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Hepatitis C Imtiaz Alam, M.D. - PowerPoint Presentation

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Hepatitis C Imtiaz Alam, M.D. - PPT Presentation

Medical Director Austin Hepatitis Center 1 Hepatitis C amp PCPs 2 LACK OF AWARENESS LACK OF APPROPRIATE ACTION Expand Quantitative Landscape Study Oct 2013 Gilead Sciences 3550 of PCP believe HCV can be cured ID: 748677

rbv hcv cirrhosis weeks hcv rbv weeks cirrhosis sofosbuvir treatment genotype patients aasld idsa svr compensated 400 liver elbasvir

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Slide1

Hepatitis C

Imtiaz Alam, M.D.Medical Director, Austin Hepatitis Center

1Slide2

Hepatitis C & PCP’s

2

LACK OF AWARENESS

LACK OF APPROPRIATE ACTION

Expand Quantitative Landscape Study – Oct 2013 [Gilead Sciences]

35-50% of PCP believe HCV can be cured

<10% Aware of DAA’s and new treatment regimens

20% Plan to screen all baby boomers

50% PCP consider LFT’s as their “Initial” screen

<25% pf PCPs order HCV RNA test

Only 20% of PCP “Would Definitely” refer an asymptomatic patientSlide3

3

The Critical Questions?

WHY

WHO

HOW

WHAT

Is There An Urgent Need For HCV Diagnosis?

Is Most at Risk For HCV and What Is the Guidance on Testing?

How Can You Test Patients For HCV At The Point of Care?

Can You Do To Ensure Your Patients Are Not Only Tested But Linked to Care?Slide4

4

Action Plan

Aware

Engage

Act

Drive Awareness of HCV and Treatment Actions

Cultivate Interest and Intent to Learn

Prompt consistent and Quality

Screening, Diagnosis and Referral Slide5

5

An RNA virus that used to be known as non-A,

non-B hepatitis until it was discovered in 1988

1

No vaccine available

First therapy approved in 1986

2

Before 2011, HCV treatment could last as long as

a year, with cure rates sometimes being at 40%-50%

3

Since that time, scientific advances have made

HCV treatment shorter and more effective than

it was previously

HCV History

1. CDC.

MMWR

Morb

Mortal

Wkly

Rep.

1998;47(RR-19):1-39.

2. FDA.

http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/ucm151494.htm

.

3.

Ghany

MG et al.

Hepatology

. 2011;54(4):1433-1444.Slide6

6

Epidemiology of HCV Infection: United States

Approximately 3.2 million persons in the United States have chronic hepatitis C virus (HCV) infection

1,a

Seroprevalence

is higher among

2

Individuals born between 1945-1965 (3.5%)

Black non-Hispanics (2.2%)

Males (1.9%)

6

a

This

figure may be an underestimate because the sampling frame of National Health and Nutrition Examination Survey (NHANES) did not include certain high-risk populations.

4

1. Armstrong GL, et al.

Ann Intern Med.

2006;144:705-714; 2.

Ditah

I, et al.

J

Hepatol

.

2013 Nov 27 [

Epub

ahead of print];

3.

Nainan

OV, et al.

Gastroenterology.

2006;131:478-84

; 4.

Chak

E, et al.

Liver Int.

2011;31:1090-1101.

Distribution of HCV Genotypes (GTs) in the US

3Slide7

7

HCV and HIV-1 Co-infection

Of people with HIV-1 in the US, about 25% are co-infected with HCV

1

About 85% of people with HIV who inject drugs also have HCV infection

2

HIV infection in a person who is also infected with HCV results in

2

Higher levels of HCV in the blood

More rapid progression to HCV-related liver disease

Increased risk for cirrhosis and HCC

7

1. Thomas DL.

Ann Rev Med.

2008; 59:473-485; 2.

Sulkowski

MS, Thomas DL.

Ann Intern Med.

2013;138:197-207.

All HIV-infected

1

HIV-infected

Injection-drug users

2

HCC = hepatocellular carcinoma; HIV = human immunodeficiency virus.Slide8

8

8

Population Studies Show a Significant Gap in Hepatitis c Care in the United States

Yehia BR,

et al.

PLoS One

. 2014;9:e101554

.

Zein

NN, et al.

Ann Intern Med

. 1996;125:634-639

.

Chronic HCV

infection

Diagnosed and aware

Access to outpatient care

Prescribed HCV treatment

Achieved sustained virologic response (SVR)

50%

43%

16%

9%

73%

GT 1a

2

27%

GT 1b

2

3.5 Million

79%

Genotype (

GT) 1

2

US Cascade of Care, 2003-2013

1Slide9

Natural History

9

Acute Infection*

Chronic Infection

75%-85%

Clearance of

HCV RNA

15%-25%

Extrahepatic

Manifestations

Cirrhosis

10%-20% over 20 years

HCC

1%-4% per year

Decompensated

Cirrhosis

5-yr survival rate 50%

Adapted from Chen SL, Morgan TR.

Int

J Med Sci

. 2006;3:47-52

.

*20%-30% of individuals are symptomatic.

HCC=hepatocellular carcinoma.Slide10

10

Host Factors Associated with More Rapid Disease Progression

1. Malnick S, et al.

Drugs Aging.

2014;31:339-347; 2. Maasoumy B, Wedemeyer H.

Best Pract Res Clin Gastroenterol.

2012;26:401-412; 3

. Nishida N, et al.

Dig Dis.

2012;30:547-553; 4. Noureddin M, et al.

Hepatology.

2013;58:1548-1557;

5

. Missiha SB, et al.

Gastroenterology.

2008;134:1699-1714; 6. Yoon YH, et al.

Alcohol Clin Exp Res.

2011;35:240-249; 7

. Younossi ZM, Stepanova M. Clin Gastroenterol Hepatol. 2010;8:718-723.

Nonmodifiable Host Factors

Older

age at infection

Associated with accelerated cirrhosis development

1

Increasing age (longer duration of infection)

Associated with accelerated fibrosis progression

1

Male gender

Associated with accelerated fibrosis progression and more frequent HCC development

2,3

IL28B

CC allele

More likely to develop adverse

clinical outcomes

a

but not associated with fibrosis progression

4

Transfusion-associated HCVAssociated with accelerated progression to cirrhosis (versus community- or childhood-acquired HCV)5

Hispanic ethnicityHigher mortality rates from HCV-related cirrhosis6 Hispanic ethnicity is an independent risk factor for HCC-related mortality7Caucasian

Increased histologic activity and incidence of cirrhosis (as compared to blacks)

2

a

Clinical outcomes were defined as one of the following: death, development of ascites, spontaneous bacterial peritonitis, variceal hemorrhage, hepatic encephalopathy, HCC, and increase in Child-Pugh-Turcotte score by ≥2 points on 2 consecutive clinic visits 12 weeks apart.

10Slide11

Host Factors Associated with More Rapid Disease Progression (cont.)

HBV = hepatitis

B virus.

a

Moderate and high consumption were defined as 1-19 g/day and ≥30 g/day, respectively.

2

b

Lifetime consumption of ≥20 pack-years.

c

Liver biopsy staging/fibrosis score ≥4.

3

1. Lim JK, et al.

Clin Infect Dis.

2014;58:1449-1458; 2. Younossi ZM, et al

. Aliment Pharmacol Ther.

2013;37:703-709; 3. Tsochatzis E, et al.

Scand J Gastroenterol.

2009;44:752-759; 4. Kang W, et al.

Expert Rev Gastroenterol Hepatol.

2014;8:247-266; 5. Oh JK, et al.

BMC Cancer.

2012;12:452; 6. Lambrecht RW, et al.

Gastroenterology.

2011;140:1490-1500; 7. Goossens N, Negro F.

Clin Liver Dis.

2014;18:147-156; 8. Hung CH, et al.

World J Gastroenterol.

2010;16:2265-2271; 9. El Ray A, et al.

Eur J Gastroenterol Hepatol.

2013;25:421-427; 10.Ghany MG, et al.

Gastroenterology. 2010;138:136; 11. Kurosaki M, et al. Hepatol Res. 2010;40:870-877.

Behavioral and Clinical/Laboratory Host Factors

Moderate to high alcohol consumption

a

Associated with significant risk of advanced hepatic fibrosis and mortality (all-cause and liver-related)

1,2

Heavy smoking

b

Factor for severe fibrosis

c

in CHC

3

HIV-1 co-infection

Associated with higher viral load, rapid progression to cirrhosis, liver failure, and HCC

4

HBV co-infection

Associated with increased risk of HCC

5

Iron overload

Correlated with decompensated cirrhosis, HCC, or death

6

Combined obesity and diabetes mellitus

Associated with 100-fold increase in risk of HCC

development

7

Insulin resistance

Independent predictor of HCC development

8

and associated with increasing fibrosis

9

Hepatic steatosis

Associated with ≥2-point increase in Ishak fibrosis score

10

and HCC development

11

Platelet counts, AST/ALT ratio, bilirubin, and albumin

Independent predictors of fibrosis progression or clinical decompensation

10

11Slide12

12

Cumulative Incidence of Fibrosis Progression

Year

Year

Progression to fibrosis stage 1-2

1

Progression to fibrosis stage 3-4

1

1. Bochud PY, et al.

J Hepatol.

2009;51:655-666; 2. Kanwal F, et al.

Hepatology.

2014;60:98-105.

HCV GT 3 Was Associated with Accelerated Fibrosis Progression and Increased Risk of HCC

GT 3 was associated with accelerated fibrosis progression

1

Patients from the Swiss Hepatitis C Cohort Study enrolled before December 2008 (N=1189)

GT 3 was associated with an increased risk of developing HCC

2

Retrospective study of patients in the VA HCV Clinical Case Registry, 2000-2009

Proportion Free of HCC

Incident HCC

2

Year

Adjusted HR

a

=1.8 (1.61, 2.03)

a

Adjusted for

prespecified

demographic, clinical, and treatment

factors.

2

HR = hazard ratio;

VA = Veterans Administration

.

1.00

0.90

0.80

0.70

0.60

0.50

0.40

0.30

0.20

0.10

0.00

0

5

10

15

20

25

30

35

40

GT 1 or 4

(n=492

, ref)

GT 2

(n=65

,

P

=.003)

GT 3

(n=244

,

P

<.001)

0

5

10

15

20

25

30

35

40

GT 1 or 4

(n=630

, ref)

GT 2

(n=92

,

P

=.04)

GT 3

(n=342

,

P

<.001)

1.00

0.98

0.96

0.94

0.92

0.90

0.88

0.86

0.84

0.82

0.80

0

1

2

3

4

5

6

7

11

GT 1 (n=88,348)

GT 2 (n=13,077)

GT 3 (n=8,337)

GT 4 (n=1,082)

8

9

10

N=110,484Slide13

13

HCV Is Leading Cause of Liver Transplants in the US

Available at: http://srtr.transplant.hrsa.gov/annual_reports/2011/pdf/03_%20liver_12.pdf.

Primary cause of disease among adult liver transplant recipients, 2011

All others

22.3%

Acute hepatic necrosis

Alcoholic

liver disease

17.6%

HCV

23.5%

Cholestatic disease

Metabolic liver disease

Malignancy

20.9%

2.5%

4.0%

All others

26.4%

Acute hepatic necrosis

Alcoholic liver disease

23.2%

HCV

30.1%

Cholestatic disease

HBV

Malignancy

2.6%

2.8%

Primary cause of disease among adults on the liver transplant wait list, 2011

6.0%

9.0%

9.1%Slide14

14

Annual Prevalence Rates Between 1996 and 2006 Among HCV-Infected Veterans

Progressive Increase in Incidence of

HCV-Related Cirrhosis and HCC in US

El-

Serag

HB.

Gastroenterology

2012;142:1264–1273.Slide15

15

Presentation of Patients Infected With HCV

Patients often asymptomatic in early stages of infection

1

1. http://www.cdc.gov/knowmorehepatitis/Media/PDFs/FactSheet-ChronicHepC-GenInfo.pdf; 2.Ali A, Zein NN.

Cleve Clin J

Med.

2005;72:1005-1008.

Fever

Fatigue

Loss of appetite

Nausea

Vomiting

Abdominal pain

Dark urine

Grey-colored stools

Jaundice

Joint pain

Symptoms may include

1

Arthralgias

Paresthesias

Myalgias

Pruritus

Sicca

syndrome

First symptoms may be those of

extrahepatic

manifestations

2Slide16

16

Extrahepatic

Manifestations of HCV

Mixed cryoglobulinemia

Sjögren (sicca) syndrome

Lymphoproliferative disorders

Porphyria cutanea tarda

Neuropathy

Membranoproliferative glomerulonephritis

Cryoglobulinemic vasculitis

Corneal ulcers

(Mooren ulcers)

Thyroid disease

Lichen planus

Pulmonary fibrosis

Type 2 diabetes

Systemic vasculitis (polyarteritis nodosa, microscopic polyangiitis)

Arthralgias, myalgias, inflammatory polyarthritis

Autoimmune thrombocytopenia

Adapted from Ali A, Zein NN.

Cleve Clin J

Med.

2005;72:1005-1008.

Strongly associated

Possibly associatedSlide17

17

Mortality Rates in the US, 1999-2007

*Mortality rates = HBV, HCV, HIV listed as cause of death

Because decedent can have multiple causes of death, a record listing more than 1 type of infection was counted for each type of infection

Ly KN, et al. Ann Intern Med. 2012;156:271-278.

7

6

5

4

3

2

1

0

1999

2001

2002

2003

2004

2005

2006

2007

2000

Rate per 100,000 PY*

Yr

Hepatitis B

Hepatitis C

HIVSlide18

Property Of BioCentra, LLC

18

HCV Viral Replication Associated With Higher All-Cause Mortality

Lee MH, et al. J Infect Dis. 2012;206:469-477.

All Causes

Cumulative Mortality (%)

30.1%

12.8%

12.4%

P

< .001 for comparison among 3 groups

P

< .001 for HCV RNA detectable vs undetectable

Anti-HCV seropositives, HCV RNA detectable

Anti-HCV seropositives, HCV RNA undetectable

Anti-HCV seronegatives

Follow-up (Yrs)

0

2

4

6

8

10

12

14

16

18

20

35

30

25

20

15

10

5

0

18Slide19

19

Liver Transplant Projection From 2013 to 2043

Potential Transplant Need: Treatment of all candidates and SVR of 90% will still require ≈22,000 transplants/year in 2033

Number of Persons

20,000

0

5

10

15

20

25

30

40,000

60,000

80,000

100,000

120,000

140,000

160,000

180,000

0

Year in Model

150,617

162,559

162,747

24,258

21,994

49,013

91,310

126,296

18,193

25,573

27,175

26,207

No treatment

25% treated

50% treated

75% treated

All treated

Desai

et al. AASLD 2013. Abstract

1427Slide20

Healthcare Costs

20

Razavi

H, et al.

Hepatology

. 2013.

Epub

ahead of print.

Prevalence

(95% CI)

Health Care Cost

(95% CI)

While the prevalence of HCV infection is declining from its peak, the incidence of advanced liver disease and associated health care costs continue to rise

Modeling does not take into account any impact of birth cohort screening

A system dynamic modeling framework was used to quantify the HCV-infected population, the disease progression, and the associated cost from 1950-2030.

CI=confidence interval.

Prevalence (Million)

Health Care Cost (Billion)Slide21

21

Average Annual All-Cause Healthcare Costs

Patient Population

Mean Annual All-Cause Healthcare

Cost per Person, $

HCV uninfected

[1]

9979

HCV

positive, noncirrhotic

[2

]

17,277

HCV positive, compensated cirrhosis

[2]

22,752

HCV positive, ESLD

[2]

59,995

1.

McAdam-Marx C, et al. J Manag Care Pharm. 2011;17:531-546.

2. Gordon SC, et al. Hepatology. 2012;56:1651-1660.Slide22

22

HCV-Related Health Care Costs

by Liver Severity (USD 2010)

Gordon SC, et al.

Hepatology

. 2012;56:1651-1660.

Numbers in parentheses are

+

SD. *

P

<0.001 versus non-cirrhotic liver disease.

HCV-Related Costs

(per-patient-per-month)

Total

Total Health

Care Costs

Inpatient

Ambulatory

Pharmacy

Costs

Medical Costs

650

(2714)

1060*

(2941)

3505*

(10,996)

467

(2648)

663*

(2815)

3328*

(10,996)

313

(2587)

334

(2674)

2608*

(10,359)

130

(444)

304*

(587)

579*

(1721)

183

(612)

404*

(847)

177*

(591)

Non-cirrhotic liver disease (n=41,858)

Compensated cirrhosis (n=3718)

End-stage liver disease (n=8220)Slide23

23

Patients Should be Screened for HCV According to Birth Cohort and Risk Factors

1,2

Smith BD, et al.

MMWR Recomm Rep

. 2012;61:1-32.

Moyer VA; US Preventive Services Task Force.

Ann Intern Med

. 2013;159:349-357.

Persons

Born Between

1945

and

1965

1,2

The 1945-1965 birth cohort was selected on the basis of HCV prevalence and disease burden

One-time screening for HCV infection in

the birth cohort may identify infected patients at earlier stages of disease

Birth Cohort Screening

Risk

Factor–Based

Screening

Past or current injection drug use

Receiving a blood transfusion before 1992

Long-term hemodialysis

Being born to an HCV-infected mother

Incarceration

Intranasal drug use

Getting an unregulated tattoo

Other percutaneous exposures

Important Risk

Factors

1,2

Patient Screening for HCVSlide24

24

www.prevent.org/National-Commission-on-Prevention-Priorities/Rankings-of-Preventive-Services-for-the-US-Population.aspx.

Rein DB, et al.

Ann Intern Med

. 2012;156:263-270.

2-Drug

Treatment

Cost Per QALY Saved (Dollars)

Cost-Effectiveness of HCV Testing vs Other Routine Preventive Services

*Birth cohort testing, 1945-1965.

2-drug treatment=PegIFN+RBV; 3-drug treatment=PegIFN+RBV+PI.

QALY=quality-adjusted life-year.

With Treatment

With Treatment

3-Drug

TreatmentSlide25

25

Laboratory Diagnosis of Chronic HCV Infection

RNA testing identifies active disease in HCV- seropositive patients

HCV antibodies appear by

6–8 weeks following infection

1

Can be detected by EIA

2

Serum ALT is not a reliable indicator of liver damage

1

FDA-approved rapid point-of-care testing is available

3

OraQuick® HCV Test

Image adapted from MicrobiologyBytes:Virology:HCV

1

1. www.microbiologybytes.com/virology/HCV.html; 2. Alter MJ, et al.

MMWR

Recomm

Rep

. 2003;52(RR-3):1-13, 15;

3.

Shivkumar

S, et al.

Ann Intern Med

. 2012;157:558-566.

ALT=alanine aminotransferase; EIA=enzyme immunoassay; RNA=ribonucleic acid; ULN=upper limit of normal.

Time After Exposure

Months

Years

0

1

2

3

4

5

6

1

2

3

4

Titer

Anti-HCV

ALT

Symptoms +/–

HCV RNA

ULN

ALT (U/L) Slide26

26

HCV Diagnostic Algorithm Based on

Serologic Testing

Ghany MG, et al.

Hepatology

. 2009;49:1335-1374

.

*If patient lacks pre-existing antibodies to HAV or HBV.

HAV=hepatitis A virus, HBV=hepatitis B virus.

Anti-HCV Antibody

HCV RNA

No Further Testing

No Active Disease

Positive

Positive

Negative

Negative

HCV Genotype

Consider Liver Biopsy

Vaccinate for HAV / HBV*Slide27

27Slide28

28

Scoring Systems for Histologic Stage

1. Bedossa P, Poynard T.

Hepatology

. 1996;24:289-293; 2. Ishak K, et al.

J Hepatol

. 1995;22:696-699.

Figure adapted from Standish RA, et al.

Gut

. 2006;55:569-578.

Appearance

Ishak

Description

Ishak

Score

1

METAVIR

Score

2

No fibrosis

0

F0

Fibrous expansion of some portal areas ± short fibrous septa

1

F1

Fibrous expansion of most portal areas ± short fibrous septa

2

F2

Fibrous expansion of most portal areas with occasional portal to portal (P–P) bridging

3

Fibrous expansion of most portal areas with marked bridging (P–P and portal to central [P–C])

4

F3

Marked bridging (P–P and/or P–C) with occasional nodules (incomplete cirrhosis)

5

Cirrhosis

6

F4Slide29

29

Invasive and Noninvasive Fibrosis Tests

Liver Biopsy

Serum Markers

Transient

Elastography

MRE

Methodology

Direct observation

Measures direct and

indirect serum markers* of fibrosis

Liver stiffness by detection of ultrasound-propagated shear waves

Liver stiffness by MRI of

vibration-propagated shear waves

Accuracy for detecting cirrhosis

High

Moderate (APRI) to high (

FibroSURE

TM

, ELF)

High

High

Accuracy for detecting intermediate fibrosis

High

Low (APRI) to moderate (

FibroSURE

TM

, ELF)

Moderate to high

High

Risk of complications

Risk of pain/bleeding

Minimal

Minimal

Minimal

Contraindications

Coagulopathy

Minimal

Obesity;

narrow rib spaces

Claustrophobia; other MRI contraindications

Limitations

Sampling error

Observer

variation

False-positives

with

hemolysis, inflammation, Gilbert’s syndrome

False-positives with inflammation, congestion

False-positives with inflammation, congestion

Longitudinal monitoring

Unsuitable

Indices may change with disease progression / therapy

Liver stiffness changes with disease progression / therapy

Liver stiffness changes with disease progression / therapy

Cost

Highest per-test cost

Low per-test cost

High initial equipment cost

Very high initial equipment cost

Nguyen D,

Talwalkar

JA.

Hepatology

. 2011;53:2107-2110.Slide30

FibroScan

30Slide31

31

Indirect Serum Tests for Fibrosis

Test

Test

C

omponents

Sensitivity (%)*

Specificity

(%)*

PPV (%)*

NPV (%)*

Cirrhosis Discrimination

Fibrosis Discrimination

AST/ALT

ratio

1

AST,

ALT

53

100

100

81

+

APRI

2

AST/platelet count

77

72

70

79

+

+/– (moderate)

FIBROSpect

II®

3,4

HA, TIMP-1,

a

2-

macroglobulin

72

74

61

82

+

+

FibroSURE

TM

5,6

FibroTest

a

2-macroglobulin,

haptoglobin

, Apo A1, GGT, total bilirubin, ALT

84

95

76

91

+

+

HepaScore®

7

Age, gender, bilirubin, GGT, HA,

g

2-

macroglobulin

77

70

71

77

+

+

ELF

8

HA

, N-terminal

propeptide

of type III collagen, TIMP-1

86

62

80

70

+

+

1. Sheth SG, et al.

Am J Gastroenterol

. 1998;93:44-48; 2. Lin ZH et al.

Hepatology

. 2011;53:726-736; 3. Zaman A, et al.

Am J Med

. 2007;120:280.e9-e14;

4. www.prometheuslabs.com/Resources/Fibrospect/Fibrospect_II_Product_Detail.pdf; 5. Poynard T, et al.

Comp Hepatol

. 2004;3:8;

6. www.labcorp.com/.EdosPortlet/TestMenuLibrary?libName=File+Library&compName=L1080;

7. Guéchot J, et al.

Clin Chim Acta

. 2010;411:86-91; 8. Guéchot J, et al.

Clin Chem Lab Med

. 2012 ;50:693-699.

ALT=alanine aminotransferase; Apo A1=apolipoprotein A1; GGT= gamma-glutamyl transpeptidase; HA=hyaluronic acid; NPV=negative predictive value; PPV=positive predictive value; TIMP-1=tissue inhibitor of metalloproteinase.*Sensitivity, specificity, PPV, and NPV values are for significant fibrosis, with the exception of AST/ALT ratio, where the values are for cirrhosis.Slide32

32

Counseling Recommendations for

HCV-Infected Individuals

Avoid sharing toothbrushes and dental or shaving equipment

Prevent blood contact with others

Stop using illicit drugs; those who continue to inject drugs should take precautions to avoid viral transmission

Risk of sexual transmission is low, but practice “safe sex”

Avoid alcohol consumption

Excess alcohol may lead to progressive liver disease, increased HCV RNA replication, and reduced response to treatment

Consider treatment for hepatitis C*

Vaccinate for hepatitis A and B

Get tested for HIV

Encourage family members to get screened

Additional Recommendations

To Prevent HCV Transmission

*If patient meets generally accepted indications for HCV treatment.

Adapted from Ghany MG, et al.

Hepatology

. 2009;49:1335-1374.Slide33

33

Images adapted from Soriano V, et al.

1

1. Soriano V, et al.

J Antimicrob Chemother

. 2008;62:1-4; 2. Swain MG, et al.

Gastroenterology.

2010;139:1593–1601.

cccDNA=covalently closed circular DNA; HBV=hepatitis B virus.

HIV

HBV

Treatment Goal:

Life-long viral suppression

1

Treatment Goal:

Life-long viral suppression

1

HIV

HBV

HCV

Treatment Goal:

SVR

1

HCV

Majority of patients who achieve an SVR do not experience viral recurrence

2

Host Cell

Nucleus

Proviral DNA

Host DNA

Host Cell

Nucleus

cccDNA

Host DNA

Host Cell

Nucleus

Viral RNA

Host DNA

Treatment Goal in HCV Is SVR Slide34

34

SVR

ETR

RVR

Weeks After Start of Therapy

HCV RNA (log

10

IU/mL)

Relapse

EVR

Partial Response

Virologic Response to Therapy

Adapted from Ghany MG, et al.

Hepatology

. 2009;49:1335-1374.

†Shown for 48-week fixed-treatment course; follow stopping rules for treatment.

Null Response

UndetectableSlide35

35

Sustained

Virologic

Response (SVR) Achieved After Treatment Is Durable

SVR = HCV RNA negative (by a sensitive assay, <25 IU/mL) at

12 weeks after cessation of treatment

1

99% of patients who achieved an SVR had undetectable levels of HCV RNA in serum samples throughout the follow-up period

2,*

“These data suggest that the recurrence of HCV RNA is extremely rare in patients who achieve an SVR, and it now appears likely that such patients may be considered “cured” from a

virologic

standpoint”

2

For patients with cirrhosis, current guidelines recommend monitoring those who have achieved an SVR at 6- or 12-month intervals for the development of HCC

1

*After treatment with peginterferon alfa-2a ± ribavirin; mean follow-up, 3.9 years (range, 0.8–7.1 years).

1. Ghany MG, et al.

Hepatology

. 2009;49:1335-1374; 2. Swain MG, et al.

Gastroenterology.

2010;139:1593–1601.Slide36

36

SVR and All-cause Mortality in CHC Patients with Advanced Fibrosis

Baseline factors significantly associated with

all-cause mortality:

Older age

GT 3 (2-fold increase in mortality and HCC)

Higher Ishak fibrosis score

Diabetes

Severe alcohol use

SVR patients

Non-SVR patients

10-year cumulative

occurrence rate (%)

8.9

26.0

1.9

27.4

5.1

21.8

2.1

29.9

25

20

15

10

5

0

30

All-cause

mortality

Liver-related

mortality or

liver transplant

HCC

Liver failure

530 patients followed for a median of 8.4 years

Van der Meer A,

et al. JAMA

2012; 308:2584‒2593.Slide37

37

Years

Years

Years

0

1

2

3

4

5

6

0

1

2

3

4

5

6

0

1

2

3

4

5

6

Cumulative Mortality (%)

Genotype 1

(n=12,166)

SVR

Non-SVR

P

<.

0001

SVR rate: 35%

Genotype 2

(n=2904)

SVR

Non-SVR

P

<.

0001

SVR rate: 72%

Genotype 3

(n=1794)

SVR

Non-SVR

P

<.

0001

SVR rate: 62%

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.

SVR Reduced Risk of All-Cause Mortality in a Retrospective VA StudySlide38

38

Achieving SVR Was Associated With a 62-84% Reduction in the Risk of All-Cause Mortality

Saleem

J et al, AASLD 2014; Abstract #44Slide39

39

Achieving SVR Was Associated With a 68-79% Reduction in the Risk of HCC

Saleem

J et al, AASLD 2014; Abstract #44Slide40

40

Achieving SVR Was Associated With a 90% Reduction in the Risk of Liver Transplantation

Saleem

J et al, AASLD 2014; Abstract #44Slide41

41

SVR Was Associated with Improved Quality of Life in a Real-World Clinic Population

A study of community patients from hospitals in Vancouver has shown that sustained responders reported higher scores than treatment failures on each domain of the SF-36 and on utility measures

This analysis was part of a larger study examining the quality of life and economic burden of HCV in community patients recruited from 5 clinical settings in Vancouver, British Columbia, and included a cross-sectional administration of questionnaires with retrospective review of medical records

.

Of these, 235

patients

(133 responders and 102 treatment failures) completed questionnaires at an average of 3.7 years after end of treatment. Patients with advanced liver disease were excluded.

Sustained

responders = undetectable

HCV viral levels 6 months after therapy; treatment

failures = detectable

HCV viremia after therapy, or patients with an end-of-treatment response who relapsed.

MCS = mental

summary score (0-100);

PCS = physical

summary score (0-100). *

P

<.0001;

P

<.001;

P

<.01.

John-Baptiste AJ, et al.

Am J Gastroenterol.

2009;104:2439-2448.

Mean Difference

Bodily Pain

General Health

Physical Functioning

Role Physical

Role Emotional

Social Functioning

Vitality

Mental Health

PCS

MCS

SF-36 Scales

*

*

*

Mean difference in scores (SVR

versus

treatment failure)Slide42

42

SVR Was Associated With Improved HRQOL in a Survey of Patients With Advanced Fibrosis or Cirrhosis

Study assessed change from baseline to week 72 in HRQOL and sexual health in patients with advanced fibrosis or cirrhosis in the HALT-C Trial.

HRQOL=Health-related quality of life.

HRQOL was assessed with the 36-item Short Form Health Survey (SF-36), plus 3 additional questions that addressed self-reported sexual functioning, desire, and satisfaction and were hypothesized to measure sexual effects of chronic HCV and its treatment.

Bonkovsky HL, et al.

J Hepatol

. 2007;46:420-431.

HRQOL Scale

Mean Change From BaselineSlide43

43

Mean per-patient-per-month (PPPM) follow-up costs

by treatment history and liver disease severity (2010)

CC = compensated

cirrhosis;

ESLD = end-stage

liver disease;

NCD = noncirrhotic

disease.

Covariates adjusted for in the analysis included age, sex, geographical region, index year, baseline comorbidities, and baseline treatment for HCV.

Gordon SC, et al.

Aliment Pharmacol Ther

. 2013;38:784-793.

Treating HCV Has Been Shown to Reduce Healthcare Costs in the US

HCV-related costs

Medical costs

Total costsSlide44

44

Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting,

April 27-28, 2011, Silver Spring, MD

.

SVR (%)

IFN

6 mos

PegIFN/ RBV

12 mos

IFN

12 mos

IFN/RBV

12 mos

PegIFN

12 mos

2001

1998

2011

Standard

IFN

RBV

PegIFN

1991

DAAs

PegIFN/

RBV/

DAA

IFN/RBV

6 mos

6

16

34

42

39

55

70+

0

20

40

60

80

100

DAA

+/-

RBV

90+

2017

The Good NewsSlide45

45

Multi-targeted Approach for Treatment:

Approved Protease, Polymerase and NS5A Inhibitors

Simeprevir

Paritaprevir

Grazoprevir

Asunaprevir

Sofosbuvir

Dasabuvir

B

eclabuvir

Ledipasvir

Ombitasvir

Daclatasvir

Elbasvir

Adapted from McGovern B, Abu

Dayyeh

B, and Chung RT.

Hepatology

. 2008; 48:1700-12

*agents in red will be briefly discussed but are investigational in the USSlide46

46

DAAs in Late-Stage Clinical Development for Chronic HCV Infection

NS3

/

4A

Protease

Inhibitors

Nucleotide

NS5B

Polymerase Inhibitors

Non-Nucleoside

NS5B

Polymerase Inhibitors

NS5A

Replication Complex Inhibitors

Cyclophilin Inhibitors

Approved

Simeprevir

Boceprevir

Telaprevir

Paritaprevir/r

Grazoprevir

Sofosbuvir

Dasabuvir

Ledipasvir

Ombitasvir

Daclatasvir

Elbasvir

Phase 3

Asunaprevir

ABT-493

GS-9857

Beclabuvir

Velpatasvir

ABT-530

Phase 2

Vedroprevir

Sovaprevir

ACH-3422

MK-3682

ALS-335

TMC647055

Odalasvir

MK-8408

PPI-668

SCY

-635

Not all inclusive.Slide47

47

Genotype

1a

Genotype

1b

No Cirrhosis

With Cirrhosis*

No Cirrhosis

With Cirrhosis*

Ledipasvir/sofosbuvir (90/400 mg qd)

12

12

12

12

Elbasvir/grazoprevir (50/100 mg)

12

12

12

12

Ombitasvir/paritaprevir/r (25/150/100 mg qd)

+ dasabuvir (250 mg bid)

+

RBV

12

(with RBV)

NR

12

(no RBV)

12

(no RBV)

Sofosbuvir (400 mg qd) + simeprevir (150 mg qd)

12

NR

12

NR

Daclatasvir (60 mg qd)

+ sofosbuvir (400 mg qd)

12

NR

12

NR

AASLD-IDSA: Recommended HCV Regimens for Treatment-Naïve, Genotype 1

Duration of Therapy (weeks)

*Compensated cirrhosis.

No baseline high fold-change NS5A RAVs for elbasvir (includes

M28A

/G/T,

Q30D

/E/H/G/K/L/R,

L31F

/M/V,

Y93C

/H/N/S).

Dose may need to increase or decrease when used concomitantly with cytochrome

P450

3A

/4 inducers and inhibitors, respectively.

NR: not an AASLD-IDSA recommended regimen for this patient type.

Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]).

AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February

24

,

2016

.Slide48

48

General Outcomes With AASLD-IDSA Recommended HCV Regimens for Genotype 1 Patients

Treatment-Naïve, No Cirrhosis

SVR12

Rate

Relapse Rate

Discontinuations

Due to Adverse Events

Ledipasvir/sofosbuvir

8 weeks

12 weeks

97

(119/123)

97

(385/395)

2

(2/123)

<1

(3/395)

0

(0/123)

<1

(2/395)

Elbasvir/grazoprevir

12 weeks (non-cirrhotics and cirrhotics combined)*

97

(271/279)

*

4

(10/279)

*

1

(4/279)

*

Ombitasvir/paritaprevir/r + dasabuvir

Genotype 1a (with RBV), 12 weeks

Genotype 1b (no RBV), 12 weeks

97

(97/100)

99 (207/209)1 (1/98)0 (0/207)0 (0/98)0 (0/207)

Simeprevir + sofosbuvir 12 weeks

97

(112/115)

3

(4/154)

0

(0/115)

Daclatasvir

+ sofosbuvir

12 weeks

98

(111/113)

<1

(1/113)

0

(0/113)

Ledipasvir/sofosbuvir: 8 weeks (ION-3, pre-treatment HCV RNA <6 M IU/mL), 12 weeks (ION-3 and ION-1).

Elbasvir/grazoprevir: 12 weeks (C-EDGE, C-WORTHY).

Ombitasvir/paritaprevir/r + dasabuvir: genotype 1a (PEARL-IV), genotype 1b (PEARL-III).

Simeprevir + sofosbuvir: 12 weeks (OPTIMIST-1 [SVR12 rate for genotype

1a+Q80K

: 96%, 44/46]).

Daclatasvir + sofosbuvir (not FDA approved for genotype 1): 12 weeks (study 040 and ALLY-2).

*Genotype 1a: no baseline high fold-change NS5A RAVs for elbasvir (SVR12 rate for genotype 1a + these RAVs: 22%, 2/9).

Includes treatment-naïve and treatment-experienced patients.Kowdley KV, et al. N Engl J Med.

2014;370:1879-1888; Afdhal N, et al. N Engl J Med. 2014;370:1889-1898; Zeuzem S, et al. Ann Intern Med. 2015; 163:1-13; Sulkowski MS, et al. Lancet. 2015;385:1087-1097; Ferenci P, et al. N Engl J Med. 2014;370:1983-1992; Kwo P, et al.

Hepatology. 2016; Jan 22. [Epub ahead of print]; Sulkowski MS, et al. N Engl J Med. 2014;370:211-221; Wyles DL, et al. N Engl J Med. 2015;373:714-725.

Percent (n/N)Slide49

49

General Outcomes With AASLD-IDSA Recommended HCV Regimens for Genotype 1 Patients

Treatment-Naïve, Compensated Cirrhosis

SVR12

Rate

Relapse Rate

Discontinuations

Due to Adverse Events

Ledipasvir/sofosbuvir

12 weeks

94

(32/34)

3

(1/34)

0

(0/34)

Elbasvir/grazoprevir

12 weeks*

97

(96/99)

1

(1/99)

2

(2/99)

Ombitasvir/paritaprevir/r + dasabuvir

Genotype 1b (no RBV), 12 weeks

100

(22/22)

0

(0/22)

0

(0/22)

Ledipasvir/sofosbuvir: 12 weeks (ION-3 and ION-1).

Elbasvir/grazoprevir: 12 weeks (C-EDGE, C-WORTHY).

Ombitasvir/paritaprevir/r + dasabuvir: genotype 1b (TURQUOISE-II).

*Genotype 1a: no baseline high fold-change NS5A RAVs for elbasvir.

Afdhal

N, et al.

N Engl J Med.

2014;370:1889-1898; Lawitz E, et al.

Lancet

. 2015;385:1075-1086;

Poordad F, et al.

N Engl J Med

. 2014;370:1973-1982;

AASLD-IDSA. http://

www.hcvguidelines.org

/full-report-view. February 24, 2016.

Percent (n/N)Slide50

50

No

Cirrhosis

Compensated

Cirrhosis

Sofosbuvir (400 mg qd) + RBV

12

16-24

Daclatasvir (60 mg qd)* + sofosbuvir (400 mg qd)

Not eligible to receive RBV

12

16-24

AASLD-IDSA: Recommended HCV Regimens for Treatment-Naïve, Genotype 2

Duration of Therapy (weeks)

*Dose may need to increase or decrease when used concomitantly with cytochrome

P450

3A

/4 inducers and inhibitors, respectively.

Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]).

AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February

24

,

2016

.Slide51

51

No

Cirrhosis

Compensated

Cirrhosis

Sofosbuvir (400 mg qd) + PR

Eligible to receive pegIFN

12

12

Daclatasvir (60 mg qd)* + sofosbuvir (400 mg qd)

+

RBV

12

(no RBV)

24

(

+

RBV)

AASLD-IDSA: Recommended HCV Regimens for Treatment-Naïve, Genotype 3

Duration of Therapy (weeks)

*Dose may need to increase or decrease when used concomitantly with cytochrome

P450

3A

/4 inducers and inhibitors, respectively.

PR: pegIFN/RBV.

Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]).

AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February

24

,

2016

.Slide52

52

General Outcomes With AASLD-IDSA Recommended HCV Regimens for Genotype 3 Patients

Foster GR, et al.

Gastroenterology

. 2015;149:1462-1470.

Nelson DR, et al.

Hepatology.

2015;61:1127-1135.

Hezode

C, et al.

Hepatology.

2015;62(suppl

S1

):

314A

. Abstract 206.

Sofosbuvir + PR: 12 weeks (FISSION and VALENCE).

Daclatasvir + sofosbuvir: 12 weeks (ALLY-3); 24 weeks (French Compassionate Use Program).

*Includes genotype 3 treatment-naïve/experienced patients regardless of cirrhosis status.

Also includes genotype 3, treatment-naive cirrhotics and genotype 2, treatment-naive cohort.

Combined data from the 12- and 24-week treatment groups.

Treatment-Naïve, No Cirrhosis

SVR12

Rate

Relapse Rate

Discontinuations

Due to Adverse Events

Sofosbuvir + PR

12 weeks

96

(68/71)

5*

(9/181)

1

(1/94)

Daclatasvir + sofosbuvir 12 weeks97 (73/75)3 (2/75)

0

(0/75)

Daclatasvir

+ sofosbuvir

24 weeks (

+

RBV)

85

(155/183)

7*

(16/219)

<1*

(3/468)

Percent (n/N)

Treatment-Naïve, Compensated CirrhosisSlide53

53

No

Cirrhosis

Compensated

Cirrhosis

Ledipasvir/sofosbuvir (90/400 mg qd)

12

12

Elbasvir/grazoprevir (50/100 mg)

12

12

Ombitasvir/paritaprevir/r (25/150/100 mg qd) + RBV

12

12

AASLD-IDSA: Recommended HCV Regimens for Treatment-Naïve, Genotype 4

Duration of Therapy (weeks)

Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]).

AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February

24

,

2016

.Slide54

54

General Outcomes With AASLD-IDSA Recommended HCV Regimens for Genotype 4 Patients

Treatment-Naïve, Treatment-Experienced

SVR12

Rate

Relapse Rate

Discontinuations

Due to Adverse Events

Ledipasvir/sofosbuvir 12 weeks

No cirrhosis

Compensated cirrhosis

93

(39/42)

100

(10/10)

7

(3/42)

0

(0/10)

0

(0/42)

0

(0/10)

Elbasvir/grazoprevir 12 weeks

No cirrhosis

Compensated cirrhosis

96

(54/56)

100

(6/6)

2

(1/56)

0

(0/10)

0

(0/56)

0

(0/6)

Ombitasvir/paritaprevir/r + RBV

12 weeks

No cirrhosis

Compensated cirrhosis

100

(91/91)

96

(52/54)

0

(91/91)

0

(0/52)

0

(0/91)

0

(0/52)

Ledipasvir/sofosbuvir: 12 weeks (study 1119 and ION-4 [no cirrhosis]).

Elbasvir/grazoprevir: 12 weeks (pooled analysis of phase 2/3 studies).

Ombitasvir/paritaprevir/r + RBV: 12 weeks (PEARL-I [non-cirrhotics] and AGATE-1[cirrhotics]).

*Includes cirrhotics/non-cirrhotics.

Abergel

A, et al.

J Hepatol.

2015;62(suppl 2):

S219

. Abstract

O056

;

Naggie S, et al.

N Engl J Med

. 2015;373:705-713; Asselah T, et al. Hepatology. 2015;62(suppl S1):340A. Abstract 251; Hezode

C, et al. Lancet. 2015;385:2502-2509; Asselah T, et al.

J Hepatol. 2016;64(suppl 2):S827. Abstract SAT-278.Percent (n/N)Slide55

55

No

Cirrhosis

Compensated

Cirrhosis

Ledipasvir/sofosbuvir (90/400 mg qd)

12

12

AASLD-IDSA: Recommended HCV Regimens for Treatment-Naïve, Genotype 5 and 6

Duration of Therapy (weeks)

AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February

24

,

2016

.Slide56

56

General Outcomes With AASLD-IDSA Recommended HCV Regimens for Genotype 5 and 6 Patients

Genotype 5: Treatment-Naïve, Treatment-Experienced

Ledipasvir/sofosbuvir (12 weeks): genotype 5 (study 1119) and genotype 6 (ELECTRON).

Abergel

A, et al.

Lancet Infect Dis.

2016;16:459-464.

Gane EJ, et al.

Gastroenterology

. 2015;149:1454-1461.

Percent (n/N)

SVR12

Rate

Relapse Rate

Discontinuations

Due to Adverse Events

Ledipasvir/sofosbuvir 12 weeks

No cirrhosis

Compensated cirrhosis

97

(31/32)

89

(8/9)

3

(1/32)

11

(1/9)

0

(0/32)

0

(0/9)

Ledipasvir/sofosbuvir 12 weeks

No cirrhosis/compensated cirrhosis

96

(24/25)

4

(1/25)

0

(0/25)

Genotype 6: Treatment-Naïve, Treatment-ExperiencedSlide57

57

AASLD-IDSA: Alternative HCV Regimens for Treatment-Naïve Patients

AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February

24

,

2016

.

Genotype

No Cirrhosis

Compensated Cirrhosis

1a

None

Ombitasvir/paritaprevir/r (25/150/100 mg qd) + dasabuvir (250 mg bid) + RBV for 24 weeks

Elbasvir/grazoprevir* (50/100 mg) + RBV for 16 weeks

Sofosbuvir (400 mg qd) + simeprevir

(150 mg qd)

+

RBV for 24 weeks

Daclatasvir (60 mg qd)

+ sofosbuvir (400 mg qd)

+

RBV for 24 weeks

1b

None

Sofosbuvir (400 mg qd) + simeprevir (150 mg qd)

+

RBV for 24 weeks

Daclatasvir (60 mg qd)

+ sofosbuvir (400 mg qd)

+

RBV for 24 weeks

2

None

None

3

Sofosbuvir (400 mg qd) + RBV for 24 weeks (daclatasvir and INF ineligible, with/without compensated cirrhosis)

4

Sofosbuvir (400 mg qd) + PR for 12 weeks (INF eligible, with/without compensated cirrhosis)

5 and 6

Sofosbuvir (400 mg qd) + PR for 12 weeks (INF eligible, with/without compensated cirrhosis)

*

With baseline high fold-change NS5A RAVs for elbasvir (includes

M28A

/G/T,

Q30D

/E/H/G/K/L/R,

L31F

/M/V,

Y93C

/H/N/S).

No baseline

Q80K

detected.

Dose may need to increase or decrease when used concomitantly with cytochrome

P450

3A

/4 inducers and inhibitors, respectively.

PR: pegIFN/RBV.

Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]).Slide58

58

Genotype

1a

Genotype

1b

No Cirrhosis

With Cirrhosis*

No Cirrhosis

With Cirrhosis*

Ledipasvir/sofosbuvir (90/400 mg qd)

+

RBV

12

(no RBV)

12

(with RBV)

24

(no RBV)

12

(no RBV)

12

(with RBV)

24

(no RBV)

Elbasvir/grazoprevir (50/100 mg)

12

12

12

12

Ombitasvir/paritaprevir/r (25/150/100 mg qd)

+ dasabuvir (250 mg bid)

+

RBV

12

(with RBV)

NR

12

(no RBV)

12

(no RBV)

Sofosbuvir (400 mg qd) + simeprevir (150 mg qd)

12

NR

12

NR

Daclatasvir (60 mg qd)

+ sofosbuvir (400 mg qd)

12

NR

12

NR

AASLD-IDSA: Recommended HCV Regimens for Prior PR Failure, Genotype 1

Duration of Therapy (weeks)

*Compensated cirrhosis.

No baseline high fold-change NS5A RAVs for elbasvir (includes

M28A

/G/T,

Q30D

/E/H/G/K/L/R,

L31F

/M/V,

Y93C

/H/N/S).

Dose may need to increase or decrease when used concomitantly with cytochrome

P450

3A

/4 inducers and inhibitors, respectively.

PR: pegIFN/RBV.

NR: not an AASLD-IDSA recommended regimen for this patient type.

Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]).

AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February

24

,

2016

.Slide59

59

General Outcomes With AASLD-IDSA Recommended HCV Regimens for Genotype 1 Patients

Prior PR Failure, No Cirrhosis

SVR12

Rate

Relapse Rate

Discontinuations

Due to Adverse Events

Ledipasvir/sofosbuvir

12 weeks

95

(83/87)

5

(4/86)

0

(0/86)

Elbasvir/grazoprevir

12 weeks (no cirrhosis and cirrhosis combined)*

94

(90/96)

*

5

(15/96)

*

1

(1/96)

*

Ombitasvir/paritaprevir/r + dasabuvir

Genotype 1a (with RBV), 12 weeks

Genotype 1b (no RBV), 12 weeks

96

(286/297)

100

(91/91)

2

(7/293)

0

(0/91)

1

(3/297)0 (0/91)Simeprevir + sofosbuvir 12 weeks95 (38/40)3

(4/154)

0

(0/155)

Daclatasvir

+ sofosbuvir

12 weeks

100

(20/20)

--

--

Ledipasvir/sofosbuvir: 12 weeks (ION-2).

Elbasvir/grazoprevir: 12 weeks (C-EDGE-

TE

from full prescribing information).

Ombitasvir/paritaprevir/r + dasabuvir: 12 weeks genotype 1a (SAPPHIRE-II) and genotype 1b (PEARL-II).

Simeprevir + sofosbuvir: 12 weeks (OPTIMIST-1 [SVR12 rate for genotype

1a+Q80K

: 96%, 44/46]).

Daclatasvir + sofosbuvir (not FDA approved for genotype 1): 12 weeks (

HEPATHER

).

*Genotype 1a: no baseline high fold-change NS5A RAVs for elbasvir (SVR12 rate for genotype 1a + these RAVs: 64%, 9/14).

Includes treatment-naïve and treatment-experienced patients.

Afdhal N, et al.

N Engl J Med. 2014;370:1483-1493; Elbasvir/grazoprevir full prescribing information; Zeuzem S, et al. N Engl J Med. 2014;370:1604-1616; Andreone P, et al. Gastroenterology

. 2014;147:359-365; Kwo P, et al. Hepatology. 2016;Jan 22. [Epub ahead of print]; Pol S, et al. J Hepatol. 2015;62(suppl 2):258. Abstract LO3.

Percent (n/N)Slide60

60

General Outcomes With AASLD-IDSA Recommended HCV Regimens for Genotype 1 Patients

Prior PR Failure, Compensated Cirrhosis

SVR12

Rate

Relapse Rate

Discontinuations

Due to Adverse Events

Ledipasvir/sofosbuvir

12 weeks (with RBV)

24 weeks (no RBV)

94

(93/99)

98

(97/99)

6

(6/99)

3

(3/99)

0

(0/99)

0

(0/99)

Elbasvir/grazoprevir

12 weeks (no cirrhosis and cirrhosis combined)*

94

(90/96)

*

5

(15/96)

*

1

(1/96)

*

Ombitasvir/paritaprevir/r + dasabuvir

Genotype 1b (no RBV), 12 weeks

98

(45/46)

1.5†

(1/68)2† (2/172)Ledipasvir/sofosbuvir: 12 weeks (ION-2 and SIRIUS).Elbasvir/grazoprevir: 12 weeks (C-EDGE-TE from full prescribing information).

Ombitasvir/paritaprevir/r + dasabuvir: genotype 1b (TURQUOISE-II).*Genotype 1a: no baseline high fold-change NS5A RAVs for elbasvir.

Percent (n/N)

Afdhal

N, et al.

N Engl J Med.

2014;370:1483-1493;

Bourlière

P, et al.

Lancet Infect Dis

. 2015;15:397-404;

Elbasvir/grazoprevir full prescribing

information;

Poordad F, et al.

N Engl J Med

. 2014;370:1973-1982;

Pol S, et al.

J Hepatol.

2015;62(suppl 2):258. Abstract

LO3

.Slide61

61

No

Cirrhosis

Compensated

Cirrhosis

Sofosbuvir (400 mg qd) + RBV

12

16-24

Daclatasvir (60 mg qd)* + sofosbuvir (400 mg qd)

Not eligible to receive RBV

12

16-24

AASLD-IDSA: Recommended HCV Regimens for Prior PR Failure, Genotype 2

Duration of Therapy (weeks)

*Dose may need to increase or decrease when used concomitantly with cytochrome

P450

3A

/4 inducers and inhibitors, respectively.

PR: pegIFN/RBV.

Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]).

AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February

24

,

2016

.Slide62

62

No

Cirrhosis

Compensated

Cirrhosis

Sofosbuvir (400 mg qd) + PR

Eligible to receive pegIFN

12

12

Daclatasvir (60 mg qd)* + sofosbuvir (400 mg qd)

+

RBV

12

(no RBV)

24

(

+

RBV)

(IFN ineligible)

AASLD-IDSA: Recommended HCV Regimens for Prior PR Failure, Genotype 3

Duration of Therapy (weeks)

*Dose may need to increase or decrease when used concomitantly with cytochrome

P450

3A

/4 inducers and inhibitors, respectively.

PR: pegIFN/RBV.

Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]).

AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February

24

,

2016

.Slide63

63

General Outcomes With AASLD-IDSA Recommended HCV Regimens for Genotype 3 Patients

Foster GR, et al.

Gastroenterology

. 2015;149:1462-1470.

Nelson DR, et al.

Hepatology.

2015;61:1127-1135.

Hezode

C, et al.

Hepatology.

2015;62(suppl

S1

):

314A

. Abstract 206.

Sofosbuvir + PR: 12 weeks (BOSON).

Daclatasvir + sofosbuvir: 12 weeks (ALLY-3); 24 weeks (French Compassionate Use Program).

*Includes genotype 3 cohort (regardless of prior treatment experience and cirrhosis status).

Includes genotype 2 and 3 cohorts (regardless of prior treatment experience and cirrhosis status).

Includes treatment-naïve and treatment-experienced patients.

§

Combined data from the 12- and 24-week treatment groups.

SVR12

Rate

Relapse Rate

Discontinuations

Due to Adverse Events

Sofosbuvir + PR

12 weeks

94

(49/52)

5*

(9/181)

1

(1/103)Daclatasvir + sofosbuvir 12 weeks94 (32/33)3 (2/75)0 (0/75)

Sofosbuvir + PR

12 weeks

86

(30/35)

5*

(9/181)

1

(1/103)

Daclatasvir

+ sofosbuvir

24 weeks (

+

RBV)

85

(155/183)

7*

(16/219)

<1*

§

(3/468)

Percent (n/N)

Prior PR Failure, Non-Cirrhotic

Prior PR Failure, Compensated CirrhosisSlide64

64

No

Cirrhosis

Compensated

Cirrhosis

Ledipasvir/sofosbuvir (90/400 mg qd)

+

RBV

12

12

(with RBV)

24

(no RBV)

Elbasvir/grazoprevir (50/100 mg)

+

RBV

Prior PR relapse

Prior PR failure

12

(no RBV)

16

(with RBV)

12

(no

RBV)

16

(with

RBV)

Ombitasvir/paritaprevir/r (25/150/100 mg qd) + RBV

12

12

AASLD-IDSA: Recommended HCV Regimens for Prior PR Failure, Genotype 4

Duration of Therapy (weeks)

PR: pegIFN/RBV.

Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]).

AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February

24

,

2016

.Slide65

65

General Outcomes With AASLD-IDSA Recommended HCV Regimens for Genotype 4 Patients

Treatment-Naïve, Treatment-Experienced

SVR12

Rate

Relapse Rate

Discontinuations

Due to Adverse Events

Ledipasvir/sofosbuvir 12 weeks

No cirrhosis

Compensated cirrhosis

93

(39/42)

100

(10/10)

7

(3/42)

0

(0/10)

0

(0/42)

0

(0/10)

Elbasvir/grazoprevir*

Prior PR relapse, 12 weeks

(no RBV)

Prior PR failure, 16 weeks (with RBV)

100

(2/2)

100

(5/5)

0

(0/2)

0

(0/5)

0

(0/2)

0

(0/5)

Ombitasvir/paritaprevir/r + RBV

12 weeks

No cirrhosis

Compensated cirrhosis

100

(91/91)

96

(52/54)

0

(91/91)

0

(0/52)

0

(0/91)

0

(0/52)

Ledipasvir/sofosbuvir: 12 weeks (study 1119 and ION-4 [no cirrhosis]).

Elbasvir/grazoprevir: 12 weeks (pooled analysis of phase 2/3 studies).

Ombitasvir/paritaprevir/r + RBV: 12 weeks (PEARL-I [non-cirrhotics] and AGATE-1[cirrhotics]).

*Includes cirrhotics/non-cirrhotics.

Abergel

A, et al.

J Hepatol.

2015;62(suppl 2):

S219

. Abstract

O056

;

Naggie S, et al.

N Engl J Med. 2015;373:705-713; Asselah T, et al. Hepatology. 2015;62(suppl S1):340A

. Abstract 251; Hezode C, et al. Lancet. 2015;385:2502-2509; Asselah

T, et al. J Hepatol. 2016;64(suppl 2):S827. Abstract SAT-278.Percent (n/N)Slide66

66

No

Cirrhosis

Compensated

Cirrhosis

Ledipasvir/sofosbuvir (90/400 mg qd)

12

12

AASLD-IDSA: Recommended HCV Regimens for Prior PR Failure, Genotype 5 and 6

Duration of Therapy (weeks)

AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February

24

,

2016

.

PR: pegIFN/RBV.

Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]).Slide67

67

General Outcomes With AASLD-IDSA Recommended HCV Regimens for Genotype 5 and 6 Patients

Genotype 5: Treatment-Naïve, Treatment-Experienced

Ledipasvir/sofosbuvir (12 weeks): genotype 5 (study 1119) and genotype 6 (ELECTRON).

Percent (n/N)

SVR12

Rate

Relapse Rate

Discontinuations

Due to Adverse Events

Ledipasvir/sofosbuvir 12 weeks

No cirrhosis

Compensated cirrhosis

97

(31/32)

89

(8/9)

3

(1/32)

11

(1/9)

0

(0/32)

0

(0/9)

Ledipasvir/sofosbuvir 12 weeks

No cirrhosis/compensated cirrhosis

96

(24/25)

4

(1/25)

0

(0/25)

Genotype 6: Treatment-Naïve, Treatment-Experienced

Abergel

A, et al.

Lancet Infect Dis.

2016;16:459-464.

Gane EJ, et al.

Gastroenterology

. 2015;149:1454-1461.Slide68

68

AASLD-IDSA: Alternative HCV Regimens for Prior PR Failure

AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February

24

,

2016

.

Genotype

No Cirrhosis

Compensated Cirrhosis

1a

None

Ombitasvir/paritaprevir/r (25/150/100 mg qd) + dasabuvir (250 mg bid) + RBV for 24 weeks

Elbasvir/grazoprevir* (50/100 mg) + RBV for 16 weeks

Sofosbuvir (400 mg qd) + simeprevir

(150 mg qd)

+

RBV for 24 weeks

Daclatasvir (60 mg qd)

+ sofosbuvir (400 mg qd)

+

RBV for 24 weeks

1b

None

Sofosbuvir (400 mg qd) + simeprevir (150 mg qd)

+

RBV for 24 weeks

Daclatasvir (60 mg qd)

+ sofosbuvir (400 mg qd)

+

RBV for 24 weeks

2

None

Sofosbuvir (400 mg qd) + PR for 12 weeks (IFN eligible)

3

None

None

4

Sofosbuvir (400 mg qd) + PR for 12 weeks (IFN eligible, no cirrhosis and compensated cirrhosis)

Sofosbuvir (400 mg qd) + RBV for 24 weeks (IFN ineligible, no cirrhosis and compensated cirrhosis)

5 and 6

Sofosbuvir (400 mg qd) + PR for 12 weeks (INF eligible, with/without compensated cirrhosis)

*

With baseline high fold-change NS5A RAVs for elbasvir (includes

M28A

/G/T,

Q30D

/E/H/G/K/L/R,

L31F

/M/V,

Y93C

/H/N/S).

No baseline

Q80K

detected.

Dose may need to increase or decrease when used concomitantly with cytochrome

P450

3A

/4 inducers and inhibitors, respectively.

PR: pegIFN/RBV.

Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]).Slide69

69

No Cirrhosis

Compensated Cirrhosis

Ledipasvir/sofosbuvir (90/400 mg qd)

+

RBV

12

12

(with RBV)

24

(no RBV)

Elbasvir/grazoprevir (50/100 mg) + RBV

Genotype 1b

Genotype 1a based on presence of baseline

high fold-change NS5A RAVs for elbasvir

No

Yes

12

12

16

12

12

16

Daclatasvir (60 mg qd)

+ sofosbuvir (400 mg qd)

12

24

(

+

RBV)

AASLD-IDSA: Recommended HCV Regimens for Prior NS3 PI +

PegIFN

/RBV Failure, Genotype 1

Duration of Therapy (weeks)

*

Dose may need to increase or decrease when used concomitantly with cytochrome

P450

3A

/4 inducers and inhibitors, respectively.

NS3 PIs: telaprevir, boceprevir, or simeprevir.

Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]).

Baseline high fold-change NS5A RAVs for elbasvir (includes

M28A

/G/T,

Q30D

/E/H/G/K/L/R,

L31F

/M/V,

Y93C

/H/N/S).

AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February

24

,

2016

.Slide70

70

No Cirrhosis

Compensated Cirrhosis

Ledipasvir/sofosbuvir (90/400 mg qd)

+ RBV

12

24

AASLD-IDSA: Recommended HCV Regimens for

Prior Sofosbuvir + RBV

+

PegIFN Failure, Genotype 1

Duration of Therapy (weeks)

Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]).

AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February

24

,

2016

.Slide71

71

Duration of Therapy (weeks)

No Cirrhosis

Compensated Cirrhosis

Sofosbuvir (400 mg qd) + PR

IFN eligible

12

12

Daclatasvir (60 mg qd)* + sofosbuvir (400 mg qd)

+

RBV

Not eligible to receive pegIFN and/or RBV

24

24

AASLD-IDSA: Recommended HCV Regimens for Prior

Sofosbuvir

+ RBV Failure, Genotype 2 and 3

*

Dose may need to increase or decrease when used concomitantly with cytochrome

P450

3A

/4 inducers and inhibitors, respectively.

PR: pegIFN/RBV.

Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]).

AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February

24

,

2016

.Slide72

72

AASLD-IDSA Recommendations for Genotype 1 Patients Who Failed Other DAA-Based Regimens

Prior

simeprevir

+

sofosbuvir

or HCV NS5A inhibitor-based regimen failures

For patients without an urgent need for treatment, deferral of retreatment is recommended pending the availability of additional data

Compensated cirrhosis or those with an urgent need for retreatment

Test for RAVs to determine susceptibility status to NS3 PIs and NS5A inhibitors

Adjust retreatment regimen based on RAV testing results

When using nucleotide-based (

eg

,

sofosbuvir

) dual therapy, a treatment duration of 24 weeks with weight-based RBV is recommended

If available, nucleotide-based (

eg

,

sofosbuvir

) triple or quadruple DAA regimens may be considered (with RBV* for 12 to 24 weeks is recommended)

*Unless contraindicated.

AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February

24

,

2016

.Slide73

73

Long-Term Follow-Up of HCV Patients Treated With DAA Regimens

Prospective, observational cohorts

SVR Registry: SVR12 achievers (n=5433)

Median follow-up: 71 weeks

Sequence Registry: virologic failure patients (n=536)

Median follow-up: 44 weeks

Maintained SVR: 99.7% (5414/5433)

Late virologic relapse: 0.1%

HCV reinfection: 0.2%

Low rates of clinical disease progression

Incidence of HCC

SVR registry: 0.3% (16/5433)

Sequence registry: 0.9% (5/536)

Lawitz EJ, et al.

J Hepatol.

2016;64(suppl 2):

S612-S613

. Abstract FRI-166.

SVR

(n=5433)

Sequence

(n=563)

Median age (years)

54

54

Male (%)

63

78

White (%)

85

84

Cirrhotics (%)

20

22

HCV genotype (%)

1

2

3

4 5 66710203<1<1

62

5

32

<1

<1

0

Registry CharacteristicsSlide74

74

Considerations for Follow-Up of SVR Patients

Serfaty

L, et al.

Liver Int

. 2016;36(suppl

S1

):67-71.

SVR12

(baseline

F0

/

F1

)

SVR12

(baseline

F2

/

F3

)

SVR12

(baseline

F4

[cirrhosis])

Post-SVR

Week 48

Post-SVR

Week 48

Post-SVR

Week 48

HCV RNA

Non-Invasive Tests

(

F0

/

F1

)

HCV RNA

Non-Invasive Tests(F2/F3)HCV RNAPWID, MSMAlcohol, Obesity, DiabetesHCV RNAEvery 12 MonthsNon-Invasive TestsEvery 12 MonthsLifestyle ChangesDiabetes ControlLiver Biopsy ifElevated ALT/AST

Liver UltrasoundEvery 6 MonthsNo

YesSlide75

75

Strategies To Advance HCV Patient Care

75

PATIENT IDENTIFICATION

SPECIALIST

REFERRAL

HCV DISEASE

MANAGEMENT

Outreach & Awareness

- Need For:

Patient Awareness regarding risk factors & testing

Provider education & awareness regarding HCV testing

Diagnosis

-

Need For:

HCV Testing Protocols

Clearly defined roles & responsibilities for HCV testing among providers

Patient education & engagement upon diagnosis

Care Coordination

- Need For:

Appropriate link to quality care – “Linkage To C Care”

Improved data sharing & communication between PCP & specialist

Patient Stratification

- Need For:

Provider understanding of benchmarks to ensure appropriate management

CLINICAL – HCV genotype, fibrosis scores, comorbidities

SOCIOECONOMIC – Health literacy

Managing Patients

-

Need For:

HCV care management protocols/AASLD Guidelines

Clearly defined roles & responsibilities for HCV management

Patient involvement to improve adherence & treatment success Slide76

76

HepCure Alliance Vision

Educate HCPs on the importance of HCV and their role in the care continuum

Implement rapid testing/screening protocols to increase the number of identified HCV patient

Increase the number of HCV Ab [+] patients that go on for PCR testing & decrease the fall off rates

Increase the number of diagnosed patients linked to care & decrease the fall off ratesSlide77

PCP HCV Screening, Referral & Treatment

Primary Care Visit

Birth Age Cohort – 1945-65

Risk Factors

Abnormal LFT

HCV

antibody

OraQuick

or Phlebotomy

NEGATIVE

No Referral

POSITIVE

HCV RNA PCR

Quantitative

HCV Genotype

Hepatitis B Surface antigen

Hepatitis B Surface Antibody

Hepatitis B Core Total Antibody

Hepatitis A Total Antibody

HIV Antibody

Abdominal Ultrasound &

Fibroscan

Hepatitis A & B Vaccination

Alcohol Abstinence Counselling

Risk Factors

Past or current injection drug use

Recipients of clotting factors (prior 1987)

Chronic hemodialysis

Persistently abnormal ALT

Recipients of transfusions or organ transplants [prior 1992]

Persons with recognized exposures (needle-sticks, mucosal exposures)

HIV-infected persons

Birth to an infected mother

REFER TO

GI/HEPATOLOGY

PRIMARY CARE PROVIDER TREATMENT PER HCV PROTOCOLSlide78

78

EHCO Model: HCV Treatment by Primary Care Providers

Retrospective analysis (2012-2015)

Academic/

speciality

sites (n=6)

Multiple ECHO sites (PCP and subspecialist)

Arizona, New Mexico, Oklahoma, Texas, Utah, Washington

Demographics of patients are similar, except for race and treatment history

More treatment-experienced, genotype 1 and 3 patients were treated by specialist

Regimens

Genotype 1

Ledipasvir

/

sofosbuvir

+

RBV (8 and 12 weeks)

Simeprevir

+

sofosbuvir

+

RBV (12 weeks)

Genotype 2:

sofosbuvir

+ RBV (12 weeks)

Genotype 3:

sofosbuvir

+ RBV (24 weeks)PCPs were as effective as specialists at treating HCV when using the ECHO model

Georgie

F, et al.

J Hepatol.

2016;64(suppl 2):

S818-S819.

Abstract SAT-260.

SVR12 (%)

97%

98%81%

ECHO Specialty

2

(n=48|82)

3

(n=43|67)

1

(n=150|373)

93%

SVR12 Rates (

mITT

)

89%

82%

GenotypeSlide79

79

ASCEND Study: HCV Treatment by Primary Care Providers (2015)

Multicenter, open-label, phase 4 study (n=600 HCV patients)

Washington, DC (3 community health)

Providers underwent 3-hour training on AASLD-IDSA guidelines

Ledipasvir

/

sofosbuvir

per full prescribing information

Patients

Male (66%), HCV genotype 1a (72%), F3/4 (36%), HIV coinfection (24%)

HCV treatment experienced (18%), HCV RNA >6 million (19%)

Treatment duration

8 (5%), 12 (90%), 24 (5%) weeks

HCV treatment administered independently by PCPs and NPs was safe and equally effective as with experienced specialists

Kattakuzhy

S, et al.

J Hepatol.

2016;64(suppl 2):

S224

.

Abstract

LBP524

.

Specialist: infectious disease or hepatology.

SVR12 (%)

94%

95%

92%

Overall

(n=304)

97%

PCP

(n=60)

NP

(n=79)

Specialist

(n=165)

SVR12 RatesSlide80

80

WHAT’S NEXT?

Lawitz

E, et al. EASL

2016: Abstract PS008.

Poordad

F, et al. EASL 2016: Abstract GS11.Hepatitis B Foundation -

http://www.hepb.org/professionals/hbf_drug_watch.htmwww.cancerresearch.org