Hepatitis C

New Treatments, New Challenges

Christopher Murphy MD, Ellis Family Medicine Residency

RFMC, Sept. 8th, 2012

Hepatitis C: A Global Health Problem~200 Million (M) Carriers Worldwide

World Health Organization. Weekly epidemiological record. 1999;74:421-428.

United States 3-4 M

Americas12-15 M

Africa 30-40

M

Southeast Asia30-35 M

Australia0.2 M

Western Europe

5 M

Eastern Europe

10 M

Far East Asia60 M

HEP C IN THE UNITED STATES

● Incidence: ~ 17,000 new cases / yr.

● 4 million HCV-

infected in U.S.

● Prevalence: General pop. 1% IVDUs 80-90% Incarcerated 15% HIV-infected 30%

● Prevalence of Cirrhosis

9.0% in 1996.18.5% in 2006.

● Prevalence of liver cancer

0.1% in 1996. 1.3% in 2006.

● ~12,000 deaths each year.

HEP C IN THE UNITED STATES

MOST

CASES ARE

NOT YET

DIAGNOSED

LIVER DISEASE IN THE UNITED STATES

Chronic Hepatitis C

The Economic Cost

Hepatitis C: Risk Factors

Sexual Transmission of HCV

• 895 monogamous heterosexual discordant couples, Italy– Yearly HCV antibody testing– Follow-up – 10 years (8,060 persons-yrs)– Average exposure, 1.8 per week, no condoms

• Three spouses – acquired HCV infection• 1 discordant genotype, other 2 –sequence

analysis – not from the partner – Intra-spousal transmission – no cases

Vandelli C et al. Am J Gastroenterol 2004

Single-stranded RNA virus

Class: Flaviviridae 6 genotypes >90 subtypes

~70% are type 1 in US 1a > 1b (57% vs. 16%)

30% are type 2 or 3

HCV RNA

Symptoms +/-

Time after Exposure

Tite

r

Anti-HCV

ALT

Normal

0 1 2 3 4 5 6 1 2 3 4YearsMonths

Serologic Pattern of Acute HCV Infection with Recovery

Source: Centers of Disease Control & Prevention, Hepatitis C, Division of Viral Hepatitis, 1/17/03, http://www.cdc.gov/ncidod/diseases/hepatitis/slideset/hep_c/hcv_epi_for_distrib_000925.pdf

Serologic Pattern of Acute HCV Followed By Chronic

Infection

•Symptoms +/-

•Time after Exposure

• Tit

er

•Anti-HCV Ab

•ALT

•Normal

•0 •1 •2 •3 •4 •5 •6 •1 •2 •3 •4•Years•Months

•HCV RNA

•//

NORMAL

Natural History of HCV Infection

100 People

Resolve (15)

15%

Chronic (85)

85%

Cirrhosis (17)

Stable (68)

80%

75%

Stable (13)Death (4)

25%

20% Leading Indication for Liver Transplant

Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. Centers for Disease Control and Prevention, MMWR, 1998 Oct 16;47(RR-19):1-39.

Hepatocyte

Stellate Cell

Kupffer cell in sinusoidal lumen

Collagen

Endothelial Cell

CD8+ CD4+

Cytokines(IL-2, IFN-TNF-a, TGF-PDGF)Cell killing

Kupffer cell

Hepatocytes

Hepatic stellate cells

TGF-Activation

Fibrosis

Death

Hepatitis C Disease Pathogenesis

Stage 1Portalfibrosis

Stage 2Periportalfibrosis

Stage 3Septalfibrosis

Stage 4Cirrhosis

fibrosi

s

F-1: @ the portal triadF-2: Periportal areaF-3 Bridging from one portal to anotherF-4 Complete encircling of the triads

F-4 pts have a lower response rate to TxAND

a higher rate of complications to Tx.

Metavir Scoring System

Evolution of HCV Therapy

2001

PegIFN/RBV

Pegylated-interferon alfa-2a + RBV: SVR in Genotype 1, High Viral Load

0

10

20

30

40

50

16

26

36

47

n = 50 n = 47 n = 190 n = 186

SV

R (

%)

24 Weeks 48 Weeks

RBV800 mg/day

RBV1000-1200 mg/day

RBV800 mg/day

RBV1000-1200 mg/day

PEG-IFN2a 180 µg SC QW + RBV

Hadziyannis et al. Ann Intern Med 2004;140:370-381

160

47

24

23

113

14

3failed

7 DNF

10

2 DNF

1 failed

9

1 failed

1 in treatment

SVREOTREVRGT 1 pts

37.5% SVR

Evolution of HCV Therapy

2001 2011

PegIFN/RBVProtease inhibitor

Important Dates in the History of Hepatitis C

Sustained virologic response= SVR = cure

Evolution of HCV Therapy

2001 2011 Beyond

PegIFN/RBVProtease inhibitor

Nucleos(t)ide polymerase inhibitorNonnucleoside polymerase inhibitor

NS5A inhibitor

Chronic Hepatitis C

Reverse fibrosis, delay decompensation, and reduce deaths

Viral clearance

Prevent HCC

Prevent cirrhosis and HCV recurrence afterliver transplantation

Goals of Antiviral Therapy

Prevent cirrhosis

Assessing Severity of Hepatitis C Estimate prognosis. Guide to aggressiveness of therapy.

Standard labs and Scans•AST / ALT•T.BILI, Albumin, INR•Platelet count•Ultrasound

Liver Fibrosis Markers

Hepascore® Fibrosure

Liver Biopsy•inflammation•fibrosis

Fibro-elastography FibroScan®

Assessing Severity of Hepatitis C

P-33

Liver Biopsy Gold standard for grading and staging disease However, not necessary to treat HCV! Invasive, expensive Needle liver biopsy samples < 1/50,000th of the

liver Incorrect staging of 1 stage in 10% to 20% of

cases Dependent on

Length of biopsy—25 mm optimal (16%)Number of biopsies performed Type of biopsy needle usedEtiology of liver disease

Bedossa P, et al. Hepatology. 2003;38:1449-1457. Reproduced with permission.

Potential for Sampling Error in Liver Biopsies

Chronic Hepatitis C

FDA-Approved TherapiesPrevious Standard of Care:• Pegylated interferon alfa-2a with ribavirin• Pegylated interferon alfa-2b with ribavirin

HCV Standard of Care Prior to May 2011

PegIFN alfa-2b 1.5 µg/kg/wk + RBV 800 mg/day for 48 Wks[1]

PegIFN alfa-2a 180 µg/wk + Weight-Based RBV (1000 or 1200 mg/day) for 48 Wks[2]

1. Manns MP, et al. Lancet. 2001;358:958-965. 2. Fried MW, et al. N Engl J Med. 2002;347:975-982.

46

76

56

Overall GT1 GT2/3

298 140453

42

82

100

80

60

40

20

0

54

Overall GT1 GT2/3

SV

R (

%)

348 147511

100

80

60

40

20

0n = n =

GT1 (most common in US, Europe) least responsive to pegIFN/RBV

HCV treatment definitions:

Definitions of Virologic ResponseResponse Definition

SVR HCV RNA undetectable by sensitive assay 24 wks after treatment end

RVR HCV RNA undetectable at Wk 4

EVR > 2 log10 IU/mL reduction in HCV RNA at Wk 12

cEVR HCV RNA detectable at Wk 4, but undetectable at Wk 12

Null response HCV RNA decline < 2 log10 IU/mL from baseline at Wk 12

Partial response HCV RNA decline > 2 log10 IU/mL from baseline at Wk 12, but HCV RNA detectable at Wks 12 and 24

Viral breakthrough HCV RNA detectable at any time during treatment after being undetectable

Relapse HCV RNA detectable after withdrawing treatment in a patient who was undetectable at end of treatment

New response categories with PI-based therapy

eRVR with boceprevir HCV RNA undetectable at Wks 8 and 24 of therapy

eRVR with telaprevir HCV RNA undetectable at Wks 4 and 12 of triple therapy

Week 8 response Among boceprevir-treated patients, HCV RNA undetectable at Wk 8 of the overall treatment course (ie, after 4 wks of pegIFN/RBV lead-in and 4 wks of triple therapy)

Lead-in RVR HCV RNA undetectable at Wk 4 for patients who had a pegIFN/RBV lead-in phase of therapy

• Genotype 1 • African-American ethnicity • High HCV RNA levels• Failure to achieve early (12-week) response• Presence of advanced fibrosis, steatosis or

cirrhosis • Long duration of disease• Older age at time of treatment (>45 y)• Higher body weight/BMI • Male gender

Chronic Hepatitis CNegative Predictive Factors for SVR

C allele is associated with SVR

Ge, Nature, 2009

HCV Life Cycle and DAA Targets

Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

Receptor bindingand endocytosis

Fusion and

uncoating

Transportand release

(+) RNA

Translation and

polyprotein processing

RNA replication

Virionassembly

Membranousweb

ER lumen

LD

LDER lumen

LD

NS3/4 protease inhibitors

NS5B polymerase inhibitors

Nucleoside/nucleotideNonnucleoside

*Role in HCV life cycle not well defined

NS5A* inhibitors

HCV-specific Enzymes: Targets for the Future

NS5B RNA-dependent

RNA polymeraseNS3 Protease

domain

NS3 Helicase domain

NS3 Bifunctionalprotease/helicase

NS3NS3CC E1E1 E2E2 NS2NS2 NS4BNS4B NS5ANS5A NS5BNS5BNS4ANS4AP7P7

5’ UTR5’ UTR 3’ UTR3’ UTR

IRES

Phase III Protease Inhibitor Studies

Telaprevir Treatment-naive

ADVANCE[1]

ILLUMINATE[2]

Treatment-experienced

REALIZE[3]

Boceprevir Treatment-naïve

– SPRINT-2[4]

Treatment-experienced

– RESPOND-2[5]

1. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 2. Sherman KE, et al. N Engl J Med. 2011;365:1014-1024. 3. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 4. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 5. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.

Schematic of Study Design International, multicenter, randomized, double-blind, placebo-controlled

phase III trial

Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

Treatment-naive patients with genotype 1

HCV infection

(N = 1088)

T12PR:Telaprevir 750 mg q8h

+ PegIFN/RBV†

(n = 363)

T8PR:Telaprevir

750 mg q8h +PegIFN/RBV†

(n = 364)

PR:Placebo +

PegIFN/RBV†

(n = 361)

Wk 8

PegIFN/RBV†‡

eRVR: follow-upNo eRVR: pegIFN/RBV†

eRVR: follow-upNo eRVR: pegIFN/RBV†

Wk 12 Wk 24* Wk 48*Stratified by genotype 1 subtype and HCV RNA level

*SVR determined after 24 wks of follow-up. †PegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/day. ‡Placebo given with pegIFN//RBV from Wks 8-12.

PegIFN/RBV†

PegIFN/RBV†

Main Findings of ADVANCE (TVR)

Response, % T8PR (n = 364)

T12PR(n = 363)

PR(n = 361)

SVR 69* 75* 44

RVR 66 68 9

eRVR 57 58 8

Undetectable HCV RNA at end of treatment

81 87 63

Undetectable HCV RNA 72 wks after starting treatment

67* 73* 44

Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

*P < .001 vs pegIFN/RBV control arm.

Main Findings

Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

Patients who attained eRVR had higher SVR rates than those without eRVR across all arms

83

SV

R (

%)

100

80

60

40

20

0PRT12PRT8PR

50

89

54

97

39

eRVRNo eRVR

SVR Rates With BOC + PegIFN/RBV in Genotype 1 Treatment-Naive Patients

P < .001

P < .001

Nonblack Patients

P = .04

P = .004

Black Patients

125/311

211/316

213/311

12/52

22/52

29/55

Pat

ient

s (%

)

PR 48 BOC RGT

100

80

60

40

20

0BOC/PR48

40

67 68

Pat

ient

s (%

)

PR 48 BOC RGT

100

80

60

40

20

0BOC/PR48

23

4253

n/N=

n/N=

Poordad F, et al. N Engl J Med. 2011;364:1195-1206.

SPRINT-2

Response-Guided Therapy With TVR in Tx-Naive Pts in 2 Studies

65% of patients eligible for shortened therapy[1]

58% of patients eligible for shortened therapy[2]

92 88

ILLUMINATE: Response-Guided TVR + PegIFN/RBV in

Treatment-Naive Genotype 1

T12PR24 T12PR48

SV

R in

Pts

Ach

ievi

ng e

RV

R (

%) 100

80

60

40

20

0

149/162

140/160

n/N=

1. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 2. Sherman KE, et al. N Engl J Med. 2011;365:1014-1024.

ADVANCE: TVR + PegIFN/RBV in Treatment-Naive Genotype 1

8997

T12PR24 PR

SV

R in

Pts

Ach

ievi

ng e

RV

R (

%) 100

80

60

40

20

0

189/212

28/29

n/N=

100

0

60

SV

R (

%)

80

40

REALIZE: SVR in Previous Relapsers, Partial Responders, Null Responders

Previous Relapsers Previous Partial Responders

n/N=

Previous Null Responders

*P < .001 vs PR48.

20121/145

124/141

83*88*

16/68

24

29/49 26/48

59*54*

4/27

15

21/72 25/75

29*33*

2/37

5

T12/PR48PR48 LI T12/PR48

Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.

SVR by Response at Wk 4 in Lead-in Arm With BOC and

TVR

1. Foster G, et al. EASL 2011. Abstract 6. 2. Bronowicki JP, et al. EASL 2012. Abstract 11.

Partial NRRelapsers Null NR

N/A

56†64

72

36

55

0

20

40

60

80

100

SV

R (

%)

< 1 log ≥ 1 log

PROVIDE (BOC)

n/N =

14/22

13/36

5/9

36/50

6/11

*Excludes 4 pts who dropped out during lead-in phase and 8 who were direct enrollers (ie no pegIFN/RBV lead-in).†Majority of prior relapsers still receiving treatment.

REALIZE (TVR)

62

94

56

59

15

54

0

20

40

60

80

100

SV

R (

%)

< 1 log ≥ 1 log

8/13 10/18

106/113 16/2

715/2

86/41

Current Standard-of-Care Therapy Is Complex

Adherence to pegIFN/RBV therapy decreases over time

Triple therapy has greatly increased treatment complexity, involves multiple daily pills plus injection drug BOC TID: 12 pills/day TVR TID: 6 pills/day RBV BID: 4-6 pills/day PegIFN: QW injection

Increased risks with nonadherence to triple therapy include potential for resistance

Lo Re V 3rd, et al. Ann Intern Med. 2011;155:353-360.

Treatment Wk

(N = 5706)

100

80

60

40

20

0PegIFN RBV

1000-1213-2425-3637-48

959589

978684

76

Mean A

dhere

nce

(%

)

Futility Rules for BOC or TVR + PegIFN/RBV in Tx-Naive

Patients

1. Boceprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.3. Telaprevir [package insert]. May 2011.

Recommendation: All therapy should be discontinued in patients with the following:

Assay should have a lower limit of HCV RNA quantification of ≤ 25 IU/mL and a limit of HCV RNA detection of approximately 10-15 IU/mL.

BOC[1,2]

Time Point Criteria Action

Wk 12 HCV RNA ≥ 100 IU/mL Discontinue all therapy

Wk 24 HCV RNA detectable Discontinue all therapy

TVR[1,3]

Time Point Criteria Action

Wk 4 or 12 HCV RNA > 1000 IU/mL Discontinue all therapy

Wk 24 HCV RNA detectable Discontinue pegIFN/RBV

Factors for Considering Treatment Candidacy for PI-Based Therapy

Factor Role

Genotype Boceprevir and telaprevir licensed only for patients with genotype 1 HCV

Fibrosis stage

Individuals with mild or moderate fibrosis have better rates of SVR with PI-based triple therapy than those with advanced fibrosis or cirrhosis

SVR rates for individuals with cirrhosis are markedly improved with PI-based therapy vs pegIFN/RBV alone, but SVR rates are still lower than for individuals with F0-F3 fibrosis

Treatment experience

Treatment-naive patients and previous relapsers or partial responders to IFN-based therapy have excellent response rates with PI-based therapy

Both previous partial responders and previous null responders have lower SVR rates with triple therapy than treatment-naive patients or relapsers. Previous null responders have the lowest SVR rates with triple therapy

Combination of fibrosis stage and treatment experience

The highest expected SVR rates with triple therapy are for treatment-naive patients or previous relapsers with minimal fibrosis

The lowest expected SVR rates with triple therapy are for those with cirrhosis who were previous null responders to IFN-based therapy

Treat

Pros and Cons of Treating vs Deferring Therapy with PIs

Protease inhibitors substantially increase chance of SVR

Successful treatment may arrest progression of liver disease (including potential for cirrhosis, HCC, etc)

Many patients already “warehoused” awaiting DAAs, but when is the right time to exit the warehouse?

Current regimens complex, challenging adverse events

Potential for better treatment options in future, eg, better response rates, fewer adverse events, shorter duration

Risk of resistance if therapy fails; impact on future options?

Defer

152/213

118/149

100

0

50

1b 1aGenotype

79

71

< 800,000 ≥ 800,000HCV RNA (IU/mL)

7874

F0-2 F3-F4Fibrosis

62

78

SV

R (

%)

75

25

ADVANCE: Influence of Baseline Patient and Virus

Factors on SVR Data from T12PR arm only

207/281

64/82

45/73

226/290

Marcellin P, et al. EASL 2011. Abstract 451.

n/N =

Similarities and Differences in Phase III Studies of TVR and BOC in GT1 Naive Pts

Parameter TVR[1] BOC[2]

PR lead-in? No Yes: 4 wks

PegIFN alfa formulation 2a 2b

PI dosing requirements TID; administer with fatty meal TID

Duration of PI triple therapy 8-12 wks followed by 12-40 wks PR

24-44 wks after 4 wks PR lead-in

Qualification for shortened therapy (response guided)

Undetectable HCV RNA until Wk 12 of triple therapy

Undetectable HCV RNA until Wk 24 of triple

therapy

Qualified for shortened therapy, % 58 (24 wks) 44 (28 wks)

SVR, % 69-75 63-66

Relapse, % 9 9

Adverse events more frequent in PI arms

Rash, anemia, pruritus, nausea Anemia, dysgeusia

1. Jacobson IM, et al. AASLD 2010. Abstract 211. 2. Poordad F, et al. AASLD 2010. Abstract LB-4.

Drugs Contraindicated With Boceprevir and Telaprevir

1. Boceprevir [package insert]. May 2011. 2. Telaprevir [package insert]. May 2011.

Drug Class Contraindicated With Boceprevir[1] Contraindicated With Telaprevir[2]

Alpha 1-adrenoreceptor antagonist

Alfuzosin Alfuzosin

Anticonvulsants Carbamazepine, phenobarbital, phenytoin N/A

Antimycobacterials Rifampin Rifampin

Ergot derivatives Dihydroergotamine, ergonovine, ergotamine, methylergonovine

Dihydroergotamine, ergonovine, ergotamine, methylergonovine

GI motility agents Cisapride Cisapride

Herbal products Hypericum perforatum (St John’s wort) Hypericum perforatum

HMG CoA reductase inhibitors Lovastatin, simvastatin Atorvastatin, lovastatin, simvastatin

Oral contraceptives Drospirenone N/A

Neuroleptic Pimozide Pimozide

PDE5 inhibitor Sildenafil or tadalafil when used for treatment of pulmonary arterial hypertension

Sildenafil or tadalafil when used for treatment of pulmonary arterial hypertension

Sedatives/hypnotics Triazolam; orally administered midazolam Orally administered midazolam, triazolam

Common AEs of DAAs in Naive PtsAgent AEs More Frequent in

Experimental Arm vs PRDiscontinuations

due to AEs, % (Wk)

Boceprevir[1] Anemia, dysgeusia 14 (48)

Telaprevir[2] Rash, anemia, pruritus, nausea 10 (48)

ANA598[3] Rash incidence and severity increased with 400-mg dose 2 (12)

BI 201335[4] Gastrointestinal events, jaundice, and rash* 5 (12)

BMS-790052[5] None reported 8 (12)

Danoprevir[6] ALT elevation, neutropenia, nausea diarrhea 4 (12)

Filibuvir[7] None reported 0 (4)

RG7128[8] None reported 2 (12)

TMC435[9] Mild bilirubin increases in first 2 wks of therapy 7 (24)

Vaniprevir[10] Vomiting with 600-mg dose 0 (6)

1. Poordad F, et al. AASLD 2010. Abstract LB-4. 2. Jacobson IM, et al. AASLD 2010. Abstract 211. 3.Lawitz E, et al. AASLD 2010. Abstract 31. 4. Sulkowski M, et al. EASL 2010. Abstract 1190. 5. Pol S, et al. EASL 2010. Abstract 1189. 6. Terrault N, et al. AASLD 2010. Abstract 32. 7. Jacobson I, et al. EASL 2010. Abstract 2088. 8. Jensen DM, et al. AASLD 2010. Abstract 81. 9. Fried M, et al. AASLD 2010. Abstract LB-5. 10. Manns MP, et al. AASLD 2010. Abstract 82.

*Higher in BID dosing than QD.

Treatment of Chronic Hepatitis C

1991 20010

20

40

60

80

100

8-12

SV

R (

%)

15-20

38-43

25-30

50-60

1995 1998

Standard interferon (6 mos)[1]

Standardinterferon

(12-18 mos)[2,3]

Interferon/ribavirin

(6-12 mos)[3,4] PegIFNmonotherapy(6-12 mos)[5,6]

PegIFN/ribavirin(6-12 mos)[6,7]

2011

70-75

PI + PegIFN/RBV(6-12 mos)[8-10]

1. Carithers RL Jr., et al. Hepatology. 1997;26(3 suppl 1):83S-88S. 2. Zeuzem S, et al. N Engl J Med. 2000;343:1666-1672. 3. Poynard T, et al. Lancet. 1998;352:1426-1432. 4. McHutchison JG, et al. N Engl J Med. 1998;339:1485-1492. 5. Lindsay KL, et al. Hepatology. 2001;34:395-403. 6. Fried MW, et al. N Engl J Med. 2002;347:975-982. 7. Manns MP, et al. Lancet. 2001;358:958-965. 8. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 9. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 10. Sherman KE, et al. N Engl J Med. 2011;365:1014-1024.

HCV Life Cycle and DAA Targets

Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

Receptor bindingand endocytosis

Fusion and

uncoating

Transportand release

(+) RNA

Translation and

polyprotein processing

RNA replication

Virionassembly

Membranousweb

ER lumen

LD

LDER lumen

LD

NS3/4 protease inhibitors

NS5B polymerase inhibitors

Nucleoside/nucleotideNonnucleoside

*Role in HCV life cycle not well defined

NS5A* inhibitors

Investigational Agents for HCV

Class Drugs

Interferons Peginterferon lambda-1a

Cyclophilin inhibitor Alisporivir

Nucleos(t)ide analogue polymerase inhibitor GS-7977Mericitabine

Nonnucleoside polymerase inhibitor ABT-072ABT-333BI 207127 Tegobuvir

Protease inhibitor ABT-450AsunaprevirBI 201335 DanoprevirGS-9451Simeprevir (TMC435)

NS5A inhibitor DaclatasvirGS-5885

New Testing Recommendations from the

CDC

HCV Testing Recommended Based on increased risk for infection

Ever injected illegal drugs Received clotting factors made before

1987 Received blood/organs before July 1992 Ever on chronic hemodialysis Evidence of liver disease High risk sexual activity

Based on need for exposure management Healthcare, emergency, public safety

workers after needle stick/mucosal exposures to blood

Children born to HCV-positive women

Large Population Underscreened and HCV Patients Underdiagnosed

Current screening practices fail to identify a large proportion of patients with chronic HCV infection[1]

As few as 25% of patients are diagnosed

Survey of 4000 primary care physicians[2]

Only 59% of 1412 respondents asked all patients about HCV risk factors

1. Kim WR. Hepatology. 2002;36:S30-S34. 2. Shehab TM, et al. J Viral Hepat. 2001;8:377-383. 3. Ghany MG, et al. Hepatology. 2009;49:1335-1374.

Large and Growing Population of Nonresponders

Based on the assumption that there will be no changes in SOC and 40-50% of treatment naive patients will not achieve SVR

Year

Pati

ents

2009 2012 2015 2018 2021 2024 2027

Nonresponder Pool

Naive Patients Treated

HCV Screening Is the First Step on the Road to a Cure

Screening

Counseling

Testing

AssessmentCure

Treatment

Harm Reduction for People with HCV

Central to identifying factors that will affect treatment Obesity and NASH HIV and other medical co-morbidities Drugs Alcohol Social issues Psychiatric issues

… To Summarize• Screening

– For ALL patients • Risk assessment and risk reduction plan

• Testing – For those at risk…and Boomers… & everyone else?

• Staging – For those who are infected

• Treatment – For those for whom benefits outweigh risks

• Education– For ALL patients

• Transmission risk reduction counseling

– For already infected• Disease progression harm reduction counseling