a discussion on hcv: what you need to know

8/12/2019 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


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


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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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



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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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Prior to transplant


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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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



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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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a discussion on hcv: what you need to know

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