a discussion on hcv: what you need to know
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"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: [email protected]
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 addedto my liver listserv
mailto:[email protected]:[email protected] -
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Disclosures
Dr Gish has consulting relationships, advisory boards andspeakers bureau status with
Gilead
BMS
Abbvie
Merck/Idenix
And donates/expends all funds from pharma to research,
education and health care policy
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Liver: An Enigma
Liver is the largest organ in the body: wt 1.2-1.5 KgLiver 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
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Liver Tests
Liver EnzymesAST
ALT
Alkaline Phosphatase GGT
Liver Synthetic Tests Bilirubin
Albumin
Protime/INR
True liver function tests
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Liver: a Unique organ
Anatomy:
- Dual blood supply
* Portal Vein
* Hepatic artery
HA supplies 35% of blood flow
Segmental anatomy
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The Appearance of aNormal Liver
Will be:
Smooth
Firm to the touch
It will not be:
Shrunken or
enlarged
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The Architecture Of The Normal liverLooks 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 themto sinusoids
Hepatic Artery Branch:
carries additional oxygen To the liver
Hepatocytes:
Normal liver cells
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Normal Liver
Edward Klatt, MD, Department of Pathology, University of Utah: 1999.
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Chronic Hepatitis
Chronic active hepatitisof mild to moderateseverity with portal and
periportalinflammation. Trappingof periportalhepatocytes and
inflammation extendingbeyond portal tract.Focal lobularinflammation is alsoevident. H&E x 200. Edward Klatt, MD, Department of Pathology, University of Utah: 1999.
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Histologic Features of FattyLiver or NASH
Steatosis and Necro-inflammation
Fibrosis
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Progressive Cell Death,Inflammation,
and Scarring will occur:
Swelling :Injured
hepatocytes
Inflammation: Cellular
Infiltration and swelling
Necrosis: death of cells
Scarring: scar tissue beginsto replace functioning liver
cells
Hepatoytes : Liver cells
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CirrhosisNormal
Nodules
Irregular surface
GROSS IMAGE OF A NORMALAND A CIRRHOTIC LIVER
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AscitesVariceal bleeding
Hepatic encephalopathy
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Portalsystemic
collaterals
Distorted
sinusoidalarchitectureleads to
increasedresistance
Portalvein
Cirrhotic Liver
Splenomegaly
ARCHITECTURAL LIVER DISRUPTION IS THE MAIN MECHANISM THAT LEADSTO AN INCREASED INTRAHEPATIC RESISTANCE
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Small varicesLower risk of bleeding Large varicesHigher risk of bleedingNo varices
7-8%/year 7-8%/year
Varices Increase in DiameterProgressively
Merli et al. J Hepatol 2003;38:266
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Physical Exam Findings inChronic Liver Disease
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Nutritional advice in patientswith 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 bereduced in cirrhotic patients Normalization promotes protein synthesis, reduces plasma ammonia
and may compete with aromatic amino acids in crossing the blood-brainbarrier; this may be achieved with protein supplements
Chadalavada et al, Nutr Clin Pract 2010:;25: 257-64Verslype et al,Acta Gastroenterol Belg2010; 73: 510-13
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Use of Liver Biopsyas the G old Standard
Needle liver biopsy samples
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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
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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
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Liver Cancer(Hepatocellular Carcinoma)
HCV I f ti
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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
vasculitisRenal Glomerulonephritis Nephrotic syndrome
EndocrineAnti-thyroid antibodies Diabetes mellitus
Salivary Sialadenitis
Ocular Corneal ulcer Uveitis
Vascular Necrotizing
vasculitis Polyarteritis nodosaNeuromuscular Weakness/myalgia Peripheral
neuropathy
Arthritis/arthralgiaAutoimmunePhenomena CRESTsyndrome
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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
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CMS and USPHSTF
Birth cohort testing and high risktesting for HCV is SOC
Where you born between 1945and 1965?
Why only pay for HCV testing whendone by primary care providers?
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HCV i d i f i f i
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HCV progression and age at time of infection
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Chronic HCV Increases Mortality from Hepaticand Non-hepatic Diseases
The REVEAL HCV Cohort Study23820 adults, Taiwan
1095 anti-HCV positive; 69,4% with detectable HCV RNA
Follow-up (years) Follow-up (years)
Cumulativ
e
mortality,(%)
Cumulative
mortality,(
%)
HCV seropositive HCV RNA detectable
HCV seropositive HCV RNA undetectable
HCV seronegative
Hepatic diseases Diseases thatare not in the
liver12,8%
1,8%
0,7 %
19,8%
11,8%
12,7%
LeeMH, et al. JI nfectDi s. 2012Aug 15;206(4):461-3.
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Chronic HCV Infection Affects Many SitesBeyond the Liver
Neurological(e.g. cognitiveimpairment)
CardiovascularDiseases
(CAD and stroke)
Metabolic(e.g.
diabetes)
Autoimmune(e.g.
cryoglobulinemia)Dermatological(e.g. porphyria
cutanea tarda)
Pulmonaryfibrosis
Renal (e.g.glomerulonephritis)
Lymphoproliferative(e.g. B celllymphoma)
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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 ?
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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
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Mason AL et al
Hepatology,
Association of Diabetes Mellitus andHCV Infection
SVR Reduces Risk of Development of
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SVR Reduces Risk of Development ofDiabetes in Patients with HCV
Veterans Affairs Clinical Case Registry: 27.636 patients with HCVFollowed for median 5 years
Antiviral treatment initiated 1998-2007
Hyder S. and et al Digestive Disease week, 2013
Projected Timing for New Regimen Launches
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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
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Genotype 1: PEG IFN/RBV +Sofosbuvir/Simprevir/Faldaprevir
Will this be the last hurrah for PEGIFN/RBV in the US?
All oral agents will be the standard ofcare in 2 years for genotype 1
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Di t A ti A ti i l A t (DAA )
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NS3 /4A Inhibitors (Protease inhibitor PI)
High potency
Limited genotypic coverage
Low barrier to resistance
NS5A InhibitorsHigh 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
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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 andribavirin
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Two Protease Inhibitors are used incombination 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)
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Simeprevir FDA approved
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Sofosbuvir (SOF, GS-7977)
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HCV-specific nucleotide polymeraseinhibitor (chain terminator)
Potent antiviral activity againstHCV 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 inclinical studies to date (>2000 patients)
No safety signal in preclinical/clinicalstudies
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COST COST COSTRep Waxman !
The 1000 $ pill
deny testing due to high cost of treatment ?
Doesnt treatment start withno alcohollose weight
stop THC usestop spread of infection
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SOFOSBUVIR
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SOFOSBUVIR:NEUTRINO Study: Virologic Response by Cirrhosis
Status
Post-treatmentOn treatment
PatientswithHCVRNA90% $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
Virologic Response During and
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EOT
Virologic Response During and
After Treatment (mITT)
H
CVRNA30 days on treatment
SOF +Riba post LT can cure >~67% of patients
HCV AND LIVER TRANSPLANTATION
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HCV AND LIVER TRANSPLANTATION
SURVIVAL
50
60
70
80
90
100
0 1 2 3 4 5
YEARS
SURVIVAL(%)
Non-HCV
HCV
ML Shiffman et al.
Am J Transpl 2006; 6:1170-1187.
SRTR database
1995-2005
HCV AND LIVER TRANSPLANTATION
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HCV AND LIVER TRANSPLANTATION
FIBROSIS PROGRESSION
0
20
40
60
80
100
1 2 3 4 5 6-10
YEARS AFTER TRANSPLANTATION
%of
Patients
CirrhosisBridgingPortal
N Yilmaz et al.
Liver Transpl 2007; 13:975-983.
HCV AFTER LIVER TRANSPLANATION
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0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10
YEARS
SURVIVAL(%)
Non-HCV
HCV
A Hackworth et al
ATC 2010
HCV AFTER LIVER TRANSPLANATION
SURVIVAL
HCV TREATMENT WITH CIRRHOSIS
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IVer
HCV TREATMENT WITH CIRRHOSISWhy we do not use Interferon
CUPIC COHORT
TRV BOC
N 295 190
Relapse
Partial ResponseNull Response
39%
46%10%
45%
42%5%
Esophageal Varices 35% 38%
SVR
RelapsePartial responseNull 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
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IVer
HCV TREATMENT WITH CIRRHOSIS
INCREASED INFECTION
N/%
N 191
Stage 0-2Stage 3Stage 4
31%19%50%
NaveRelapse
Non-response
21%30%
49%
TelaprevirBoceprevir
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
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IVer
SOFOSBUVIR-RIBAVIRIN
DECOMPENSATED CIRRHOSIS
N Afdhal et al.EASL 2014
Child Class
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HCV AND LIVER TRANSPLANTATION
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Prior to transplant
HCV AND LIVER TRANSPLANTATION
TIMING OF INTERFERON THERAPY
LiverTransplant
As soon as stable
As neededPre-emptive
SOFOSBUVIR AND RIBAVIRIN
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IVer
SOFOSBUVIR AND RIBAVIRIN
LIVER TRANSPLANT
MP Curry et al. AASLD 2013
M Charlton et al. AASLD 2013
at LT SVR when HCV RNAUD at LT
Post-LT Tx24 weeks
Pre-LTTreatment
NEED FOR LIVER TRANSPLANTATION
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NEED FOR LIVER TRANSPLANTATION
HBV AND HCV
0
100
200
300
400
500
600
700
1993 1995 1997 1999 2001 2003 2005 2007
YEAR
HBVAdditions
0
1000
2000
3000
4000
5000
HCVAdditons
HBV
HCV
WR Kim et al.
Hepatology 2007; AASLD abstract 12.
% HBV with HCC: 8% 12%
FUTURE OF LT FOR HCV
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SUMMARY
The vast majority of patients with HCV and cirrhosiscan now achieve SVR
For patients with post-LT HCV treatment with oralanti-viral agents will reduce post-LT mortality
The number of patients with HCV who will requireliver transplant will decline precipitously in 5-10years
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
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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
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Summary: To be continued
All oral therapies for all genotypes will be here in < 2years, Geno 1 Oct 2014
Prior to approval, will physicians mix and match with limiteddata?
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
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Thank you to
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Thank you to
Mitch Shiffman Paul Kwo
Doug Dieterich
Ira Jacobson
University of Washington Website
Cami Graham
For sharing so many slides !
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