"A Discussion on HCV:

What you need to know.

Messaging for the patient and their support team as well
as medical staff

July, 2014
Robert G. Gish MD
Email address: rgish@robertgish.com
Cell phone: 1 858 229 9865
Robert G Gish Consultants LLC

Professor Consultant: Stanford University

Please visit my website: robertgish.com for more information
Please send me an Email if you wish to be added
to my liver listserv


Disclosures
Dr Gish has consulting relationships, advisory boards and
speakers bureau status with

Gilead
BMS
Abbvie
Merck/Idenix

And donates/expends all funds from pharma to research,
education and health care policy
2
Liver: An Enigma
Liver is the largest organ in the body: wt 1.2-1.5 Kg
Liver is the most complex organ in the body
From ancient times liver is considered the organ of fate

Egyptians considered the liver to be the seat of the life force
Liver
Left, right
Portal veins
Portal vein
Veins from
pancreas &
duodenum
Veins from
ascending
colon
Esophageal veins
Short
Gastric veins
Left, right
gastric veins
Splenic vein
Gastro-
epiploic vein
Inferior
mesenteric
vein
Superior
mesenteric
vein
Veins from
jejunum &
ileum
Veins from
descending
& sigmoid colon
Liver Tests
Liver Enzymes
AST
ALT
Alkaline Phosphatase
GGT

Liver Synthetic Tests
Bilirubin
Albumin
Protime/INR
True liver function tests
Liver: a Unique organ
Anatomy:
- Dual blood supply
* Portal Vein
* Hepatic artery
HA supplies 35% of blood flow
Segmental anatomy
8
The Appearance of a
Normal Liver

Will be:
Smooth
Firm to the touch

It will not be:
Shrunken or
enlarged

9
The Architecture Of The Normal liver
Looks Like This;








Sinusoid:
Carries blood within the liver,
providing contact with the blood

Bile Duct:
Carries newly formed
bile away from the liver

Portal Vein Branch: brings blood,
oxygen, Nutrients, and waste
Materials into the liver and delivers them
to sinusoids

Hepatic Artery Branch:
carries additional oxygen To the liver

Hepatocytes:
Normal liver cells

Normal Liver
Edward Klatt, MD, Department of Pathology, University of Utah: 1999.
Chronic Hepatitis
Chronic active hepatitis
of mild to moderate
severity with portal and
periportal
inflammation. Trapping
of periportal
hepatocytes and
inflammation extending
beyond portal tract.
Focal lobular
inflammation is also
evident. H&E x 200.

Edward Klatt, MD, Department of Pathology, University of Utah: 1999.
Histologic Features of Fatty
Liver or NASH
Steatosis and Necro-
inflammation
Fibrosis
13
Progressive Cell Death,
Inflammation,
and Scarring will occur:



Swelling :Injured
hepatocytes
Inflammation: Cellular
Infiltration and swelling
Necrosis: death of cells

Scarring: scar tissue begins
to replace functioning liver
cells




Hepatoytes : Liver cells
Cirrhosis Normal
Nodules
Irregular surface
GROSS IMAGE OF A NORMAL
AND A CIRRHOTIC LIVER
16
Chronic Hepatitis C can lead to
cirrhosis (liver scarring) or possibly
even liver cancer.

In patients with cirrhosis,
impairment of liver function is
accompanied by changes in the livers
appearance.

The liver is deformed in early
cirrhosis, with subsequent shrinking
and hardening.





Complications of Hepatitis

Early Cirrhosis
Scarring
Abnormal Liver nodules
Ascites
Variceal bleeding
Hepatic encephalopathy
Portal
systemic
collaterals
Distorted
sinusoidal
architecture
leads to
increased
resistance
Portal
vein
Cirrhotic Liver
Splenomegaly
ARCHITECTURAL LIVER DISRUPTION IS THE MAIN MECHANISM THAT LEADS
TO AN INCREASED INTRAHEPATIC RESISTANCE
Small varices
Lower risk of bleeding
Large varices
Higher risk of bleeding
No varices
7-8%/year
7-8%/year
Varices Increase in Diameter
Progressively
Merli et al. J Hepatol 2003;38:266
Physical Exam Findings in
Chronic Liver Disease
Nutritional advice in patients
with cirrhosis
Frequent meals (6 or more a day)
Complex, not simple, carbohydrates
Balanced died of 30 kcal/kg body weight
Corrects or ideal body weight in patients with ascites
30-35% of calories consumed as fat
50-55% of calories consumed as carbohydrate
Excess carbohydrates can promote hepatic lipogenesis
Protein intake 1.21.5g/kg
Protein restricted diets have no place in management / prevention of
HE
Vegetable or casein protein maybe better tolerated
Branched-chain amino acids (leucine, isoleucine and valine) may be
reduced in cirrhotic patients
Normalization promotes protein synthesis, reduces plasma ammonia
and may compete with aromatic amino acids in crossing the blood-brain
barrier; this may be achieved with protein supplements
Chadalavada et al, Nutr Clin Pract 2010:;25: 257-64
Verslype et al, Acta Gastroenterol Belg 2010; 73: 510-13
Calcium supplements
If indicated (alcoholics, cholestasis)
Testosterone replacement if deficient help rebuild
muscle mass
Reduce salt intake (particularly in those with ascites)
Micronutrients
Vitamin deficiency a risk, particularly if cholestasis is present
Vit A, D, and E
Mg
Zinc

Proscribed use of supplements recommended
Nutritional advice in patients
with cirrhosis (Cont)
Chadalavada et al, Nutr Clin Pract 2010:;25: 257-64
Verslype et al, Acta Gastroenterol Belg 2010; 73: 510-13
Use of Liver Biopsy
as the G old Standard
Needle liver biopsy samples <1/50,000
th
of the liver
Cirrhosis can be missed in 3-5% of cases
Dependent upon
Length of Biopsy
Number of biopsies performed
Type of needle used
Etiology of Liver Disease
25
Now: 2014 To stage
Blood tests
Elastography or liver stiffness
Spleen size over 12 cm
Portal Vein over 12 mm
Platelet count under 150 000
Varices on endoscopy or imaging
Synthetic liver tests
The good news
HCV is curable with therapy: 70-90%
Seek out education from reliable sources and
support in your family, friends and groups
help4hcv.org
Stop
Alcohol use
Marijuana use
Pursue good health
Loose weight if overweight
Healthy mouth
Vaccines for HAV and HBV
Exercise
Regular health check up

Liver Cancer
(Hepatocellular Carcinoma)
Hadziyannis SJ. J Eur Acad Dermatol Venereol. 1998;10:12-21.
HCV Infection:
Extrahepatic Manifestations
Hematologic
Mixed cryoglobulinemia
Aplastic anemia
Thrombocytopenia
Non-Hodgkins b-cell lymphoma
Dermatologic
Porphyria cutanea tarda
Lichen planus
Cutaneous necrotizing
vasculitis
Renal
Glomerulonephritis
Nephrotic syndrome
Endocrine
Anti-thyroid antibodies
Diabetes mellitus
Salivary
Sialadenitis
Ocular
Corneal ulcer
Uveitis
Vascular
Necrotizing
vasculitis
Polyarteritis nodosa
Neuromuscular
Weakness/myalgia
Peripheral
neuropathy
Arthritis/arthralgia
Autoimmune
Phenomena
CREST
syndrome
HCV basics
Blood borne disease
5 M infected in the US today
20-40% life-time risk of cirrhosis
Time to cirrhosis is 20-40 years
Increased all cause mortality
Example : Renal disease
Decrease quality of life
Higher risk of cirrhosis with
NASH
ALC
HIV, or HBV or other co-infection
Risk of cancer/HCC is in patients with cirrhosis
? F3 30
CMS and USPHSTF
Birth cohort testing and high risk
testing for HCV is SOC
Where you born between 1945
and 1965?

Why only pay for HCV testing when
done by primary care providers?
31
32
HCV progression and age at time of infection
33
34
35
36
Chronic HCV Increases Mortality from Hepatic
and Non-hepatic Diseases

The REVEAL HCV Cohort Study
23820 adults, Taiwan
1095 anti-HCV positive; 69,4% with detectable HCV RNA
Follow-up (years) Follow-up (years)
C
u
m
u
l
a
t
i
v
e

m
o
r
t
a
l
i
t
y
,

(
%
)

C
u
m
u
l
a
t
i
v
e

m
o
r
t
a
l
i
t
y
,

(
%
)

HCV seropositive HCV RNA detectable
HCV seropositive HCV RNA undetectable
HCV seronegative
Hepatic diseases
Diseases that
are not in the
liver
12,8%
1,8%
0,7 %
19,8%
11,8%
12,7%
LeeMH, et al. J I nfect Dis. 2012 Aug 15;206(4):461-3.
Chronic HCV Infection Affects Many Sites
Beyond the Liver
Neurological
(e.g. cognitive
impairment)
Cardiovascular
Diseases
(CAD and stroke)
Metabolic
(e.g.
diabetes)
Autoimmune
(e.g.
cryoglobulinemia)
Dermatological
(e.g. porphyria
cutanea tarda)
Pulmonary
fibrosis
Renal (e.g.
glomerulonephritis)
Lymphoproliferative
(e.g. B cell
lymphoma)
Ration ? Deny ?
Treatment
Who should test for HCV?
Only PCP according to Medicare

Treat

Only treat F3?
Only treat F4 cirrhosis

Use Liver biopsy to triage?
Look for extra-hepatic disease?

Treat based on all cause mortality ?


39
HCV: What is the cost ?
Cost of testing: 15-20$
HCV antibody

Treatment
50-400,000$

Liver transplant
100-500,000$

Death in the hospital
150,000+$

To purchase sofosbuvir
11.2 billion $
40
Mason AL et al
Hepatology,
1999
Association of Diabetes Mellitus and
HCV Infection
SVR Reduces Risk of Development of
Diabetes in Patients with HCV
Veterans Affairs Clinical Case Registry: 27.636 patients with HCV
Followed for median 5 years
Antiviral treatment initiated 1998-2007
Hyder S. and et al Digestive Disease week, 2013
2013 2014 2015 2016
Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4
2013 2014 2015 2016
Projected Timing for New Regimen Launches
Sofosbuvir + RBV
------
GT2/3, Nave/Tx-EXP/
IFN Ineligible TX-Exp
BMS DCV/ASV/RBV*
-----
GT1b Nave/Tx-Exp/
IFN Intolerant
Daclatasvir Triple
-----
Gt1. Nave only
Sofosbuvir +
Ledipesvir
-----
GT1/2/3, Nave/TX-EXP/
IFN Ineligible
ABT-450/267/333/RBV
----
GT1, Nave/Tx-EXP
Faldaprevir
(BI201335) Triple
----
GT1 Nave, Tx-EXP
Sofosbuvir Triple
----
GT1, 4, 5, 6, Naive
Simeprevir Triple
----
GT1, Nave, Tx-Exp
Triple
IFN-Free
* Precise timing TBD
Genotype 1: PEG IFN/RBV +
Sofosbuvir/Simprevir/Faldaprevir
Will this be the last hurrah for PEG
IFN/RBV in the US?


All oral agents will be the standard of
care in 2 years for genotype 1

44
NS3 /4A Inhibitors (Protease inhibitor PI)
High potency
Limited genotypic coverage
Low barrier to resistance
NS5A Inhibitors
High potency
Multi-genotypic coverage
Low barrier to resistance
NS5B Nucleos(t)ide Inhibitors (NI)
Intermediate potency
Pan genotypic coverage
High barrier to resistance
NS5B Non Nucleoside Inhibitors (NNI)
Intermediate potency
Limited genotypic coverage
Low barrier to resistance
Direct-Acting Antiviral Agents (DAAs) -
Key Characteristics
What Is in Our very Near Future?
More dual Therapy
DAA plus IFN backbone plus ribavirin (RBV)
Second-generation PIs only with all oral
Nucleoside polymerase inhibitors
Nonstructural protein (NS)5A inhibitors
EXPECTATIONS
RVR >90%
Sustained virologic response (SVR): > 80%
Tolerability and side effects - less and less
Response guided therapy: Gone
Side effects: rare unless using interferon and
ribavirin
Two Protease Inhibitors are used in
combination with PEG IFN/RBV
NS3 protease Inhibitor
Q daily dosing
Improved side effect profile
No anemia
Fewer DDIs
Use now is only with SOF (COSMOS)
47
Simeprevir FDA approved
Sofosbuvir (SOF, GS-7977)
48
HCV-specific nucleotide polymerase
inhibitor (chain terminator)
Potent antiviral activity against
HCV genotypes 16
High barrier to resistance
Once-daily, oral, 400-mg tablet
Favorable clinical pharmacology profile
No food effect
No significant drug interactions
Generally safe and well tolerated in
clinical studies to date (>2000 patients)
No safety signal in preclinical/clinical
studies
COST COST COST
Rep Waxman !


The 1000 $ pill

deny testing due to high cost of treatment ?

Doesnt treatment start with
no alcohol
lose weight
stop THC use
stop spread of infection
49
SOFOSBUVIR:
NEUTRINO Study: Virologic Response by Cirrhosis
Status
Post-treatment On treatment
P
a
t
i
e
n
t
s

w
i
t
h

H
C
V

R
N
A

<
L
L
O
Q

(
%
)

50/54 52/54 53/53
Week 2 Week 4 Week 12 Week 12
43/54 249/273 269/271 267/267 252/273
Error bars represent 95% confidence intervals.
Lawitz E, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 1411.
Source: Camilla Graham, MD, MPH. Beth Israel Deaconess Medical Center
HCV Therapy for Genotype 1 Chronic HCV
Cost Analysis Based on Cost per SVR
Patient Characteristics Regimen Options SVR Cost per SVR
Nave, no cirrhosis
Wait until 2015 ? ?
SOF/Peg-IFN/RBV x 12 wks 92% $114,500
SOF/RBV x 24 wks ~68% $266,176
Nave, cirrhosis
SOF/Peg-IFN/RBV x 12 wks 80% $131,675
SOF/Simeprevir x 12 wks >90% $169,800
Treatment experienced,
no cirrhosis
Wait until 2015 ? ?
SOF/Peg-IFN/RBV x 12 wks ? ?
Treatment experienced,
cirrhosis
SOF/Peg-IFN/RBV x 12 wks ? ?
SOF/Simeprevir x 12 wks >90% $169,800
EOT
Virologic Response During and
After Treatment (mITT)
H
C
V

R
N
A

<

L
L
O
Q


(
%

p
a
t
i
e
n
t
s
)

Week 2 SVR
4
N =
Week 4
21
20
SVR
12
100 100

100 100
21 20 21 20 21 20 21 20
DCV + SOF
DCV + SOF
+ RBV
Missing
100

91
80
95
* 1 patient missing at post-treatment (PT) Week 12: HCV RNA was undetectable at PT Week 4 and
at PT Week 24 (preliminary)
21/41 patients have reached PT Week 24; all have achieved SVR
24

100 95*
Sofosbuvir + Simeprevir +/- Ribavirin for HCV GT 1
COSMOS Trial: Cohort 1 Results
COSMOS (Cohort 1): SVR 12 by Regimen
Source: Sulkowski M, et al. EASL. April 2014. Abstract 07.
79
93
96
93
0
20
40
60
80
100
SOF + SMV + RBV
(24 weeks)
SOF + SMV
(24 weeks)
SOF + SMV + RBV
(12 weeks)
SOF + SMV
(12 weeks)
P
a
t
i
e
n
t
s

w
i
t
h

S
V
R

1
2

(
%
)

SOF = sofosbuvir; SMV = simeprevir; RBV = ribavirin
19/24 14/15 26/27 13/14
Sofosbuvir + Simeprevir +/- Ribavirin for HCV GT 1
COSMOS Trial: Cohort 2 Results
COSMOS (Cohort 2 with F3-F4 Fibrosis): SVR12 by Regimen
Source: Lawitz E, et al. EASL. April 2014. Abstract 165.
93
100
93 93
0
20
40
60
80
100
SOF + SMV + RBV
(24 weeks)
SOF + SMV
(24 weeks)
SOF + SMV + RBV
(12 weeks)
SOF + SMV
(12 weeks)
P
a
t
i
e
n
t
s

w
i
t
h

S
V
R

4

(
%
)

SOF = sofosbuvir; SMV = simeprevir; RBV = ribavirin
28/30 16/16 25/27 13/14
24-Week Treatment 12-Week Treatment
55
SOF +Riba treatment pre LT can cure up to 95% if HCV RNA negative >30 days on treatment
SOF +Riba post LT can cure >~67% of patients
HCV AND LIVER TRANSPLANTATION
SURVIVAL
50
60
70
80
90
100
0 1 2 3 4 5
YEARS
S
U
R
V
I
V
A
L

(
%
)
Non-HCV
HCV
ML Shiffman et al.
Am J Transpl 2006; 6:1170-1187.
SRTR database
1995-2005
HCV AND LIVER TRANSPLANTATION
FIBROSIS PROGRESSION
0
20
40
60
80
100
1 2 3 4 5 6-10
YEARS AFTER TRANSPLANTATION
%

o
f

P
a
t
i
e
n
t
s
Cirrhosis
Bridging
Portal
N Yilmaz et al.
Liver Transpl 2007; 13:975-983.
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10
YEARS
S
U
R
V
I
V
A
L

(
%
)
Non-HCV
HCV
A Hackworth et al
ATC 2010
HCV AFTER LIVER TRANSPLANATION
SURVIVAL
IVer
HCV TREATMENT WITH CIRRHOSIS
Why we do not use Interferon
CUPIC COHORT
TRV BOC
N 295 190
Relapse
Partial Response
Null Response
39%
46%
10%
45%
42%
5%
Esophageal Varices 35% 38%
SVR
Relapse
Partial response
Null Response
40%
53%
32%
29%
41%
51%
40%
11%
H Fontaine et al.
EASL 2013
TPV BOC
SAE 49% 38%
Premature DC 26% 24%
Infections 26% 24%
Death 2% 1.3%
Decompensation 4.4% 4.4%
Anemia <8.0 gm/dl 10% 10%
EPO use 57% 66%
Platelets <25,000 1.3% 0.6%
TPO use 1.7% 1.9%
IVer
HCV TREATMENT WITH CIRRHOSIS
INCREASED INFECTION
N/%
N 191
Stage 0-2
Stage 3
Stage 4
31%
19%
50%
Nave
Relapse
Non-response
21%
30%
49%
Telaprevir
Boceprevir
50%
50%
K Rutter et al.
EASL 2012
N/%
Stop for:
Futility
AE
Infection

17%
20%
8%
Risk of Infection
Albumin >3.5
< 3.5
Platelets >90,000
<90,000

12%
60%
14%
24%
SVR
Stage 0-2
Stage 3
Stage 4

65%
47%
28%
IVer
SOFOSBUVIR-RIBAVIRIN
DECOMPENSATED CIRRHOSIS
N Afdhal et al.
EASL 2014
Child Class
SOFOSBUVIR-RIBAVIRIN
DECOMPENSATED CIRRHOSIS
CTP A CTP B
SOF+RBV OBS SOF+RBV OBS
Platelet +17 -9 +1 -1
Albumin (gm/dl) +0.5 -0.1 +0.4 0
ALT (IU/L) -72 +13 -75 0
Ascites HE
Baseline 6 9 5 2
Week 12 5 8 3 3
Week 24 0 7 0 4
CHANGE IN PARAMETERS OVER 24 WKS
N Afdhal et al.
EASL 2014
Prior to transplant
HCV AND LIVER TRANSPLANTATION
TIMING OF INTERFERON THERAPY
Liver
Transplant
As soon as stable
As needed Pre-emptive
IVer
SOFOSBUVIR AND RIBAVIRIN
LIVER TRANSPLANT
MP Curry et al. AASLD 2013
M Charlton et al. AASLD 2013
at LT
SVR when HCV RNA
UD at LT
Post-LT Tx
24 weeks
Pre-LT
Treatment
NEED FOR LIVER TRANSPLANTATION
HBV AND HCV
0
100
200
300
400
500
600
700
1993 1995 1997 1999 2001 2003 2005 2007
YEAR
H
B
V

A
d
d
i
t
i
o
n
s

0
1000
2000
3000
4000
5000
H
C
V

A
d
d
i
t
o
n
s
HBV
HCV
WR Kim et al.
Hepatology 2007; AASLD abstract 12.
% HBV with HCC: 8% 12%
FUTURE OF LT FOR HCV
SUMMARY
The vast majority of patients with HCV and cirrhosis
can now achieve SVR
For patients with post-LT HCV treatment with oral
anti-viral agents will reduce post-LT mortality
The number of patients with HCV who will require
liver transplant will decline precipitously in 5-10
years
Patients who will still need liver transplant:
HCC
Identified too late already with liver failure
Pre-treatment with oral anti-viral agents prior to LT
will significantly reduce post-LT HCV
Summary: To be continued
The next big advance will be


All oral therapy, no interferon, ? No ribavirin
Price decrease
Treatment of all pre and post LT and organ
transplant patients
HCV testing in all patients and linkage to care

Summary: To be continued
All oral therapies for all genotypes will be here in < 2
years, Geno 1 Oct 2014
Prior to approval, will physicians mix and match with limited
data?
Will health care payors allow this guidance therapy?
Will patients demand this?
Expect > 90% SVR, ~6-8-12 week duration
Cirrhotics: Will they require up to 24 weeks?
Interferon: Salvage therapy?
Acute HCV in high risk IVDU and sexual events
Prisons
Developing countries: Egypt and the 900$ treatment

68
Thank you to
Mitch Shiffman
Paul Kwo
Doug Dieterich
Ira Jacobson
University of Washington Website
Cami Graham


For sharing so many slides !
69