Patients

fp2.brandish.co.nz

Patients

HCV Revolution:

From curse to cure

Dr Frank Weilert

Gastroenterologist and Hepatologist

Waikato Hospital, Hamilton


Hepatiis C epidemic –

is it real for NZ?


Estimated 170 Million Persons With HCV

Infection Worldwide

3-4 million newly infected each yr worldwide

Prevalence of infection

> 10%

2.5% to 10.0%

1.0% to 2.5%

NA

* *

World Health Organization 2008. Available at: http://www.who.int/ith/es/index.html.

*


Sequelae of HCV

Chronic HCV infection is a leading cause of liver disease [1]

– 10% to 20% of patients will develop cirrhosis over 10-20 yrs

– 1% to 5% of patients with HCV cirrhosis will develop HCC

– 25% of the ~ 500,000 new HCC cases identified globally each yr are

attributable to HCV [2]

HCV-related complications estimated to increase ~ 2-fold within the

next 10 yrs [3]

Other diseases/manifestations associated with HCV infection [4]

– Mixed cryoglobulinemia vasculitis, lymphoproliferative disorders, diabetes,

renal disease, rheumatoid arthritis–like polyarthritis, sicca syndrome,

depression, cognitive impairment

1. Lavanchy D. Clin Microbiol Infect. 2011;17:107-115. 2. Montalto G, et al. Ann N Y Acad Sci. 2002;963:

13-20. 3. Milliman, Inc. Consequences of HCV: costs of a baby boomer epidemic, 2009. 4. Jacobson IM,

et al. Clin Gastroenterol Hepatol. 2010;8:1017-1029.


Strategies to Impact the HCV Epidemic

Develop novel treatments that achieve higher SVR rates

in all patients

– Overcome host factors

– Shorten therapy

Increase rate of HCV diagnosis and treatment

– Enhance screening

– Enhance treatment delivery


Screening for Hepatitis C:

The Challenge of Identifying

Infected Patients


Groups Recommended for HCV Testing by

AASLD and USPHS

Recent/past injection drug users—even if only used once

Groups with high HCV prevalence

– HIV-infected individuals

– Hemophiliacs treated with clotting factor concentrates before

1987

– Hemodialysis recipients

Patients with unexplained aminotransferase abnormalities

Ghany MG, et al. Hepatology. 2009;49:1335-1374.

CDC. MMWR Recomm Rep. 1998;47(RR-19):1-39.


Groups Recommended for HCV Testing by

AASLD and USPHS

Recipients of transfusion or transplantation before

July 1992

Children born to women infected with HCV

Healthcare, public safety, and emergency medical

personnel following needle injury or mucosal exposure to

HCV-infected blood

Current sexual partners of individuals infected with HCV

Persons who have used illicit drugs by noninjection routes

Ghany MG, et al. Hepatology. 2009;49:1335-1374.

CDC. MMWR Recomm Rep. 1998;47(RR-19):1-39.


Underdiagnosis of HCV Impedes Proper

Linkage to Care

A large proportion of patients with chronic HCV infection remain

undiagnosed

– Estimates indicate at least 50% unaware of HCV-positive status [1,2]

Estimated proportion of individuals with HCV infection who remain

undiagnosed in Europe varies between countries [3]

– France: 44%

– United Kingdom: 69%

– Northern Spain: 84%

– Germany: 90%

– Poland: 98%

1. Gordon FD. Am J Med. 1999;107:36S-40S. 2. Culver DH, et al. Transfusion. 2000;40:1176-1181.

3. Eurasian Harm Reduction Network. Comparative analysis of HCV prevalence across selected countries of

Europe and the Mediterranean area. October 2007.


Role of Frontline Providers in HCV

Screening

Assess all patients for risk factors

Offer testing to patients at risk and anyone who requests

testing

Test patients before medical procedures are performed

(eg, surgery)

Ghany MG, et al. Hepatology. 2009;49:1335-1374.


Role of Frontline Providers in HCV

Diagnosis Counseling

Counsel patients who test positive for HCV infection

– Prevention of transmission to others

– Reduce/eliminate alcohol intake

– Assist with linkage to alcohol/drug addiction treatment if

needed

– Weight management in patients who are overweight

– HAV vaccination (if no preexisting antibodies) and, if risk

factors are present, HBV vaccination (if no preexisting

antibodies)

Ghany MG, et al. Hepatology. 2009;49:1335-1374.


HCV Testing


HCV Testing

Recommended Not Needed

HCV antibody

– Initial screening test

HCV antigen (some DHB’s)

HCV RNA

– Once only

Liver function tests

– Normal ALT is OK

HCV viral load

– Quantitative pre-treatment

HCV genotype

– 1 (and 4), 2 and 3

IL28B genotyping

– Host genotype

Liver biopsy

Non-invasive (Fibroscan)


Counseling on

Treatment Candidacy


AASLD: 2009 Recommendations for

Treatment Candidacy

Therapy Widely Accepted

18 yrs of age or older and

HCV RNA positive in serum and

Liver biopsy showing significant fibrosis

(bridging fibrosis or higher) and

Compensated liver disease and

Acceptable hematologic and biochemical

indices and

Willing to be treated and adhere to

treatment requirements

Simplify criteria

Ghany MG, et al. Hepatology. 2009;49:1335-1374.

Individualize Decision to Treat

Failed previous IFN alfa ± RBV or pegIFN

alfa monotherapy

Current users of illicit drugs or alcohol but

willing to participate in a substance abuse

or alcohol support program

No or mild fibrosis by liver biopsy

Acute HCV infection

Coinfection with HIV

Younger than 18 yrs of age

Chronic renal disease

Decompensated cirrhosis

Liver transplantation recipients


EASL: 2011 Recommendations for

Treatment Candidacy

“All treatment-naive patients with compensated disease

due to HCV should be considered for therapy (A2)

Treatment should be initiated promptly in patients with

advanced fibrosis (METAVIR score F3-F4) and strongly

considered in patients with moderate fibrosis (METAVIR

score F2) (B2)

In patients with less severe disease, indication for therapy

is individual (C2)” – contra-indications due to expected

side-effects

EASL Clinical Practice Guidelines: Management of hepatitis C virus infection. June 2011.


Assessing Fibrosis When Selecting

Patients for Treatment

Need to differentiate between nonsignificant fibrosis and

significant fibrosis [1]

Assess liver fibrosis; options include

– Liver biopsy

– Noninvasive markers of hepatic fibrosis [2]

– Transient elastography (Fibroscan)

Results/score from testing

– Mild: METAVIR F0-F1

– Moderate: METAVIR F2

– Severe: METAVIR F3-F4

1. Ghany M, et al. Hepatol. 2009;49:1335-1374. 2. Ferenci P, et al. EASL 2011. Abstract 421.


Is the question: fibrosis?

FIBROSCAN

Ultrasound based on one dimensional transient elastography

22


The probe

Ultrasonic

transducer

Button

Blue diodes

Vibrator

23


Explored volume > 3 cm 3

Probe

Probe positioning

2.5 cm

4 cm

Explored volume

1 cm

24


Acquisition window









Examination

information

Results

Ultrasonic imaging

Pressure indicator

Strain rate image

Information window

Commands

Counters

25


Examples in human liver

Depth (mm)

20

25

30

35

40

45

50

55

60

65

70

75

80

0 10 20 30 40 50 60 70 80

Time (ms)

V S = 1.1 m/s

E ~ 3 kPa

Depth (mm)

20

25

30

35

40

45

50

55

60

65

70

75

80

0 10 20 30 40 50 60 70 80

Time (ms)

V S = 1.7 m/s

E ~ 9 kPa

Depth (mm)

20

25

30

35

40

45

50

55

60

65

70

75

80

0 10 20 30 40 50 60 70 80

Time (ms)

V S = 3.6 m/s

E > 12.2 kPa

No fibrosis Significant fibrosis Cirrhosis

26


Challenges Related to Uptake of Therapy

by Patients in Care

Perceived/real contraindications to treatment

Misinformation about the success of therapy

Anxiety regarding adverse effects

– Information from former patients

Limitations: cost and resources

– Staffing limitations will restrict ability to meet increased

demand for HCV treatment resulting from recent approval of

new agents [2]

– Pharmac funding

1. Stepanova M, et al. Hepatology. 2011;53:737-745.

2. Aronsohn A, et al. Hepatology. 2011;53:1789-1791.


Preparing Patients for HCV Therapy

Topics to review and discuss with patients

– Need for effective contraception

– Prognosis

– Treatment options

– Predictors of response to therapy/likelihood that they will respond

– Adverse event management

– Job-related issues

– Importance of medication adherence, need for visits/lab follow-ups

Educate about avoidance of alcohol and potential hepatotoxins

Encourage patient’s active participation in treatment decisions and

ability to ask questions


Impact of HCV on

Health-Related Quality of Life


Symptoms of Chronic HCV

Fatigue

Arthralgias and myalgias

Psychosocial functioning

– Concern for transmission to partners through intimate

interactions

– Concern for development of cirrhosis and liver cancer

Depression


Adjusted Mean Days

Impact of HCV on Work Productivity

5

4

3

2

1

0

HCV

Control

P < .0001

2.85

2.21

4.17

Su J, et al. Hepatology. 2010;52:436-442.

P < .0001

1.93

Sick Leave Short-Term

Disability

Patients with chronic HCV

infection have significantly

more lost days from work

and more days of shortterm

disability compared

with employees without

chronic HCV infection


Current funded treatment option

Standard of care (SOC)


Standard of Care HCV Therapy: 2010

SVR, % IFN Monotherapy PegIFN IFN +

24 wks 48 wks 78 wks

RBV

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

PegIFN +

RBV

All genotypes 6-19 11-19 10-22 18-39 35-43 --

GT1 -- -- -- -- 33-36 42-46

GT2/3 -- -- -- -- 61-79 76-82

Standard of Care (SOC):

Pegylated Interferon and Ribavirin


Impact of HCV Treatment on Quality of Life

Exacerbates the fatigue of chronic HCV infection and

worsens during treatment

Leads to depression and/or irritability, which can affect

relationships with friends and family

Costs of medication and adverse effects of treatment

affect family/household income

Frequent medical follow-up visits for monitoring can affect

full-time employment


Common Adverse Events Associated With

PegIFN/RBV Therapy

Influenza like (fatigue, headache, fever, and rigors): > 50%

Psychiatric (depression, irritability, and insomnia): 22% to 31%

Neutropenia (ANC < 1500/mm 3 ): 18% to 20% [1,2]

– Severe neutropenia* (ANC < 500/mm 3 ): 4%

– Serious infections are uncommon and G-CSF is rarely necessary [3]

Anemia (Hb < 12 g/dL): ~ 30% [1,2]

– Nadir within 6-8 wks

– Severe anemia † (Hb < 10 g/dL): 9% to 15%

Laboratory abnormalities are the most common reasons for HCV

therapy dose reduction

*And treatment discontinuation.

Manns MP, et al. Lancet. 2001;358:958-965.

† And dose modification.

Fried MW, et al. N Engl J Med. 2002;347:975-982. Soza A, et al. Hepatology. 2002;36:1273-1279.


Previous failure with

SOC


Relative Proportions of HCV Patients

Eligible for Treatment in United States

Nonresponders

Relapsers

Ineligible (comorbidities, etc)

Treatment naive naive


Suboptimal Virologic Responses

HCV RNA (log 10 IU/mL)

8

7

6

5

4

3

2

1

0

PegIFN/RBV

Null response

Incomplete

treatment

Partial

response

Breakthrough

Wks

Relapse

2 log 10 decline

0 4 8 12 18 24 30 36 42 48 54 60 66 72 78

McHutchison JG, et al. N Engl J Med. 2009;361:580-593.

Limit of detection


Retreatment of PegIFN/RBV Relapsers

SVR (%)

100

80

60

40

20

0

McHutchison et al [1]

20

PegIFN alfa-2a/RBV

for 48 Wks

in PegIFN/RBV

Relapsers

1. McHutchison JG, et al. N Engl J Med. 2010;362:1292-1303.

2. Poynard T, et al. Gastroenterology. 2009;136:1618-1628.

SVR (%)

100

80

60

40

20

0

EPIC3 [2]

33

PegIFN alfa-2b/RBV

for 48 Wks

in PegIFN/RBV

Relapsers


SVR (%)

Retreatment of PegIFN/RBV

Nonresponders Yields Low SVR Rates

100

80

60

40

20

0

REPEAT [1] EPIC3 [2] DIRECT [3]

8.0

PegIFN alfa-2a/RBV

for 48 Wks in

PegIFN alfa-2b/RBV

Nonresponders

SVR (%)

100

80

60

40

20

0

1. Jensen D, et al. Ann Intern Med. 2009;150:528-540. 2. Poynard T, et al. Gastroenterology.

2009;136:1618-1628. 3. Bacon BR, et al. Hepatology. 2009;49:1838-1846.

6.3

PegIFN alfa-2b/RBV

for 48 Wks in

PegIFN/RBV

Nonresponders

SVR (%)

100

80

60

40

20

0

10.7

cIFN for 48 Wks

in PegIFN/RBV

Nonresponders


Response Factors With Future Treatment

Regimens

Treatment regimen

PegIFN exposure

RBV exposure

DAA exposure

Disease features

Fibrosis, steatosis,

coinfection (HBV, HIV)

Response factors

IFN + RBV + DAA

Host factors

Age, sex, race,

obesity, IR, ETOH

Genetic factors (IL28B)

Viral factors

Genotype

HCV RNA level

Quasispecies

(baseline resistance)


HCV Life cycle:

Targets for therapy –

Direct Acting Anti-virals (DAA)


HCV Life Cycle and DAA Targets

Receptor binding

and endocytosis

Translation NS3/4 and

polyprotein

protease

processing

inhibitors

Fusion

and

uncoating

(+) RNA

ER lumen

Membranous

web

NS5A* inhibitors

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

LD

LD

*Role in HCV life cycle not well defined

Transport

and release

ER lumen

LD

Virion

assembly

NS5B polymerase

RNA inhibitors replication

Nucleoside/nucleotide

Nonnucleoside


Potential Antiviral Targets and

Approaches

IFN

Immunomodulators

Replication

assembly

Potential targets and approaches

Antiviral

targets

Therapeutic

vaccine

Polymerase NS5A

Receptor

entry

Protease

Entry

inhibitors

Host

target


Select DAAs in Clinical Development

Protease Inhibitors ABT-450

ACH-1625

GS 9451

MK-5172

VX-985

Nonnucleoside

polymerase inhibitors

Nucleoside

polymerase inhibitors

Phase I Phase II Phase III

BI 207127

IDX375

NS5A inhibitors A-831

PPI-461

BMS-650032

CTS-1027

Danoprevir

GS 9256

IDX320

Vaniprevir

ABT-333

ABT-072

ANA598

BMS-791325

Filibuvir

Tegobuvir

VX-759

VX-222

IDX184

PSI-7977

RG7128

BMS-790052

BMS-824393

CF102

BI 201335

Boceprevir

Telaprevir

TMC435


Disadvantages of complex

treatment regimen


Treatment Complexity and Adherence

Data from HIV field illustrates

virologic suppression as a

function of daily pill burden [1]

Investigational HCV triple

therapy involves multiple

daily pills plus injection

drug

– BOC TID: 12 pills/day

– TPV TID: 6 pills/day

– RBV BID: 4-6 pills/day

– PegIFN: injection QW

Patients With Plasma HIV-1 RNA

≤ 50 copies/mL at 48 Wks (%)

100

90

80

70

60

50

40

30

20

10

0

5

Virologic Response by

Daily Pill Burden

Antiretroviral Pills

Prescribed/Day, n

PI

NRTI

NNRTI

10 15 20

1. Bartlett JA, et al. Overview of the effectiveness of triple combination therapy in antiretroviral-naive HIV-

1 infected adults. AIDS. 2001;15:1369-1377.


SVR (%)

Adherence to PegIFN/RBV: Essential but

Challenging

Retrospective analysis of

pegIFN alfa-2b/RBV trials

(N = 511) [1]

100

80

60

40

20

n =

0

35

17

24

54

72

53

75

63

305

10 30 50 70 90

Adherence Rate (%)

Only ~ 60% of US patients

adhere to HCV therapy [2]

Drug exposure correlates

with SVR; ≥ 80% adherence

correlates with SVR [1,3]

Patient self-report

overestimates adherence [4]

Adherence wanes over

time [4]

1. McHutchison JG, et al. Gastroenterology. 2002;123:1061-1069. 2. Mitra D, et al. Value Health.

2010;13:479-486. 3. Raptopoulou M, et al. J Viral Hepat. 2005;12:91-95. 4. Smith SR, et al. Ann

Pharmacother. 2007;41:1116-1123.


Major advancement of cure rates


Study 107: TVR/PR Retreatment of Pts

With PR Failure in PROVE 1/2/3 Trials

SVR (%)

100

80

60

40

20

0

59

37

55

N = 177 n = 51 n = 29 n = 8 n = 29

Total Prior

Null Response

Prior Partial

Response

Berg T, et al. EASL 2010. Abstract 4. Graphic reproduced with permission.

75

Prior

Breakthrough

97

Prior

Relapse


Case 1

26-yr-old white woman infected with HCV when she

experimented with drugs at college

Subsequently finished university and recently got married

Wants to know when she should start treatment, since she

plans to become pregnant

Otherwise healthy and normal body weight

ALT: 2 x ULN, HCV RNA: 400,000 IU/mL, genotype 3a

Liver biopsy: F1


What is the patient’s likelihood of achieving SVR

to pegIFN/RBV (assuming excellent adherence)?

A. > 90%

B. 70% to 90%

C. 50% to 70%

D. < 50%


SVR (%)

Impact of HCV Genotype on SVR to

PegIFN/RBV

100

80

60

40

20

0

PegIFN alfa-2b 1.5 µg/kg/wk +

RBV 800 mg/day for 48 Wks [1]

54

42

82

PegIFN alfa-2a 180 µg/wk +

Weight-Based RBV (1000 or

1200 mg/day) for 48 Wks [2]

n = 511 348 163

n =

453

Overall Genotype Genotype

0

Overall Genotype

1 2/3

1

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

100

80

60

40

20

56

46

76

298 140

Genotype

2/3


Impact of Baseline HCV RNA on SVR to

PegIFN/RBV

Patients (%)

100

80

60

40

20

0

n =

65

Low

HCV RNA

24 wks of pegIFN alfa-2a + RBV 800 mg/day

High

HCV RNA

Hadziyannis SJ, et al. Ann Intern Med. 2004;140:346-355.

48 wks of pegIFN alfa-2a + RBV 1000-1200 mg/day

47

85 84

85 186 34 62

Low

HCV RNA

Genotype 1 Genotype 2/3

High

HCV RNA


Impact of Fibrosis Level on SVR to

PegIFN/RBV

Patients (%)

100

80

60

40

20

0

41

Advanced

fibrosis

Hadziyannis SJ, et al. Ann Intern Med. 2004;140:346-355.

48 wks of pegIFN alfa-2a + RBV 1000-1200 mg/day

24 wks of pegIFN alfa-2a + RBV 800 mg/day

57

n = 78 193 20 76

Minimal

fibrosis

75

Advanced

fibrosis

Genotype 1 Genotype 2/3

87

Minimal

fibrosis


Case 1: Summary of Baseline Parameters

Young: 26 yrs old

Female

White

Normal body weight

Favorable genotype: 3a

Not consuming alcohol

Not diabetic


The patient wants to know when she should

start treatment. What do you recommend?

A. She requires immediate treatment

B. She may opt for treatment before pregnancy to try to

prevent infection of her child

C. She can wait because disease progression is unlikely

over the next 5 yrs

D. Her ALT can be checked during pregnancy and treatment

started if values get worse


Case 2

52-yr-old man admitted for hernia repair

Slightly obese, history of previous IDU, drinks

approximately 2 bottles of beer/day

During preop assessment, found to have elevated ALT

(2.5 x ULN)

Tests positive for genotype 1a HCV with an HCV RNA

level of 7.6 million IU/mL


After surgery, what is your recommendation

regarding candidacy for hepatitis C treatment?

A. Defer treatment and check ALT in 3 months

B. Perform a liver biopsy and check IL28B status

C. Defer treatment until the patient has lost weight and

stopped alcohol

D. Treat immediately


IL28B Genotype a Strong Predictor of SVR

With PegIFN/RBV in Genotype 1 HCV

Factor Associated With SVR Odds Ratio (95% CI)

IL28B rs12979860

genotype (CC vs TT)

Baseline HCV RNA

(< vs ≥ 600,000 IU/mL)

Whites (n = 871) Blacks (n = 191) Hispanics (n = 75)

Baseline fibrosis

(METAVIR F0-F2 vs F3-F4)

0.1

Ge D, et al. Nature. 2009;461:399-401.

1.1

2.4

3.0

4.2

4.1

5.6

5.1

6.1

7.3

1.0 10.0


IDEAL Trial: SVR Rates According

to IL28B SNP rs12979860

SVR (%)

100

80

60

40

20

0

Ge D, et al. Nature. 2009;461:399-401.

n = 186 n = 559 n = 392

TT CT CC


Case 2: Summary of Baseline Parameters

Genotype analysis shows that he is has IL28B TT

genotype

Male

Black

Obese

Consumes alcohol


In light of his IL28B TT genotype, what is his

likelihood of SVR with a PI + pegIFN/RBV vs

pegIFN/RBV alone?

A. No significant improvement (< 30%)

B. Improved but still < 50%

C. Improved to 50% to 75%

D. Improved to > 75%


SVR (%)

Subanalysis of Phase III Boceprevir Trials:

IL28B as a Predictor of Response

SPRINT-2: GT 1, treatment naive RESPOND-2: GT 1 relapsers and

partial responders to pegIFN/RBV

100

80

60

40

20

0

n

N =

80 82

78

44

55

63

77

50

64

71

82

115

65

67

103

BOC/PR48

33

116

CC* CT TT

*~ 90% eligible for short duration therapy.

BOC/PR RGT

100

Poordad F, et al. EASL 2011. Abstract 12. Graphics used with permission.

59

26

44

55

28 27

23

42

10

37

SVR (%)

80

60

40

20

0

n

N =

77

17

22

79

22

28

PR48

46

6

13

73

48

66

61

38

62

17

5

29

72

13

18

55

6

11

CC* CT TT

*~ 80% eligible for short duration therapy.

50

5

10


Subanalysis of ADVANCE: IL28B as a

Predictor of Response to Telaprevir

Phase III: genotype 1, treatment naive

– 42% (454 of 1088) of patients available for IL28B analysis; all patients in analysis

were white

SVR (%)

100

80

60

40

20

90

84

64

0

n/N = 45/50 38/45 35/55 48/68 43/76 20/80 16/22 19/32 6/26

CC

CT

TT

Jacobson IM, et al. DDW 2011. Abstract 904. Graphics used with permission.

71

57

25

T12PR T8PR PR

73

59

23


REALIZE: SVR Rates to Telaprevir by

IL28B Genotype and Previous Response

Phase III: genotype 1, failed previous pegIFN/RBV

SVR (%)

n/N=

100

80

60

40

20

0

Previous Relapsers

88 85 85

33

20

Previous Partial

Responders

Pooled T12/PR48

0 n/a

Previous Null

Responders

CC CT TT CC CT TT CC CT TT

PR48

51/58 4/12 100/117 6/30 29/34 3/10 5/8 1/5 33/57 2/10 10/14 0/5 4/10 27/92 1/18 10/32 1/15

Pol S, et al. EASL 2011. Abstract 13. Graphics used with permission.

30

63

58

20 20

71

40

29

6

31

7


A liver biopsy reveals stage 3 fibrosis. How does

this affect his likelihood of SVR to PI + pegIFN/RBV?

A. No effect; SVR rates are similar to patients with

no/minimal fibrosis

B. SVR rates are lower than in patients with no/minimal

fibrosis, but still higher than with pegIFN/RBV alone

C. SVR rates are similar to patients treated with

pegIFN/RBV alone


ADVANCE: SVR to Telaprevir-Based Tx

According to Fibrosis/Cirrhosis

Phase III: genotype 1, treatment naive

SVR (%)

100

80

60

40

20

0

78

73

T12PR

T8PR

PR48

Jacobson IM, et al. AASLD 2010. Abstract 211. Graphics used with permission.

47

No, Minimal, or Portal Fibrosis Bridging Fibrosis or Cirrhosis

62

Recommended regimen for

cirrhotic patients:

T12PR (PR for 24 or 48 wks

based on RGT, but cirrhotic

patients may also benefit

from PR48)

n = 290 279 288

73

85 73

53

33


RESPOND-2: SVR to Boceprevir-Based Tx

in Advanced Fibrosis/Cirrhosis

Phase III: genotype 1, previous relapse or partial response to

pegIFN/RBV

SVR (%)

100

80

60

40

20

68

BOC/PR48

BOC/PR RGT

PR48

0

n = 119 117

F0/1/2

61 31 32

F3/4

15

Bruno S, et al. EASL 2011. Abstract 7. Graphics used with permission.

66

23

68

44

Recommended regimen

for all cirrhotic patients

13


Case 3

65-yr-old Italian woman diagnosed with genotype 2 HCV

Presents with increased ALT (4 x ULN), a high HCV RNA

level (1.2 million IU/mL), and a borderline platelet count

(95,000 cells/mm 3 )


How would you manage this patient?

A. Treat without further investigations if there are no

contraindications

B. Perform a liver biopsy

C. Check IL28B status

D. Measure her vitamin D level


IL28B Polymorphisms and Response to

PegIFN/RBV by HCV Genotype

SVR (%)

100

80

60

40

20

0

Genotype 1 Genotype 2/3 Genotype 4

85

Stättermayer AF, et al. Clin Gastroenterol Hepatol. 2011;9:344-350.

45

41

79

78

50

88

32

25

CC

CT

TT


Investigational Agents for HCV:

Towards Interferon-Free

Regimens


Mean ALT (IU/L)

Final Results From SYNCH: High-Dose

Oral Silymarin for Chronic Hepatitis C

Treatment-experienced patients in multicenter trial randomized to receive 24 wks

silymarin (milk thistle) 700 mg TID, silymarin 420 mg TID, or placebo (N = 154)

– 92% to 98% of patients were > 80% adherent

Silymarin ineffective in reducing ALT or HCV RNA levels, or in improving quality of life

300

200

100

0

ALT During Therapy*

Placebo Silymarin

420 mg

*Analysis limited to those with complete ALT data (n = 131).

Fried MW, et al. AASLD 2011. Abstract 228.

Silymarin

700 mg

0 4 8 12 16 20 24

Treatment Wk

HCV RNA (log 10 IU/mL)

0.5

0.4

0.3

0.2

0.1

0

-0.1

Mean Change in HCV RNA

0.07

-0.03

0.04

Placebo

Silymarin

420 mg

Silymarin

700 mg


PILLAR: TMC435 + PegIFN/RBV in

Genotype 1 Treatment-Naive Patients

TMC435: NS3/4A protease inhibitor administered once daily

Treatment-naive

patients with

genotype 1

HCV

(N = 386)

TMC435 75 mg + PR

(n = 78)

TMC435 150 mg + PR

(n = 77)

Wk 12

TMC435 75 mg + PR

(n = 75)

TMC435 150 mg + PR

(n = 79)

PR

(n = 77)

PR

(n = 78)

PR

(n = 77)

Wk 24

PR

(n = 77)

Wk 48

*Treatment ended at Wk 24 if HCV RNA < 25 IU/mL detectable/undetectable at Wk 4, and

HCV RNA < 25 IU/mL undetectable at Wks 12, 16, and 20; all others continued on PR to Wk 48.

Fried MW, et al. AASLD 2011. Abstract LB-5.

Follow-up* or PR

(n = 78)

Follow-up* or PR

(n = 75)

Follow-up* or PR

(n = 77)

Follow-up* or PR

(n = 79)

Wk 72

Follow-up


PILLAR: TMC435 + PegIFN/RBV in

Genotype 1 Treatment-Naive Patients

Addition of TMC435 to pegIFN/RBV significantly improved SVR rates vs

pegIFN/RBV alone at Wk 24

80

60

40

Patients (%) 100

82

Overall SVR24 (ITT) SVR24 by IL28B Genotype*

P = .008 P = NS P = .013 P = < .001

75

81

86

20

n =

0

78 75 77 79 77

TMC435

75 mg

12-Wk

PR

TMC435

75 mg

24-Wk

PR

TMC435

150 mg

12-Wk

PR

TMC435

150 mg

24-Wk

PR

Fried MW, et al. AASLD 2011. Abstract LB-5.

65

Pbo

PR

80

60

40

20

Patients (%) 100

0

TMC435 75-mg dose groups combined

TMC435 150-mg dose groups combined

Placebo + pegIFN/RBV

97 100

84

73 78

n = 31 35 12 78 72 34

CC CT/TT

IL28B Genotype

*Analysis performed in consenting patients (67.9%);

distribution was 30% CC, 58% CT, 12% TT.

50


ELECTRON: PSI-7977 ± RBV ± PegIFN in

Genotype 2/3 Treatment-Naive Patients

Nucleotide analogue PSI-7977

400 mg QD + RBV for 12 wks

– PegIFN included for 0, 4, 8,

or 12 wks

All patients in all arms had

undetectable HCV RNA by

Wk 4

100% SVR12 in all RBVcontaining

arms

– SVR24 in 100% of patients with

evaluable data (n = 20)

PSI-7977 monotherapy (RBV

free) arm added; 60% SVR4

Gane EJ, et al. AASLD 2011. Abstract 34.

Patients (%)

100

80

60

40

20

0

100 100 100 100

PSI-7977/

RBV

+ 0 Wks

PegIFN

(IFN Free)

SVR12 Outcomes

n/N = 10/10 9/9 10/10 11/11

PSI-7977/

RBV

+ 4 Wks

PegIFN

PSI-7977/

RBV

+ 8 Wks

PegIFN

PSI-7977/

RBV

+ 12 Wks

PegIFN


PROTON: Potent Activity of PSI-7977 +

PegIFN/RBV in Genotype 1 Tx-Naive Pts

PSI-7977 200 or 400 mg QD + pegIFN/RBV for 12 wks, then

PR to Wk 24 if eRVR or Wk 48 if no eRVR (N = 121)

Patients (%)

100

80

60

40

20

92

88

91 91

0

n/N = 44/48 42/48

PSI-7977 200 mg

43/47 43/47

PSI-7977 400 mg

13/26* N/A

PR

*2/26 data pending. QD + PR

QD + PR

N/A, data not yet available.

ITT analysis.

Lawitz E, et al. AASLD 2011. Abstract 225.

50

EOT

SVR12


ZENITH Wk 36 Interim Analysis: VX-222 +

Telaprevir + PegIFN/RBV in GT1 Tx Naive

SVR (%)

100

80

60

40

20

0

n/N = 24/

29

83 90

27/

30

SVR12

82

9/

11

93

14/

15

SVR12

82

9/

11

93

SVR24

Overall Pts Eligible for

12 Wks

of Tx

Nelson DR, et al. AASLD 2011. Abstract LB-14.

14/

15

83 87

15/

18

13/

15

SVR12

Pts Eligible

for 24 Wks

of Tx

VX-222 100 mg +

telaprevir + PR (n = 29)

VX-222 400 mg +

telaprevir + PR (n = 30)


HCV is an epidemic

Conclusion

Most patients remain undiagnosed

– Screening of at risk population

– MOH funded HCV project (Hepatitis Foundation)

Counselling toward treatment

Achieving better cure rates

Achieving Interferon-free regimens

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