agonist
2a
NASH
Enrolling
Change in hepatic fat

by MRI
IMM-124E
Hyperimmune bovine
colostrum
2a
NASH
Enrolling

by MRI
GALMED
Aramchol
Synthetic Fatty Acid/

bile acid conjugate
2b
NASH
Enrolling

by MRI
GALECTIN
GR-MD-02
Galectin-3 inhibitor
2a
Liver fibrosis/NASH
Enrolling
Safety (+ elevation of
liver in enzymes)
INTERCEPT
(NIDDK)
OCA
FXR agonist (bile

acid)
NASH
CENTAUR
Cenicriviroc
Inhibitor of ligand
binding to
CCR2/CCR5
2a
GILEAD
Simtizumab
Mab against LOXL2
NGM Biopharm
NGM282
Immuron
FLINT Trial Design- Obeticholic Acid (OCA)

N=283
Patients w/
Histological Evidence
of NASH*
Screening (Biopsy)
OCA 25 mg QD
Follow-up
Placebo QD
Follow-up
72-week treatment period
24 week off treatment
Primary endpoint: liver histological improvement defined as decrease in

NAFLD Activity Score (NAS) of 2 points with no worsening in fibrosis
*Entry was based upon histologic diagnosis of nonalcoholic steatohepatitis (NASH) based on local CRN site pathologists read
(end-of-study blinded central read of baseline biopsies revealed 80% of patients enrolled had definite NASH);
interim analysis was conducted when 50% of patients completed treatment and had repeat liver biopsy; NAFLD: nonalcoholic fatty liver disease;
Neuschwander-Tetri B, et al. Lancet. 2014:S0140-6736(14)61933-4.
Neuschwander-Tetri B, et al. Presented at EASL, 50th annual meeting; 2015; Vienna, Austria (Poster LB18).
FLINT primary endpoint
Improvement in NAFLD activity score* (NAS) 2 pts

* NAS = steatosis grade (0-3) + inflammation grade (0-3) + ballooning grade (0-2)
No worsening of fibrosis
Results:
p = 0.0002
Percent
of Subjects
50%
40%
30%
20%
10%
0%
21%
(23/109)
46%
(50/110)
Placebo
OCA
25 mg/day
Neuschwander-Tetri et al, The Lancet, http://dx.doi.org/10.1016/S0140-6736(14)61933-4.
Improvement in Fibrosis and NASH Resolution

Fibrosis
Change in Score
Percent of Subjects
Improved
p = 0.004
19%
Placebo
1.0
0.6
0.2
-0.2
-0.6
-1.0
NASH Resolution
p = 0.08 (NS)
35%
OCA
p = 0.01
+0.1
-0.2
Placebo
OCA
Neuschwander-Tetri et al, The Lancet, http://dx.doi.org/10.1016/S0140-6736(14) 61933-4.
13%
22%
Placebo
OCA
Lipid Concentrations
-.25
Placebo
12
24
36
48
60
72
96
.2
0
12
24
36
Weeks
72
96
-.05
-.1
-.15
-6
12
24
36
48
Weeks
60
72
96
.75
.5
*
*
*
*
.25
Placebo
-.25
Placebo
-.5
Low-density Lipoprotein
Mean (95% Cl) change - mmol/L
.1
+4
mg/dl
.05
60
*p<0.05
High-density Lipoprotein
48
Weeks
*p<0.05
Placebo
.1
-.1
-.2
.25
Triglycerides
-.3
Median (95% Cl) change - mmol/L
.5
-.5
Total Cholesterol
*
12
24
36
48
60
72
96
Weeks
Data from Tetri et al. The Lancet and Supplementary Appendix. Published online November 7, 2014.
All p-values compared to placebo. *p<0.05 3Converted mean values using factor of 38.6 for cholesterol and 88.5 for triglycerides.
1
2
Adverse Events
Percent of
Patients
6 severe adverse events in obeticholic acid group

4 severe pruritus (1 stopped treatment)
1 hypoglycemia
1 possible cerebral ischemia (dysarthria and dizziness)
Moderate or severe pruritus
23% in obeticholic acid
P < 0.0001
6% in placebo
40
30
20
10
0
Mild
Mod
Placebo
OCA
Neuschwander-Tetri et al, The Lancet, http://dx.doi.org/10.1016/S0140-6736(14) 61933-4.
Patients at High Risk for Disease Progression
Established fibrosis is the best predictor of liver-related mortality1,2
Various factors have been shown to be associated with higher rates of fibrosis
progression3-5:
Hazard ratio (HR) = 20.4 for histologic documentation of fibrosis stage 2
Diabetes
Elevated body mass index (BMI)
Elevated ALT
Based on the literature, we defined the following high-risk FLINT subgroup:
Fibrosis stage 2 (perisinusoidal and portal/periportal) or stage 3 (bridging); or

Fibrosis stage 1 (perisinusoidal or periportal) if accompanied by one or more of:
Diabetes
Obesity (BMI 30 kg/m2)
Elevated ALT (ALT 60 U/L)
1. Younossi ZM, et al. Hepatology. 2011;53(6):1874-82; 2. Ekstedt M, et al. Hepatology. 2014 Aug. doi:10.1002/hep.27368
[epub ahead of print]; 3. Adams LA, et al. J Hepatol. 2005;42(1):132-8; 4. Ekstedt M, et al. Hepatology. 2006;44(4):865-73;
5. Singh S, et al. Clin Gastroenterol Hepatol. 2015;13(4):643-654.
NASH Resolution in High-Risk Subgroup

30
Overall Subgroup
Subgroup by Baseline Fibrosis Stage

Obeticholic Acid
Placebo
30
% of Patients
27%
20
20
18%
16%
10
10
5%
0
12%
11%
3%
3%
Obeticholic Acid
n = 84
Placebo
Stage 1
Stage 2
Stage 3
n = 76
OCA n=26
Placebo n=18
OCA n=25
Placebo n=29
OCA n=33
Placebo n=29
*p=0.014; NASH resolution as defined by NASH CRN pathologists; High-risk subgroup: patients with NAS 4 and fibrosis stage 2 or
stage 3 or stage 1 with diabetes, BMI 30 kg/m2 or ALT 60 U/L; Intercept post hoc analyses.
Fibrosis Improvement in High-Risk Subgroup

Overall Subgroup
Subgroup by Baseline Fibrosis Stage

Obeticholic Acid
Placebo
50
50
% of Patients
40
**
40
44%
42%
39%
30
30
31%
20
21%
10
28%
20
21%
10
11%
Obeticholic Acid
Placebo
Stage 1
Stage 2
Stage 3
n = 84
n = 76
OCA n=26
Placebo n=18
OCA n=25
Placebo n=29
OCA n=33
Placebo n=29
*p=0.014; NASH resolution as defined by NASH CRN pathologists; High-risk subgroup: patients with NAS 4 and fibrosis stage 2 or
stage 3 or stage 1 with diabetes, BMI 30 kg/m2 or ALT 60 U/L; Intercept post hoc analyses.
NAFLD and NASH
NAFLD is a complex disease tied closely to obesity and diabetes

NASH patients with fibrosis most likely to progress
Personalized targeted treatment may be the best future option to

treat NASH
Some considerations for current patients with NASH:
NAFLD/NASH in the setting of DM/MS has adverse outcomes
Life style modifications for all

Vitamin E for non-DM NASH
??Pio for DM with NASH but be aware of safety concerns
Clinical trials (OCA and others)
Consider bariatric surgery for morbidly obese+/-DM with NASH
More than XXX clinical trials underway in the USA to treat NASH
Hepatitis B
More Than 2 Billion People Show

Evidence of Hepatitis B (HBV) Infection 1
8% HBsAg prevalence
27% HBsAg prevalence
<2% HBsAg prevalence
240 million people are chronically infected with HBV worldwide1,3, 4

1.
2.
3.
4.
World Health Organization. Hepatitis B. http://www.who.int/mediacentre/factsheets/fs204/en/.

Map: Adapted from Liaw Y-F et al. Antiviral Therapy. 2010; 15 (suppl 3): 2533.
Hepatitis B Foundation Statistics. Accessed on 4 March 2011. Available at http://www.hepb.org/hepb/statistics.htm.
WHO 2015
Global Burden of Disease Study 2010:

Causes of Death From Chronic Liver Disease
Global 2010
50
45%
10
30%
26%
28% 27%
20%
14%
9%
Liver Cancer
29%
30
20
40% 39%
16%
HBV HCV ETOH Other
Cirrhosis
13%
14%
8%
10
0
HBV HCV ETOH Other
Patients (%)
Patients (%)
20
40%
40
40
30
USA 2010
50
HBV HCV ETOH Other
Liver Cancer
Increase in liver-cancer deaths (past 20 years): Globally (from 1.25 to 1.75 million/year); USA (45,000 to 70,000/year).
Lancet 2012
HBV HCV ETOH Other
Cirrhosis
HDV
Consider delta testing in all HBV patients with
anti-HDV blood test
Risk Factors Associated With Perinatal HBV

Infection Due to Immunoprophylaxis Failure
Overall: 4.9%
12
Maternal HBV DNA >6 log10 copies/mL:

5.7%
10
Independent risk factor for vertical

transmission of HBeAg positive mothers
Immunoprophylaxis Failure
Immunoprophylaxis failure rate
Maternal HBV DNA levels
Immunoprophylaxis failure occurred in a

significant proportion of infants born to
mothers with anti-partum hemorrhage,
meconium-stained amniotic fluid,
independently
Infants (%)
9.6%
8
6
5.5%
4.9%
3.0%
2
0
0%
Overall
(n=1242)
<6
(n=174)
6-6.99
(n=298)
7-7.99
(n=531)
Maternal HBV DNA

Han G, et al.; Hepatology 2011; 54(suppl): 444A, Abstract 170.
(log10 copies/mL)
>8
(n=531)
Alignment of HBV Screening Recommendations

From USPSTF, CDC, and AASLD
USPSTF
CDC
AASLD
People born in regions with prevalence of HBV infection of 2%1-3

US-born people not vaccinated as infants whose parents were born in regions with prevalence of HBV infection of
8%1-3
Household and sexual contacts of persons with HBV infection1-3
All pregnant women2-4
Men who have sex with men1-3
Injection drug users1-3
Individuals infected with human immunodeficiency virus (HIV)1-3
People with certain medical conditions2,3,5
Needing immunosuppressive therapy

Undergoing hemodialysis
For a complete list of screening recommendations, please see:

AASLD=American Association for the Study of Liver Diseases.
LeFevre ML; USPSTF. Ann Intern Med. 2014;161:58-66.
CDC=Centers for Disease Control and Prevention.
CDC. Morb Mortal Wkly Rep. 2008;57:1-20.
USPSTF=United States Preventive Services Task Force.
Lok ASF, McMahon BJ. Hepatology. 2009;50(3):1-36.
USPSTF. Ann Intern Med. 2009;150:869-873.
USPSTF. Consumer Fact Sheet. May 2014. http://www.uspreventiveservicestaskforce.org/uspstf/uspshepb.htm. Accessed August 12, 2015.
Liver Disease Progression

Normal
HBV
PRIMARY
PREVENTION
Vaccination
Time 20-30 Years

Cirrhosis
Cirrhosis
HCC
ACUTE /CHRONIC
HEPATITIS B
CIRRHOSIS
ESLD
HEPATOCELLULAR
CARCINOMA
CHEMO
PREVENTION
Cytokines
IFN-, Peg-IFN-
Antivirals
LMV, ADV, ETV, LdT
CANCER
Surveillance
Tumour Marker
Ultrasound
Transplantation
Hepatocellular Carcinoma: Incidence and

Risk for Patients with Family History of HCC
Study in Taiwan of 22,472 individuals with

18 year f/u and linkage to national cancer registry
374 cases of HCC identified during

362,000 person/yrs of follow-up
Family history of HCC and HBsAg-positive had

synergistic interaction with the risk of HCC in
multivariable-adjusted analysis
(age-sex-BMI-alcohol-smoking-ALT-DM)
(HR: 32.33, 95% CI [20.8-50.3],
p-value <0.01)
Conclusion: HBV patients with family history
of HCC should be considered very high risk
for HCC.
Loomba R, et al. Clinical Gastroenterology and Hep Dec 2013.
Family History of HCC, HBsAg and HBeAg Serostatus,

HBV DNA level, and Risk of Incident HCC
0.45
Cumulative Incidence of HCC (%)
40.0%
0.4
0.35
0.3
0.25
0.2
19.1%
17.6%
0.15
10.3%
0.1
0.05
0
0
10
Follow-up Time (years)
12
14
16
5.4%
2.5%
0.64%
0.62%
18
Phases of Chronic HBV Infection

HBeAg
Anti-HBe
HBV DNA
ALT activity
Phase
Immune Trained
Immune Clearance
Inactive Carrier State
Reactivation
Liver
Minimal inflammation and

fibrosis
Chronic active
inflammation
Mild hepatitis and

minimal fibrosis
Active
inflammation
Optimal treatment times

Yim HJ, et al. Hepatology. 2006;43:S173S181.
HBV: Who to Treat

Active viremia
>2,000-20,000 IU/ml
Some evidence of liver injury

Elevated ALT
Histologic injury
Family history HCC

Special populations
Elevated HCC biomarkers
Always treat patients with cirrhosis and any HBV DNA (+)
FDA Approved Therapies

First Line Therapy
Peginterferon alfa-2a
PEGASYS
Roche Laboratories
2005
Entecavir
BARACLUDETM
Bristol-Myers Squibb
2005
Tenofovir
VIREAD
Gilead Sciences
2008
Second Line Therapy

Adefovir dipivoxil
HEPSERA
Gilead Sciences
2002
Telbivudine
TYZEKA
Idenix and Novartis
2006
Third Line Therapy

Lamivudine
EPIVIR-HBV
GlaxoSmithKline
1998
Liver Fibrosis in Regression over 5 Years of

Treatment with TDF
Patients with Ishak score 4: 38% at Baseline, 12% at Year 5

Patients with cirrhosis (Ishak score 5): 28% at Baseline, 8% at Year 5
P < 0.001
Percentage of Patients
P < 0.001
100
90
Ishak Fibrosis
Scores
12%
6
5
38%
80
70
60
50
40
30
20
4
3
2
63%
39%
10
0
0
Baseline
Marcellin P, et al. Lancet; Vol 381, No. 9865, pp 468-475.
Year 1
Year 5
Cumulative Probability (%)
Nucleoside-nave Cohort (HBeAg+ and HBeAg-):

Cumulative Probability of ETV Resistance Through 6 Years
ETVr = LVDr (M204V L180M) + T184, S202, and/or M250 substitutions
20
15
10
5
0
Years
0.2
0.5
1.2
1.2
1.2
1.2
1
n=663
2
n=278
3
n=149
4
n=120
5
n=108
6
n=99
HBV DNA <300 copies/mL in 94% of patients (n=99) in Year 6
Kitrinos. Hepatology 2014
Treatment: How Long?

HBeAg positive
Seroconversion
Consolidation 6-12 months after
HBeAg negative
until patient has achieved HBsAg clearance
Indefinite?
6 Endpoints in HBV Treatment

Milestone 1:
Start of decline
of HBV DNA
HBV DNA
9
>10 copies/mL
Milestone 2:
HBeAg/ antiHBe sero-
Milestone 3: HBV
DNA decreased
to undetectable
Milestone 4:
Clearance of
HBsAg
Milestone 5:
Clearance
of cccDNA
conversion
HBV DNA level
Milestone 6:
Clearance of
cells with
integrated HBV
DNA sequences
HBeAg(-), anti-HBe(+)
HBeAg(+), anti-HBe(-)
HBeAg/
anti-HBe status
Low HBV DNA (<2000 IU/mL)

for reduced progression risk
Undetectable level
of HBV DNA
HBsAg+
HBsAg status
HBsAg-
This is where we would

like our patients to be
ALT level
Immune trained
Slide courtesy R Gish
Immune clearance
Immune control
Inactive carrier
state
Functional cure
Absolute
cure
Trying to Stop Treatment

APASL guidelines recommend discontinuing if
undetectable HBV-DNA on 3 occasions >6
months apart
Study tested stopping rule in patients treated
with entecavir
95 patients (39 with cirrhosis)
Treated median of 721 days (395-1762 days) and
then monitored off therapy
Jeng WJ et al Hepatology 2013 Dec; 58(6): 1888-96
Off Therapy Cumulative Relapse Rate (%)
Time to Relapse: ETV vs LAM or LdT
100
80
LAM, LdT
60
P=0.027
ETV
40
45%
360
20
Pt. at risk (NO.)

LAM, LdT 52
ETV 95
90
180
270
Time to Relapse (Days)

36
94
29
80
27
69
23
56
Fig. 1. One-year cumulative relapse rate after cessation of ETV

therapy was 45.3%, significantly lower and relapses occurred later than
those after cessation of LAM or LdT.
Jeng WJ et al Hepatology 2013 Dec; 58(6): 1888-96
Clinical relapse defined as ALT >2X ULN +

HBV DNA >2000 IU/mL)
Overall relapse: 45% (43/95)
Relapse in cirrhotics: 43% (17/39) and 1
developed decompensation
Median duration until relapse:
230 days (74% >6 months)
HBV DNA <2 x 105 IU/mL only
independent factor for response (29% vs
53% relapse)
Consolidation therapy >64 weeks
appropriate for those with higher BL HBV
DNA
Even When You SeroconvertRelapse May

Happen Over Time
Percent Serological Recurrence
100
80
60
44%
40
20
Rejinders et al
12
24
36
48
Treatment Month
Number of patients without

serological recurrencea
42
31
24
17
17
Total number of patientsb

in follow-up
42
38
34
30
28
What is Really a Cure?
Natural Cure
Functional Cure
Based on the clinical outcome, in which the patients life expectancy becomes the same
as that of an individual who has resolved his HBV infection without therapy
Apparent Virologic Cure
Clearance of HBsAg without therapy and serum HBV DNA is undetectable
Based on the stable off-drug suppression of HBV viremia and antigenemia and the
normalization of ALTs and other laboratory tests
Absolute Cure
In which an individual with chronic hepatitis B completely resolves the infection, and is
then at the same risk of death from liver disease as someone the same age who has never
been infected
Block and Gish, et al, AVR 2013
Cure Will Include

Clearance of all cells with cccDNA
Elimination of cells with integrated HBV DNA
Prevent risk of HBV reactivation in anti-HBc(+) patients
Remove integrated HBV DNA to completely eliminate risk
of HCC
Rituximab-Associated HBV Reactivation

in Lymphoproliferative Disorders
Meta-analysis and review of FDA

safety profiles
Case reports (n=27)
Case series reports (n=156)
Onset post last rituximab dose

Median: 3 months (range: 0-12
months)
>6 months: 29%
Reactivation in anti-HBc positive

patients receiving rituximab versus no
rituximab
Odds ratio: 5.73 (P=0.0009)
Evens AM, et al. Ann Oncol. 22:1170-1180, 2011
HBV Reactivation Risk:

Rituximab-Treated Lymphoma Patients
12.44
Hui
(n=233)
5.24
Tsutsumi
3.38
(n=47)
9.39
Targhetta
(n=319)
1.60
5.64
(2.18-14.54)
Yeo
(n=50)
Fukushima0.32
(n=48)
1.0
3.16
Odds Ratio
31.62
Barriers to Resolution of Chronic HBV Infection

cccDNA
reservoir
Dysfunctional
T-cell response
Insufficient
B-cell response
PD-1
CD8+
T cell
B cell
Treatment Challenges: Barriers to Curing

Chronic Hepatitis B
Reservoir of cccDNA
Dysfunctional T-cell Response
T cell exhaustion
Insufficient B-cell Response

Strategies to overcome these barriers
Deplete or Silence cccDNA
Activate Antiviral Immunity
Current Treatment Challenges

If use low genetic barrier NAs, drug resistance
a serious problem
Long term therapy with NAs (> 3 years) affects
patient compliance and typically has little effect
on HBsAg levels
Peg-IFN has substantial toxicity
New Treatment Approaches: Future

Developments
Strategy
HBV life cycle
Target
Agents/Company
HBV Pol
TAF
Viral entry
Myrcludex-B
cccDNA
Zinc finger nucleases
cccDNA conversion inhibitors
mRNA transcription/ stability
Zinc finger proteins
Epigenetic silencers
Viral assembly
HAPs
Phenylpropenamides
HBV antigen secretion
REP 9AC
Small molecule inhibitors of HBsAg secretion (e.g. glucovirs, triazolopyrimidines)
mRNA
Antisense
iRNA
ISIS OAS product 3rd Gen DNA, Arrowhead iRNA, Tekmira iRNA, Analym
siRNA (formally Merck now Arrowhead)
Capsid
Multiple
Novorio, Emery
PegIFN-1a (IL29)
Cytokines
R. Gish
BMS, Nanogen
rIL-7
rIL-21
Ribozymes
Summary
Viral suppression is successful but limited
Regression of fibrosis can occur
Cancer risk still exists
Special populations
Prevention of MTCT, mother to baby
Prevention of reactivation
Chance for a cure?

Multiple viral replication cycle targets
Immune modulators
Still early in development
Chronic Hepatitis C Infection

is a Major Concern in the US
HCV is Nearly 4 Times as Prevalent as HIV and

HBV
Prevalence of Chronic Viral Infections
2.7 to 5 Million1,3,4
75% Unaware of Infection
Total No. Infected

(millions)
4
3
Undiagnosed
Diagnosed
2
1
0
~800,000 to 2 Million1,3
1.1 Million1
HIV
HBV
HCV
A 2011 study estimated that as many as 5.2 million persons are living
with HCV in the United States2
HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus.

1. Institute of Medicine. Washington, DC: The National Academies Press; 2010.
2. Chak E, et al. Liver Int. 2011;31(8):1090-1101. 3. Gish Hepatology 2015 4. Edlin Hepatology 2015
By 2007, Deaths From HCV

Surpassed Those From HIV
Change in Mortality Rates From 1999 to 2007
Rate per 100,000 People
7
6
HIV
5
4
15,106
12,734
Hepatitis C
3
2
1
0
Hepatitis B
1999
2000
1,815
2001
2002
2003
Year
Ly KN, et al. Ann Intern Med. 2012;156(4):271-278.
2004
2005
2006
2007
Chronic HCV Infection May Lead to

Chronic Liver Disease and Liver Cancer
~75% of patients infected with HCV will develop a chronic infection

and approximately 65% of those are expected to develop chronic
liver disease
Fibrosis
Cirrhosis
Hepatocellular Carcinoma
(with cirrhosis)
Factors Associated With Accelerated

Fibrosis Progression in HCV
Modifiable
Alcohol consumption
Nonalcoholic fatty liver disease
Obesity
Insulin resistance
THC (2 prospective studies)*
Viral
Genotype 3
Coinfection with HBV or HIV
Non-modifiable
Fibrosis stage
Inflammation grade
Older age at time of infection
Male sex
Organ transplant
*As modified from: AASLD, IDSA, IASUSA. Recommendations for testing, managing, and treating hepatitis C.
http://www.hcvguidelines.org. Accessed July 15, 2015.
Complications Due to HCV-Related Cirrhosis Expected

to Rise Over the Next 10 Years
Projected Number of Cases of Hepatocellular Carcinoma
and Decompensated Cirrhosis Due to HCV
Cases, N
160,000
140,000
120,000
100,000
80,000
60,000
40,000
20,000
0
Decompensated
cirrhosis
Hepatocellular carcinoma
1950
1960
Davis GL, Gastroenterology. 2010;138:513-521.
1970
1980
1990
Year
2000
2010
2020
2030
Does Chronic Hepatitis C Increase Rates of Cancers

Other Than Liver Cancer?
Retrospective cross-sectional study from Kaiser

Permanente Southern CA
Adults diagnosed with CHC (ICD-9 code) or
positive HCV RNA test between JAN08-DEC12
Excluded patients with HIV or history of solid
organ/bone marrow transplant
Nyberg AH et al., EASL Conference 2015.
Patient Demographics
HCV/Cancer
HCV/No Cancer
Non HCV
1831
33881
5297191
62.6 (9.25)
59.4 (8.40)
71.9 (14.59)
Female
679 (37.1%)
13789 (40.7%)
2695862 (50.9%)
Male
1152 (62.9%)
20092 (59.3%)
2601142 (49.1%)
Asian
137 (7.5%)
2188 (6.5%)
377248 (7.5%)
Black
358 (19.6%)
4236 (12.5%)
412310 (7.8%)
Hispanic
425 (23.2%)
9670 (28.5%)
1862557 (35.2%)
White
871 (47.6%)
14040 (41.4%)
1543486 (29.1%)
14 (0.8%)
2949 (8.7%)
928943 (17.5%)
N (%)
Age Years Mean (SD)
Gender
Race
Unknown
Baseline Comorbidities and Health Status

Charlson Index
(N)
Mean (SD)
HCV/Cancer
HCV/No Cancer
Non HCV
1504
25161
2834195
2.1 (2.30)
1.50 (1.93)
0.5 (1.22)
469 (25.8%)
10798 (33.7%)
3087355 (70.3%)
1351 (74.2%)
21247 (66.3%)
1307074 (29.7%)
11 (0.6%)
1836 (5.4%)
902763 (17%)
1488 (81.3%)
29370 (86.7%)
5184626 (97.9%)
343 (18.7%)
4511 (13.3%)
112566 (2.1%)
Tobacco Smoking
Never
Ever
Missing
Alcohol Abuse
Never
Ever
Baseline Comorbidities and Health Status

HCV/Cancer
HCV/No Cancer
Non HCV
1262 (68.9%)
26962 (79.6%)
4898006 (92.5%)
569 (31.1%)
6919 (20.4%)
399186 (7.5%)
1312 (71.7%)
11766 (34.7%)
352294 (6.7%)
1825
32459
4319284
28.1 (6.30)
29.0 (6.25)
26.4 (7.18)
6 (0.3%)
1422 (4.1%)
977907 (18.4%)
Diabetes
Never
Ever
Cirrhosis
BMI
N
Mean
Missing
Forest Plot: Crude HCV vs. Non-HCV Cancer Rates

0
20
40
60
Esophagus
2.51
<0.0004
Stomach
3.03
<0.0001
Colon_rectum
1.88
<0.0001
Liver
68.67
<0.0001
Pancreas
2.79
<0.0001
Myeloma
3.41
<0.0001
Non_Hodgkin_lymphoma
3.59
<0.0001
Head_neck
2.56
<0.0001
Lung
2.44
<0.0001
Renal
3.05
<0.0001
Prostate
2.05
<0.0001
All_sites_including_HCC
2.33
<0.0001
All_sites_excluding_HCC
1.84
<0.0001
RR (95%Cl) HCV vs. Non-HCV

0.1
10
100
HCV Can Now Be Cured in Most Patients

Unlike HIV and HBV infection, HCV infection is a
curable disease
HCV does not archive its genome, no integration
What does cure mean?

Undetectable HCV RNA 12 weeks after completion of
antiviral therapy for chronic HCV infection
SVR12 is almost invariably durable
Ghany MG, et al. Hepatology. 2009;49(4):1335-1374.
Majority of Persons Chronically Infected With HCV Are

Baby Boomers (Those Born Between 1945-1965)
Estimated Prevalence by Age Group
1,600,000
Individuals, N
1,400,000
1,200,000
1,000,000
800,000
600,000
400,000
200,000
0
<1920
1920
1929
1930
1939
1940
1949
1950
1959
1960
1969
Birth Year Group

Centers for Disease Control and Prevention. MMWR. 2012;61(RR-4):1-32.
1970
1979
1980
1989
1990+
CDC and USPSTF Recommendations

for HCV Screening
Regardless of risk factors, one-time testing for HCV of
adults born between 19451965
Testing of persons of all ages at risk for HCV infection
CDC also recommends for those identified with

HCV infection
Brief alcohol screening and intervention as clinically indicated
Referral to appropriate care and treatment services for HCV
infection and related conditions
Centers for Disease Control and Prevention (CDC). MMWR. 2012;61(4):1-18
Moyer VA; on behalf of the U.S. Preventive Services Task Force. Ann Intern Med. 2013;159(1):51-60.
Current Status of HCV in the US: Screening

and Linkage to Care Rates Remain Low
US population with chronic HCV infection
5 million
HCV detected
1.6 million (<<50%)
Referred to care
1.0 1.2 million (32%-38%)
HCV RNA test
630,000 750,000 (20-23%)
Liver biopsy
380,000 560,000 (12%-18%)
Treated
220,000 360,000 (7-11%)
Successfully treated
170,000 200,000 (5-6%)
Holmberg SD et al, New Engl J Med. 2013; 1859-1861, Gish Hepatology, 2015.
Highly Efficacious Treatments Are Not Enough: Higher Rates

of Screening, Diagnosis and Treatment Are Necessary
PEG-IFN/RBV
95% SVR
95% SVR and higher rates

of diagnosis/treatment
100%
100%
100%
20%
20%
90%
10%
19%
85%
All HCV
patients
Diagnosis
and treatment
Cure
Slide courtesy of Prof. Michael Manns
Rising Cure Rates for Chronic HCV

2 Gen DAAs
IFN-Free
Regimens
nd
100%
Telaprevir or
Boceprevir +
PegIFN/RBV
80%
Cure Rate*
60%
3rd Gen DAAs

IFN-Free
Regimens
70%
PegIFN/RBV
40%
20%
IFN/RBV
35%
44%
IFN
16%
0%
1991
*Cure rates based on data from clinical trials
1998
2001
2011
Year
2013
2014+
Global Distribution and Prevalence

of HCV Genotypes
Messina JP et al, Hepatology, 2015; 61: 77-87.
Core E1
E2
NS2
NS3
4A
5UTR
p7
Approved Direct-Acting Antiviral Agents from

Multiple Classes: Combination Regimens for HCV
NS4B
NS5A
Protease
Ribavirin
NS3
Protease
Inhibitors
Simeprevir
Paritaprevir/r
NS5B
3UTR
Polymerase
NS5A
Replication
Complex
Inhibitors
Daclatasvir
Ledipasvir
Ombitasvir
NS5B
NUC
Inhibitors
NS5B
Non-NUC
Inhibitors (NNI)
Sofosbuvir
Dasabuvir
Note the common root name for each drug class
Principles of All Oral Regimens for HCV

Combine drugs from different classes
Target multiple targets to increase efficacy
Decrease risk of viral resistance
If done properly
Near universal efficacy
Shortened duration of therapy
Adverse events have minimal impact on patients
quality of life
General Concepts About Selecting HCV Regimens

Choice of regimen, treatment duration, and use of
ribavirin depends on:
Presence of cirrhosis
Prior treatment experience
PEG-RBV failure
Prior protease inhibitor failure
Prior sofosbuvir failure
Genotype
Genotype 1a vs 1b
Genotypes 2-6
Important Information Needed at Diagnosis:

Consultation With a Liver Specialist
Making sure the patient is not cirrhotic: Accurate staging of liver

disease is important
History, physical exam
Laboratory data:
Focus on platelets
Subtle clues: Decreased albumin
Hepatic imaging may be suggestive of cirrhosis

Non-invasive testing
Fibrosure or equivalent serum tests
Fibroscan or equivalent
Use clinical judgment to reconcile conflicting results
Excluding Cirrhosis is Important

Presence of cirrhosis
Triggers routine cirrhosis care
Evaluation for varices
Surveillance for hepatocellular carcinoma
Impacts SVR
May affect treatment duration
May impact use of ribavirin
Reviewing Potential Drug: Drug Interactions is Important

Is the patient taking any drugs that could have a potential
drug:drug interaction with a DAA?
Antiarrhythmics e.g.
digoxin, amiodarone
Herbal supplements
PPIs/acid
reducing agents
HIV antivirals
e.g. tenofovir,
lopinavir/ritonavir
Drugs that are

renally cleared
Is a co-medication contraindicated or is a dose adjustment required?

Can plasma levels of co-medications be easily monitored to ensure they
remain within the established therapeutic range?
PPI = proton pump inhibitor
Approved Treatments for

Patients with GT 1 Infection
see AASLD and EASL
guidelines for regular
updates
Paritaprevir/r (protease inhibitor/ritonavir)

+ ombitasvir (NS5A inhibitor) + dasabuvir
(non-nucleoside polymerase inhibitor) + RBV
(PTV/RTV/OMV + DSV + RBV)
Integrated Efficacy: SVR12 in GT 1a Non-cirrhotic

Patients Treated with PTV/RTV/OMV + DSV for 12 Weeks
(+/- RBV) (SAPPHIRE-I and II, PEARL-IV)
p=0.004
100
90
96
p=0.006
90
96
95
94
Placebo
Ribavirin
80
SVR12
60 (%)
40
20
0
182/
202
569/
593
All Patients
Everson G, et al. Abstract #83, AASLD 2014
182/
202
403/
420
47/
50
36/
36
Treatment Nave Relapse Partial
83/
87
Null
Prior PegIFN/RBV Response
Logistic
regression:
baseline BMI and
treatment regimen
(+/- RBV) were
significant
variables for not
achieving SVR
Integrated Efficacy: SVR12 in GT 1a Cirrhotic Patients Treated with

PTV/RTV/OMV + DSV + RBV for 12 vs 24 Weeks (TURQUOISE-II)
p=0.08
100
89
95
p=0.13
p=0.73
92
95
93
100
100 100
93
12 weeks
24 weeks
80
80
Logistic regression:
IL28B TT, prior null,
North American region
and history of IDU were
significant variables for
not achieving SVR
60(%)
SVR12
40
20
0
126/
142
115/
121
61/
66
Everson G, et al. Abstract #83, AASLD 2014
53/
56
14/
15
13/
13
11/
11
10/
10
40/
50
Prior PegIFN/RBV Response
39/
42
SVR12 in GT 1b Non-cirrhotic Patients Treated with

PTV/RTV/OMV + DSV for 12 Weeks (+/- RBV)
Pooled analysis of Phase 3 trials
SVR12 (%)
100
90
80
70
60
50
40
30
20
10
0
100
301
/301
98.3
562
/572
100
100
98.9
210
/210
357
/361
+ RBV
100
98.5
33
/33
67
/68
100
98.1
26
/26
- RBV
52
/53
95.6
32
/32
86
/90
Treatment-experienced
Colombo M, et al. AASLD 2014, Boston. #1931
*Includes 1 treatment-naive G1b pt

who was enrolled in PEARL-IV study
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
100
100
98.5
100
100
100
24 Weeks
100
100
100
100
85.7
SVR12 (%)
80
60
40
20
0
67
/68
51
/51
22
/22
18
/18
14
/14
10
/10
6
/7
3
/3
25
/25
20
/20
Colombo M, et al. AASLD 2014, Boston. #1931
Do GT 1b Cirrhotics Really Need RBV? NO

Phase 3 program included RBV for all cirrhotics
TURQUOISE III trial
60 GT 1b patients with cirrhosis received PTV/RTV/OMV + DSV
(no RBV) for 12 weeks
100% SVR4 (SVR12 results expected at AASLD 2015)
AASLD/IDSA guidance document updated in August 2015: 12
week duration WITHOUT RBV for GT 1b cirrhotics
Feld J, et al. J of Vir Hep. 2015 (suppl 2); pp. 134-135
Paritaprevir/r (PTV/r) + ombitasvir (OMV) + dasabuvir

(DSV) + RBV: GT 1
Interferon not necessary; ribavirin necessary for some patients (GT1a to increase
SVR from 90 to 99%)
Very manageable safety profile
Two tablets once daily + one tablet twice daily
Approved regimens
12 weeks for noncirrhotic GT1a + RBV
24 weeks for cirrhotic GT1a + RBV
12 weeks for noncirrhotic GT1b
12 weeks for cirrhotic GT1b + RBV (interim SVR4 from TURQUOISE III suggests RBV not
necessary; AASLD/IDSA guidance document recommends 12 weeks without RBV)
No dose adjustment necessary in patients with severe or ESRD requiring dialysis
Drug:drug interactions (e.g., drugs cleared by CYP3A, omeprazole, statins)
AASLD, IDSA, IASUSA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed August 6, 2015
Ledipasvir (LDV) (NS5A inhibitor)

+ sofosbuvir (SOF) (nucleotide
polymerase inhibitor)
(LDV/SOF)
LDV/SOF RBV for 12 vs 24 Weeks: SVR12 in GT 1

Treatment-nave Patients (ION-1)
Non-Cirrhotic
100
99
98
97
Cirrhotic
99
100
SVR12 (%)
SVR12 (%)
80
60
40
20
0
179/
180
LDV/SOF
178/
184
LDV/SOF
+ RBV
181/
184
LDV/SOF
12 Weeks
Afdhal et al. N Eng J Med. 2014;370:1889-98.
179/
181
LDV/SOF
+ RBV
24 Weeks
94
100
100
94
80
60
40
20
0
32/
34
LDV/SOF
34/
34
LDV/SOF
+ RBV
12 Weeks
31/
33
36/
36
LDV/SOF
LDV/SOF
+ RBV
24 Weeks
GT 1 Treatment Nave Non-Cirrhotics With BL Viral Load <6 Million

IU/mL: 8 Weeks Can Be Considered But May Impact Insurance Coverage
LDV/SOF
8 Weeks
(N=215)
LDV/SOF
12 Weeks
(N=216)
94% (202/215)
96% (208/216)
97% (119/123)
96% (126/131)
Relapse Rates
(Overall)
5% (11/215)
1% (3/216)
<6M IU/mL
>6M IU/mL
2% (2/123)
10% (9/92)
2% (2/131)
1% (1/85)
SVR12 (Overall)
SVR12 (BL viral load
<6M IU/mL)
Ledipasvir/sofosbuvir (HARVONI) Prescribing Information. Gilead Sciences, Foster City, CA. March, 2015 (Adapted from Table 6).
LDV/SOF RBV for 12 vs 24 Weeks:

SVR12 in GT 1 Treatment-experienced Patients (ION-2)
12 Weeks
SVR12 (%)
100
95
86
100
24 Weeks
82
99
100
99
100
80
No cirrhosis
60
Cirrhosis
40
20
0
83/
87
19/
22
LDV/SOF
Afdhal EASL Abst O109
89/
89
18/
22
LDV/SOF + RBV
86/
87
22/
22
LDV/SOF
88/
89
22/
22
LDV/SOF + RBV
Ledipasvir (LDV) + Sofosbuvir (SOF): GT 1
Interferon and ribavirin not necessary

Very manageable safety profile
One pill once a day
Duration
12 weeks for patients without cirrhosis (consider 8 weeks for
some patients)
12 weeks with ribavirin or 24 weeks without ribavirin for patients with cirrhosis
Potential drug:drug interactions (e.g., PPI, P-gp inducers, amiodarone)

Not recommended in patients with severe or ESRD
requiring dialysis
Simeprevir (SMV) (protease

inhibitor) + sofosbuvir (SOF)
(nucleotide polymerase inhibitor)
(SMV/SOF)
SMV/SOF x 12 Weeks
SVR12 in GT 1 Non-cirrhotics (OPTIMIST-1)
SMV+SOF 12 weeks
97
100
SMV+SOF 8 weeks
85
Proportion
of
80
patients (%)
77
60
40
20
112/115
88/103
38/40
Treatment-nave
97
100
79
80
Proportion
of
patients
(%)
60
97
92
84
97
96
40/52
73
40
20
0
112/116 92/116
GT1a
Kwo et al. Abstract #LP-14, EASL 2015.
44/46
36/49
GT1a
with Q80k
68/70
56/67
GT1a
38/39
36/39
GT1b
without Q80k
Proportion of patients (%)
SMV/SOF x 12 Weeks
SVR12 in GT 1 Cirrhotics (OPTIMIST-2)
SVR12: SMV + SOF 12 weeks
100
80
60
40
44/50
42/53
20
0
Treatment-_x000d_naive Treatment-experienced
Implication: SMV+SOF insufficient for GT1 cirrhotics

Lawitz E, et al. EASL 2015, Vienna. #LP04
Simeprevir (SMV) + Sofosbuvir (SOF): GT 1
Interferon not necessary; ribavirin may be necessary for some patients

Manageable safety profile
One tablet and one capsule once daily
Regimens (+/- RBV)
SMV/SOF x 12 weeks for patients without cirrhosis

SMV/SOF x 24 weeks for patients with cirrhosis
Not recommended in patients with moderate or severe hepatic impairment (ChildPugh Class B and C)
No dosage adjustment of SMV required in patients with mild, moderate or severe
renal impairment (remember SOF warning in severe renal impairment)
Drug:drug interactions (e.g., moderate/strong inducers or inhibitors of CYP3A,
amiodarone due to the SOF component)
DAC SOF for GT1

In AASLD guidelines
Approved Treatments for Patients

with GT 2 or GT 3 Infection
GT 3 Is Associated With a Significantly Higher Risk

of Cirrhosis and HCC vs GT 1
VA HCV Clinical Case Registry (2000-2009)
88,348 patients with genotype 1 (80%)

13,077 genotype 2 (12%)
8,337 genotype 3 (7.5%)
Mean follow-up 5.4 years
After adjustment for demographic, clinical and antiviral treatment factors,

comparison between genotypes 3 and 1
Hazard Ratio
Confidence Interval
Cirrhosis
1.31
1.22-1.39
HCC
1.80
1.61-2.03
Conclusion: GT 3 is associated with a significantly higher risk of cirrhosis and

HCC vs GT 1, independent of age, diabetes, BMI or antiviral treatment
Kanwal F et al, Hepatology 2014;60:98-105
SOF+PEG/RBV x 12 Wks vs SOF + RBV x 24 Weeks:

SVR12 in GT 2 vs GT 3 Patients (BOSON Study)
SOF + RBV 16 weeks
SVR12 (%)
100
100
87
SOF + RBV 24 weeks
SOF + PEG/RBV 12 weeks
94
84
80
93
71
60
40
20
0
13/15
Error bars represent 95% confidence intervals.

Foster et al., Abstract #L-05, EASL 2015
17/17
15/16
128/181
GT 2
153/182
GT 3
94/112
83/100
10/11
168/181
SOF+PEG/RBV x 12 Wks vs SOF+RBV x 24 Weeks:

SVR12 in GT 3 Patients By Subgroup (BOSON Study)
SOF + RBV 16 weeks
100
SOF + PEG/RBV 12 weeks
91
90
82
80
SVR12 (%)
SOF + RBV 24 weeks
76
86
82
77
57
60
47
40
20
0
58
70
65
72
68
71
12
18
94/112 22
21
21
83/100
23
TN
cirrhosis
TN
cirrhosis
NonoCirrhosis
Cirrhosis
Treatment Nave
Foster et al., Abstract #L-05, EASL 2015
41
54
44
49
10/11 52
54
17
36
26
34
30
35
TENo
noCirrhosis
cirrhosis
TE
cirrhosis
Cirrhosis
Treatment Experienced
Daclatasvir/Sofosbuvir for GT 3: SVR12 in Treatmentnave and Treatment-experienced Patients Treated for 12

Weeks (ALLY-3)
(FDA Approval: July 2015)
100
90
86
SVR12 (%)
80
60
40
20
0
91/101
44/51
Treatment-naive
Nelson DR et al., Hepatology 2015; 61: 1127-1135.
Daclatasvir/Sofosbuvir for GT 3: SVR12 in Patients With and

Without Cirrhosis Treated for 12 Weeks (ALLY-3) (FDA Approval:
July 2015)
100
Overall
Tx-naive Tx-experienced
SVR12
(%)
80
60
40
97
96
63
94
58
20
0
No
Yes
Nelson DR et al., Hepatology 2015; 61: 1127-1135.
No
Yes
Cirrhosi
s
No
69
Yes
AASLD/IDSA Guidance Document on GT 2

Patients
Treatment-nave (HCV has never been treated)
SOF + RBV for 12 weeks (extend to 16 weeks in
patients with cirrhosis)
Treatment-experienced (HCV was previously

treated)
SOF + RBV for 12 weeks (extend to 16 weeks in
patients with cirrhosis)
SOF + PEG/RBV for 12 weeks (alternative)
www.hcvguidelines.org (accessed July 15, 2015)
Treatment of GT 3 Patients
In July 2015, daclatasvir (DCV) + sofosbuvir (SOF) x 12
weeks was approved by the FDA for patients without
cirrhosis
Recommended regimens in guidance document
SOF + PEG/RBV x 12 weeks
DCV + SOF x 12 weeks
GT 3 infected patients with cirrhosis remain the biggest

challenge to cure, EASL guidelines rec: DAC SOF Riba for
24 weeks
www.hcvguidelines.org (accessed August 27, 2015)
SVR and All-cause Mortality in CHC Patients

with Advanced Fibrosis
530 patients followed for a median of 8.4 years
SVR patients
Van der Meer A, et al. JAMA 2012; 308:25842593.
Non-SVR patients
29.9
30
10-year cumulative
occurrence rate (%)
Baseline factors
significantly
associated with allcause mortality:
Older age
GT 3 (2-fold
increase in
mortality and HCC)
Higher Ishak
fibrosis score
Diabetes
Severe alcohol use
27.4
26.0
25
21.8
20
15
10
8.9
5.1
5
0
2.1
1.9
All-cause
mortality
Liver-related
mortality or
liver transplant
HCC
Liver failure
SVR Reduced Risk of All-Cause Mortality

in a Retrospective VA Study
Genotype 1
(n=12,166)
SVR rate: 35%
Cumulative Mortality (%)
0.3
Genotype 3
Genotype 2
(n=2904)
SVR rate: 72%
0.3
0.3
0.25
0.25
0.25
0.2
0.2
0.2
Non-SVR
0.15
P<.0001
0.1
NonSVR
0.15
0.05
Years
P<.0001
0.1
0.05
0.05
SVR
0
NonSVR
0.15
P<.0001
0.1
(n=1794)
SVR rate: 62%
SVR
6
Years
SVR
5
Years
Retrospective analysis of veterans who received pegylated interferon plus ribavirin at any VA medical facility (2001-2008).
SVR=sustained virological response.
Backus LI, et al. Clin Gastroenterol Hepatol. 2011;9:509-516.
HCV Screening: The Hidden Problem in Linkage to

Care
3 Approaches
Population
Screening
Birth Cohort
Screening
Risk FactorBased
Screening
Targeted screening programs are effective in increasing HCV testing, detection of

HCV cases and referrals to specialist care 1
But, insufficient data to show impact on patient outcomes
4085% of infected persons are unidentified 2

Varies greatly by setting, documented risk level in population, and
site-specific screening practices
1. Guidelines for the screening, care and treatment of persons with hepatitis infection. WHO, 2014. Available at
http://www.who.int/hiv/pub/hepatitis/hepatitis-c-guidelines/en/ (accessed April 2015)
2. Smith BD, Yartel AK. Am J Prev Med 2014;47:23341
WHO: World Health Organization
GT 4, 5, 6
Discuss treatment options
GT4 Harvoni 12 weeks no ribavirin
GT 5 and 6, multiple options
Conclusions
Who to test
One time testing of all baby boomers
is essential
Test all patients with ALT over 20 (women), 30 (men)
Any history of blood exposure
Immigrant populations
Linkage to infectious / liver experts that can assess disease progression

and treatment options
Highly efficacious, short duration regimens with favorable safety profiles
are available
Rapidly evolving field
AASLD/IDSA Guidance Document Remains Current

Recommendations for Testing, Managing, and Treating Hepatitis C
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Whats New and

Updates/Changes
HCV Guidance
Background of the Hepatitis C

Guidance
New direct-acting oral agents capable of curing hepatitis C
virus (HCV) infection have been approved for use in the
United States. The initial direct-acting agents were
approved in 2011, and many more oral drugs are expected
Wednesday, J anuary 29,

2014
to be approved in the next few years. As new information is
The Recommendations for
reviewed journals, health care practitioners have expressed
Testing, Managing, and
a need for a credible source of unbiased guidance on how
Treating Hepatitis C are now
best to treat their patients with HCV infection. To provide
available.
healthcare professionals with timely guidance, the American
Read more >>
Association for the Study of Liver Diseases (AASLD) and
presented at scientific conferences and published in peer-
the Infectious Diseases Society of America (IDSA) in

collaboration with the International Antiviral Society-USA
Official Press
Release
(IAS-USA) have developed a web-based process for the
Wednesday, J anuary 29,

2014
management.
View Official Press Release:
New sections will be added, and the recommendations will
Online...
be updated on a regular basis as new information becomes
Read more >>
available. An ongoing summary of "recent changes" will
rapid formulation and dissemination of evidence-based,

expert-developed recommendations for hepatitis C
also be available for readers who want to be directed to
www.hcvguidelines.org
Managing the Complications

of Cirrhosis
Compensated Cirrhosis May Be Difficult to Recognize

Asymptomatic (compensated)
Subtle clues may be overlooked
Thrombocytopenia
Muscle wasting
AST>ALT without alcohol consumption
Liver enzymes may not be abnormal
Albumin < 3.5 mg/dL
Bili > 1.0-1.2
Etiology may be remote

Prior alcohol use
Uncontrolled diabetes mellitus and obesity
Decompensated (Symptomatic)
Portal hypertension: ascites, overt hepatic encephalopathy, variceal bleeding
Hepatic failure: jaundice, coagulopathy
From http://digestive.niddk.nih.gov/ddiseases/pubs/cirrhosis/. Accessed July 2015.
Trichrome stain micrograph from http://en.wikipedia.org/wiki/Cirrhosis. Accessed July 2015.
Cirrhosis: Symptoms and Signs
Anorexia, weight loss

Weakness, fatigue
Muscle loss, cramps
Nausea
Vague (RUQ) abdominal pain
Pruritus
Easy bruising, epistaxis
GI bleeding
Confusion, sleep disturbance
Amenorrhea or irreg menses
Spider angiomata
Palmar erythema
Gynecomastia, testicular atrophy
Abdominal distention, edema
Parotid hypertrophy
Dupuytrens contractures
Clubbing, leukonychia
Jaundice, icterus
Caput medusa
Splenomegaly
Enlarged left or caudate lobe
Asterixis, fetor hepaticus
Cachexia
However..often asymptomatic
Cirrhosis: Diagnosis
Gold standard remains liver biopsy
Biopsy not required for all, Clinical or radiologic cirrhosis
Clues: physical exam, abdominal imaging, low platelet
count, AST:ALT ratio >1, cholestasis, low albumin,
prolonged INR
Non-invasive assays (FibroTest=FibroSure, APRI, FIB-4)
U/S Elastography (FibroScan, Aixplorer), Magnetic
Resonance Elastography
Non-invasive Markers of Fibrosis

FibroTest / FibroSure
FibroSpect
Bili, gGT, g-globulin, haptoglobin, a2 M, apolipoprotein

Hyaluronic acid, TIMP-1, a2 M
HA, Procollagen III amino terminal peptide
(PIIINP),TIMP1
ELF
HepaScore
Hyaluronic acid, gGT, a2 M
Forns
GGT, cholesterol, platelets, age
APRI
AST /ULN X 100 / platelets (109/ L)
SHASTA; (HIV/HCV)
FIB-4
AST, HA, albumin

AST, ALT, platelets, age
NONE ARE ACCURATE IN THE MIDDLE FIBROSIS RANGES
Non-Invasive Alternative: Hepatic Elastography
2.5cm
Explored
volume
1cm
4cm
The probe induces

an elastic sound wave
through
the liver
The velocity of the sound wave is evaluated in a

region located from 2.5 to 6.5 cm below the skin
surface
Sampled volume:
1:500
Technical Limitations of Transient Elastography
Ascites
Morbid obesity
Adipose tissue within the chest wall
Acute hepatitis
Congestive hepatopathy
Post-prandial variability
Breath hold, patient movement, targeting liver
Afdhal NH. Gastroenterol Hepatol (NY) 2012;8:605-607.
Prevalence of Cirrhosis
Experts estimate that 5.5 million people in the
United States have cirrhosis
Many cirrhotics remain undiagnosed
40% of cases of cirrhosis latent
Twelfth leading cause of death in US
Khungar V, Poordad F. Clin Liver Dis 2012;16:73-89.
US Hospital Discharges Due to Cirrhosis

Are Increasing
10% increase
700000
Number600000
of Discharges
With Cirrhosis*
500000
403665
400000
411029
436901
444883
459496
2006
2007
2008
498181
526096
576573
300000
200000
100000
0
2004
2005
Year
2009
2010
*ICD-9-CM diagnosis codes 571.2. 571.5, 571.6; all listed diagnoses.

HCUPnet, Healthcare Cost and Utilization Project. Agency for Healthcare Research and Quality, Rockville, MD. http://hcupnet.ahrq.gov.
Accessed January 2014
2011
Progressive Increase in Incidence of

HCV-Related Cirrhosis and HCC in US
Annual Prevalence Rates Between 1996 and 2006 Among HCV-Infected Veterans
5%
18%
Cirrhosis
4%
16%
14%
3%
12%
Decompensated
Cirrhosis
10%
2%
8%
HCC
6%
4%
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006
El-Serag HB. Gastroenterology 2012;142:12641273.
1%
0%
Hepatocellular Cancer (HCC)
Cirrhosis and
Decompensated Cirrhosis
20%
Stages of Cirrhosis
Definition
1-year
mortality
Compensated without varices
1%
Compensated with varices
3%
Decompensated with ascites without

variceal hemorrhage
20%
Decompensated with or w/out ascites

with variceal hemorrhage
57%
Stage
DAmico G et al. J Hepatol. 2006;44:217-231.
Decompensated
Compensated
Baveno IV International Consensus Workshop Staging

System for Cirrhosis: 1-Year Outcome Probabilities
Stage 1
7%
Stage 2
4.4%
VARICES
NO ASCITES
6.6%
Stage 3
1%
NO VARICES
NO ASCITES
ASCITES
VARICES
3.4%
DEATH
4%
20%
7.6%
Stage 4
BLEEDING
ASCITES
57%
Proportion of Patients
Cumulative Proportion of Patients Transitioning from

Compensated to Decompensated Cirrhosis Over Time
1.00
0.75
Half of patients decompensated over 5 years
0.50
0.25
0.0
0
0
Pts at risk 120
806
217
24
513
48
402
72
302
96
243
months
Classification of Cirrhosis:
Child-Turcotte-Pugh (CTP)
Points
1
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
INR
<1.7
1.7-2.3
>2.3
Total Numerical Score
Child-Pugh Class
5-6
7-9
10 - 15
Class A considered compensated

Class B/C considered decompensated
Adapted from Garcia-Tsao G et al. Am J Gastroenterol. 2009;104:1802-1829.
Classification of Cirrhosis Severity

Model for End Stage Liver Disease
Score
Calculated from 3 variables:

INR
Bilirubin
Serum creatinine
The MELD score equation:

[9.6 x loge creatinine (mg/dL) + 3.8 x loge bilirubin (mg/dL) + 11.2 x loge
INR + 6.4]
Eliminates subjectivity of HE and ascites evaluation used in CTP

Etiology removed without affecting predictive ability
Murray KF, Carithers RL. Hepatology 2005;41:1-26.

Wiesner R et al. Gastroenterology 2003;124:91-96.
MELD Score: 3 Month Mortality**
% Mortality
100
79
80
60
60
40
20
0
23.5
7.7
2.9
<9
n=124
10 to 19
20 to 29
30 to 39
n=1800
n=1098
n=295
> 40
n=120
MELD Score
Wiesner, R et al. Gastroenterology 2003; 124:91-96
**Mortality includes death on waitlist and removed for too sick
Liver-Related Mortality in the US is Underestimated

Deaths Due to Liver-Related Causes in US, 2008
Liver related mortality in the US is

underestimated by the National
Center for Health Statistics (NCHS),
in part, as a result of incomplete
inclusion of liver-related deaths
Use of an updated definition of liver

mortality (includes other specific liver
diagnoses such as hepatorenal
syndrome, viral hepatitis and
hepatobiliary cancerns) increased
the estimated death rate by >2 fold
from 11.7 to 25.7 deaths/100,000
30
25.7
25 100,000
Rate per
20
15
11.7
10
5
0
Updated Estimate
NCHS
Asrani, SK et al. Gastroenterology 2013;145:375-382.
% of Patients
Hospital Readmissions Among Patients with

Decompensated Cirrhosis
are
Common
80
70
60
50
40
30
20
10
0
Hospital Readmissions
Within 1 wk Within 1 mo
Volk ML et al. Am J Gastroenterol 2012;107:247-252.
Overall
Retrospective study of 402 patients from

an academic transplant center
Follow-up time censored at death,
elective admissions such as transplant or
post-procedure observation, or the date
of last clinic note; median follow-up was
203 days
Included cirrhotic patients hospitalized for
ascites, SBP, renal failure, hepatic
encephalopathy, or variceal hemorrhage
Median time to readmission was 67 days
Median number of readmissions was 2
(range 0-40); overall rate was 3
hospitalizations/person-year
Costs for Readmissions Among Patients

with Decompensated Cirrhosis
The mean costs for readmissions within 1 week
and between Weeks 1 and 4 were $28,898 and
$20,581 respectively.
Volk ML et al. Am J Gastroenterol 2012;107:247-252.
Complications of Cirrhosis: Distinguish

Portal Hypertension from Liver Insufficiency
Portal
hypertension
Cirrhosis
Hepatopulmonary syndrome
Portopulmonary hypertension
Variceal hemorrhage
Ascites,
Hydrothorax
Liver
insufficiency
SBP
Hepatorenal
syndrome
Encephalopathy
Coagulopathy
Jaundice
Hypoalbuminemia
General Management Guidelines - Cirrhosis

Surveillance for hepatocellular carcinoma
Abdominal US (or CT/MRI) every 6 months
Alfa-fetoprotein (AFP) no longer recommended by AASLD but many experts
still utilize, AFPL3% and DCP are FDA cleared for HCC risk
Vaccinate for HAV, HBV, influenza (annual), Pneumovax; consider Zoster

and HPV
Avoid non-steroidals; acetaminophen preferred but in limited quantities
(consider < 2-3gm/day)
Cautious use of benzodiazepines and opioids; contraindicated in
decompensated cirrhosis w/ HE
Beware of raw shellfish (Vibrio vulnificus)
Dietary considerations: adequate protein intake (1-1.2gm/kg/day), careful
sodium intake (ideally <2gm/day)
General Management Guidelines - Varices
Screening and surveillance endoscopy
Non-selective beta-blocker (NSBB: propranolol, nadolol, carvedilol)*
Childs B/C with small varices or Childs A with small varices with red signs (Class IIa, Level C)
Childs A with medium/large varices without red signs (Class I, Level A)
Childs A with small varices without red signs (optional) (Class III, Level B)
NSBB or Esophageal Variceal Ligation (EVL, banding)
All cirrhotic patients at diagnosis (Class IIa, Level C)

Every 2-3 years in Childs A with no or small varices
Annually in Childs B/C (or at time of decompensation)
Medium/large varices in Childs B/C or Child A with red signs (Class I, Level A)
EVL
Acutely bleeding varices

Medium/large EV in Childs A, intolerant or non-compliant with NSBB (Class I, Level A)
All patients with previously bleeding varices (in combination with NSBB, secondary prophylaxis)
(Class I, Level A)
*Stop beta-blockers in patients with cirrhosis and ascites to avoid acute kidney injury and cardiac
events
AASLD Guidelines,
Updated 2009
Varices Increase in Diameter Progressively
No varices
7-8%/year
Merli et al. J Hepatol 2003;38:266
Small varices
Large varices
Lower risk of bleeding
Higher risk of bleeding
7-8%/year
Hepatic Encephalopathy: Pathophysiology

Astrocyte
NH3
Glutamate
& NH3
Proinflammatory Cytokines
Glutamine
Nitric Oxide & Oxidative Stress
Cerebral
Blood Flow
Astrocyte
Swelling
ICP
Adapted from Mullen KD et al. Semin Liver Dis. 2007;27(Suppl 2):32-47.
Inflammation
Increased brain water,

deterioration in
neuropsychological
function & hepatic
encephalopathy
Characterization of HE Stages
Overt HE Stages
Normal
Covert HE
Categorization is often arbitrary and

varies between raters
Worsening cognitive dysfunction
Bajaj JS, et al. Hepatology. 2009;50:2014-2021.
II
III
IV
coma
Clinical
Diagnosis
Clinical Classification of HE
Type
A
Grade
MHE
1
B
C
2
3
4
Time Course
Covert
Episodic
Spontaeous or
Precipitated
Spontaeous
Recurrent
Overt
Persistent
Precipitated (specify)
Hepatic encephalopathy should be classified according to

the type of underlying disease, severity of manifestations,
time course, and precipitating factors (GRADE III, A, 1).
Role of Ammonia Testing in HE

Increased blood ammonia alone does not add
any diagnostic, staging, or prognostic value for
HE in patients with CLD. A normal value calls for
diagnostic reevaluation (GRADE II-3, A, 1)
Specific Approach to Overt HE Treatment

Four-pronged approach to management of HE
(GRADE II-2, A, 1):
Initiation of care for patients with altered consciousness
Alternative causes of AMS should be sought and treated
Identification of precipitating factors and their correction
Commencement of empirical HE treatment
Management of Overt HE (OHE)
Lactulose is the first choice for treatment of episodic OHE (GRADE II-1, B, 1)
Rifaximin is an effective add-on therapy to lactulose for prevention of OHE

recurrence (GRADE I, A, 1)
Oral BCAAs can be used as an alternative or additional agent to treat

patients nonresponsive to conventional therapy (GRADE I, B, 2).
IV LOLA can be used as an alternative or additional agent to treat patients

nonresponsive to conventional therapy (GRADE I, B, 2).
Neomycin is an alternative treatment (GRADE II-1, B, 2)
Metronidazole is an alternative treatment (GRADE II-3, B, 2)
Probiotics and PEG cathartics appear to be equivalent to lactulose for HE

therapy*
*As modified from: AASLD Practice Guideline, 2014.
Prevention of Overt HE (OHE)
Lactulose is recommended for prevention of recurrent episodes of HE after

the initial episode (GRADE II-1, A, 1)
Rifaximin as an add-on to lactulose is recommended for prevention of

recurrent episodes of HE after the second episode (GRADE I, A, 1)
Routine prophylactic therapy (lactulose or rifaximin) is not recommended for

the prevention of post-TIPS HE (GRADE III, B, 1)
Under circumstances where the precipitating factors have been well

controlled (i.e., infections and VB) or liver function or nutritional status
improved, prophylactic therapy may be discontinued (GRADE III, C, 2)
Probiotics and PEG cathartics appear to be equivalent to lactulose for HE

therapy*
* As mofdifed from : AASLD Practice Guideline, 2014.
Treatment Approach for Episodic OHE:

Lactulose + Rifaximin vs. Lactulose
172 Cirrhotic Patients Screened
120 Patients Enrolled
Randomization
Lactulose (30-60 mL TID) +

Lactulose (30-60 mL TID) +
Rifaximin (one 400 mg capsule TID)
Placebo (one sugar capsule TID)
n=63 (10 grade 2, 20 grade 3, 33 grade
n=57
4) (12 grade 2, 20 grade 3, 25 grade 4)
Sharma BC et al. Am J Gastroenterol 2013;108:1458-1463.
Treatment Approach for Episodic OHE:

Lactulose + Rifaximin vs. Lactulose
P=0.004
80
70
60
% of Patients
50
40
30
20
10
48/63 25/57
0
Reversal of HE
Sharma BC et al. Am J Gastroenterol 2013;108:1458-1463.
Lactulose +
Rifaximin
P=<0.05
15/63 28/57
Death
Given via nasogastric

tube until recovery of HE
or a maximum of 10 days
Hospital stay was shorter

with Lactulose+ Rifaximin
than with Lactulose +
Pbo (5.83.4 vs. 8.24.6
days, P=0.001)
Summary
Cirrhosis is increasing in prevalence in the US and recognition
with accurate diagnosis is critical for patient care
Histologic or clinical diagnosis
Be familiar with the various staging and prognostic tools
Recognize the clinical importance of transition from compensated to
decompensated cirrhosis
HE is a frequent complication of cirrhosis

Familiarize yourself with new guidelines for its diagnosis,
classification, and treatment
Hepatocellular Carcinoma
16.0%
14.0%
AIR
Survival
12.0%
10.0%
8.0%
6.0%
4.0%
1
2007
2006
2005
2004
2003
2002
2001
2000
1999
1998
1997
1996
1995
1994
1993
1992
1991
1990
1989
1988
1987
1986
1985
1984
1983
1982
1981
1980
1979
1978
1977
1976
1975
1974
1973
2.0%
Year of HCC Diagnosis

El-Serag HB. N Engl J Med 2011
0.0%
5-year Survival
Incidence rate per 100,000
The Incidence and 5-Year Survival of

HCC in United States
25
11.4
47.1
South Korea
Male:female
ratio
4.1
11.4
47.1
North Korea
4.1
38.6
Thailand
2.2
37.9
China
2.7
Japan
3.0
Vietnam
4.1
Italy
3.1
Indonesia
4.3
France
4.8
Mexico
1.0
15
15
25
17.2
14.2
7.6
23.1
5.8
Women
Men
23.7
5.1
15.9
2.6
2.2
4.9
10.5
5.0
45
55
2.3
6.1
South Africa
2.7
2.0
5.5
USA
2.8
Russia
2.2
2.1
GLOBOCAN 2002
11.3
35
4.6
2.6
3.6
Poland
1.4
2.4
3.4
Brazil
1.4
2.0
Sweden
1.9
1.9
3.7
3.5
Argentina
1.8
1.7
3.3
United Kingdom
1.9
Turkey
1.7
Iran
0.7
1.5
1.9
2.6
1.4
Seroprevalence of HBsAg, antiHCV-Ab, Both and Neither in

Patients with HCC in the US in Three Time Periods
100
2000
2001-2005
2000
n=25297
n=464
n=7224
Percentage (%)
80
60
40
20
0
HBV
De Martel C et al, Hepatology 2015; online version (July)
HCV
Both
None
Risk Factors for HCC in Chronic HCV:

Host Factors
Older age
Duration of HCV infection
Male sex
Race
Alcoholism
Obesity
Diabetes
HBV co-infection esp if they have Delta infection
HIV co-infection
HCV Genotype 3 in the VA HCV Clinical

Case Registry 2000-2009: Cirrhosis and
HCC
88,348 patients with genotype 1 (80%)

13,077 genotype 2 (12%)
8,337 genotype 3 (7.5%)
Mean follow up 5.4 years
After adjustment for demographic, clinical and antiviral treatment
factors, comparison between genotypes 3 and 1:
Hazard Ratio
Confidence
Interval
Cirrhosis
1.31
1.22.-1.39
HCC
1.80
1.61-2.03
Conclusion: Genotype 3 is associated with a significantly higher

risk of cirrhosis and HCC vs genotype 1, independent of age,
diabetes, BMI or antiviral treatment
Kanwal F et al, Hepatology 2014;60:98-105
HBV: Risk Factors for Progression to HCC

Viral factors
Persistently high
HBV DNA levels
HBV CP variant
HBV genotype
(C > B)
Delta infection
Host Factors
External Factors
Older age
Male gender
Alcohol
Asians??
Aflatoxin
Advanced fibrosis
Smoking
Persistent ALT elevation
Recurrent hepatitis
flares
HDV, HCV coinfections
HIV coinfection
Family history of HCC
Increased or increasing:
AFP, AFPL3% and DCP
Tobacco Smoking
Smoking alone
Positive associations and no associations reported in
different studies
Smoking PLUS HBV and HCV infection

More than additive interaction between HBV infection
and cigarette smoking
More than multiplicative interaction between HCV
infection and cigarette smoking
ChuangSC,etal.CancerEpidemiolBiomarkersPrev.2010;19:12611268
NAFLD and Risk of HCC

No evidence from population based data
Possible increase in HCC risk in clinic based cohorts
of NASH
? Magnitude
? Risk factors
Consistent evidence from clinic based cohorts with

NAFLD/NASH cirrhosis
Magnitude < HCV cirrhosis
White D, Kanwal F, El-Serag. Clin Gastro Hep 2012
HCC Rate (%)
Diabetes Is Associated with a Two-fold

Increase in Risk of HCC
0.25
Diabetes
N=173,643
0.20
0.15
P<0.0001
No Diabetes
N=650,620
0.10
0.05
0.00
0
Years of Follow up
El-Serag HB, et al, Gastroenterology 2004
10
12
14
HCC in the Absence of Cirrhosis in

United States Veterans
~13% of 1500 HCC cases developed in
absence of cirrhosis
These cases were more likely than HCC in
cirrhosis to have
NAFLD or idiopathic compared to HCV or
alcohol
Co-morbidities associated with metabolic
syndrome
While a small proportion, this poses

logistical problems for HCC surveillance
El-Serag HB et al. DDW 2014
Prevention of HCC
HCC and Hepatitis C Treatment

B
Cumulative Incidence
of HCC (%)
<65 years
30
Non-SVR
20
10
SVR
0
0
10
12
14
16
Non-SVR
65 years
Cumulative Incidence
of HCC (%)
30
SVR
20
10
0
0
Year
10
12
14
16
Year
5 yrs.
10 yrs.
15 yrs.
SVR
Patients with HCC

0
Patients at risk
565
Cumulative incidence 0%
of HCC
6
376
1.2%
12
164
3.3%
12
56
3.3%
Non
SVR
Patients with HCC

0
Patients at risk
980
of HCC
33
723
3.6%
72
345
10.9%
85
141
15.5%
5 yrs.
10 yrs.
15 yrs.
SVR
Patients with HCC

0
Patients at risk
121
of HCC
7
67
6.0%
10
21
11.0%
10
5
11.0%
Non
SVR
Patients with HCC

0
Patients at risk
376
of HCC
46
179
14.1%
61
43
25.5%
64
25
31.1%
Ashahina et al., Hepatology 2010
HBV Vaccination and HCC:

Taiwan Experience
National HBV immunization program was launched in July 1984.

Results
Incidence rate of HCC in children 6-19 years of age was statistically
significantly reduced for those born after initiation of vaccination
program
HCC prevention extended from childhood to early adulthood
Higher risk of development of HCC in those who received

incomplete vaccination (fewer than 3 doses) or who were born to
HBsAg or HBeAg-seropositive mothers
Chang et al., J Natl Cancer Inst 2009;101:1348-1355
Hepatitis B: Association Between Viral Load

and Incidence of HCC>> treatment guidelines
Baseline HBV DNA Level (copies/ml)
14
106
105<106
104<105
300<104
<300
12
HCC (%)
10
8
13.50%
7.96%
6
4
3.15%
0.89%
0.74%
0
0
10
11
12
13
Year of follow-up
HBeAg negative, normal ALT, no liver cirrhosis at entry (n=2,925)
Chen CJ et al. JAMA. 2006;295:6573
Adapted from Chen CJ et al. JAMA. 2006;295:6573
Statins and HCC

Systematic Review
Ten studies
7 observational, 3 clinical trials
Pooled OR: 0.63 (0.52-0.76)

Not in the 3 clinical trials
Not other lipid lowering medications

Unclear
Dose, duration, type
Singh S, et al Gastroenterology 2009
Metformin and Reduced Risk of HCC in

Diabetic Patients: a Meta-analysis
Seven studies:
Three cohort studies
Four case-control studies
Significantly reduced risk of HCC in metformin

users versus nonusers in diabetic patients
RR: 0.24, 95% CI 0.130.46, p < 0.001
Zhang H et al. Scand J Gastroenetrol 2013
Coffee and Hepatocellular Carcinoma

Epidemiologic studies: coffee consumption
is inversely related to
Serum liver enzyme activity
Liver cirrhosis
HCC
For each additional 1 cup of coffee:

Case-control studies
(0.77, 0.72-0.83)
Cohort studies
(0.75, 0.65-0.85)
Recommended Groups for HCC Surveillance

Threshold Incidence
for Efficacy of
Surveillance
(>0.25 LYG)(%/year)
Incidence of HCC
(%/year)
Asian male hepatitis B carriers > age 40
0.2
0.40.6
Asian female hepatitis B carriers > age 50
0.2
0.30.6
Hepatitis B carrier with family history of HCC
0.2
Incidence higher than

without family history
African/North American Blacks
0.2
HCC occurs at a
younger age
0.2-1.5
38
1.5
35
Population Group
Cirrhotic hepatitis B carriers

Hepatitis C cirrhosis
Sherman M. Semin Liver Dis. 2010;30(1):3-16.
AFP and Des-gamma-carboxy Prothrombin

(DCP) in the Early Diagnosis of HCC
1031 patients randomized in the Hepatitis C Antiviral Long-term

Treatment Against Cirrhosis (HALT-C) Trial
Nested case-control study of 39 HCC cases and 77 controls
Testing within one month prior to HCC diagnosis

DCP: sensitivity (74%) and specificity (86%) at a cutoff of
40 mAU/mL
AFP: sensitivity (61%) and specificity (81%) at a cutoff of 20 ng/mL
Combining both markers increased the sensitivity to 91% at month 0
but the specificity decreased to 74%
Lok, et al. Gastroenterology 2009
AFPl3% and DCP are FDA cleared as risk markers for HCC
HCC Surveillance Recommendations

The target population for surveillance are those
with liver cirrhosis (and HBV-infected patients
without cirrhosis in special circumstances)
US and AFP are the recommended screening
tests for HCC in patients at the highest risk
US is central
Not AFP alone
Roberts Gastro 2015
HCC Surveillance Recommendations

Premature to recommend dropping AFP
RCTs used AFP + US
Only population based cohort used AFP
Approximately 20% of HCC cases are detected based only on
an increase in AFP (with normal results from
US analysis)
Most of the current community-based surveillance
is either nothing or AFP
Adjust AFP for ALT and plt count
Singal, Clin Gastro Hep 2015,
El-Serag Gastro 2014
Barcelona-Clinic Liver Cancer (BCLC) Staging Classification

and treatment Schedule for Hepatocellular Carcinoma
HCC
Very early stage
Early stage
1 HCC <2 cm
Carcinoma in situ
1 HCC or 3 nodules
<3 cm, PS 0
1 HCC
3 nodules
<3 cm
Portal pressure /
bilirubin
Intermediate
stage
Advanced stage
Chemoembolization
Sorafenib
No portal vein
thrombosis
Multinodular, PS 0
Portal invasion
Metastases,
PS 0-2
Terminal
stage
Associated
diseases
Normal
Resection
OLT
PEI / RFA
Potentially curative treatments

El-Serag HB, et al. Gastroenterology 2008
Palliative treatments
Symptomatic
Therapy
Phase III SHARP Trial in Advanced HCC:

Overall Survival Benefit with Sorafenib
Survival Probability
1.00
Sorafenib
Median: 10.7 months

(95% CI, 40.9-57.9)
0.75
Placebo
Median: 7.9 months

(95% CI, 29.4-39.4)
0.50
0.25
0
Patients at risk
Sorafenib:
Placebo:
Hazard ratio (Sorafenib/Placebo): 0.69

(95% CI, 0.55-0.87)
P = 0.00058*
0
10 11 12 13 14 15 16 17
Time (months)
299
303
274
276
241
224
205
179
161
126
108
78
*OBrien-Fleming threshold for statistical significance was P = 0.0077; CI=confidence interval

Llovet JM et al. NEJM. 2008; 359(4):378
67
47
38
25
12
7
0
2
HCC in the United States
HCC fastest rising cause of cancer related death

#1 cause of cancer death in VN and SE Asian men
NASH, HCV and HBV
Modifiable risk factors (alcohol, obesity, diabetes) for

individual management
Non modifiable risk factors (age, duration, sex)
Likely to continue for the near future
Possible role for NAFLD with and w/o cirrhosis
Prevention
HBV vaccination
Antiviral treatment
Detection: Surveillance in high risk groups
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-No Relevant Relationships

Identify the risk factors and overall disease processes in chronic

Describe current and evolving treatment strategies for chronic liver

Effectively adhere to long-term surveillance recommendations

Primary Biliary Cholangitis (PBC)

Causes and Markers of PBC

AASLD Suggested Diagnostic Algorithm

Ursodeoxycholic Acid (UDCA)

Ursodeoxycholic Acid (UDCA)

Pares A, Gastroenterology, 2006; Marschall HU, Gastroenterology, 2005.

ALP <1.67 x ULN and Normal Bilirubin after 1 Year

Lammers, EASL, AASLD. 2013.

Ursodeoxycholic Acid (UDCA)

Backbone of therapy in PBC in the past 20 years

Obeticholic Acid (OCA): A Modified Bile Acid

FXR EC50 = 8.6 M

~100x increased potency

Obeticholic Acid (OCA): A Modified Bile Acid

OCA in Patients with PBC: POISE Study Design

Remain at OCA 5 mg (n=36)

OCA Titration at 6 Months: Subjects in OCA

The primary endpoint (ALP <1.67x ULN

Primary Objective and Patient Population

To assess the proportion of patients achieving ALP <1.67 xULN and a

1. Corpechot, Hepatology 2008.

Demographic and Baseline Characteristics

UDCA use, n (%)

Daily UDCA dose, mg/kg

Pretreatment Liver Biopsy Performed

Age at PBC diagnosis, y

Data are mean SD where applicable.

Disposition of OCA Titration Group

32 Ineligible for Titration

37 Eligible for Titration to

Percent Achieving Primary Endpoint

*p<0.0001 vs. placebo

p values obtained using Cochran-Mantel-Haenszel stratified by randomization strata factor

OCA Treatment Significantly Reduced ALP

Titration OCA (n=70)

A Significantly Greater Proportion of OCA-treated

OCA Treatment Resulted in Significant Decreases

***p<0.001 vs. placebo

OCA Treatment Decreased Bilirubin Over Time

LS Mean (SE) Change from Baseline ( m ol/L)

LS Mean (SE) Change from Baseline ( m ol/L)

Titration OCA (n=70)

*p<0.05 vs. placebo

The incidence of AEs other than pruritus was no

The effect of OCA was consistent independent of age at diagnosis,

Long-term Management of Patients

Liver tests every 3-6 months

Nonalcoholic Fatty Liver Disease (NAFLD)

Adult Obesity in America 2014

Adult Obesity in America 2011-12

Childhood Obesity in America 2011-12

Diseases Associated with Visceral Obesity

The Spectrum of NAFLD

Exclusion of liver diseases (HCV & ETOH)

Not very good in our hands at predicting fibrosis in NAFLD patients