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Hepatitis C Choices in Care. Future of Western Management of Hepatitis C. Robert Gish, MD. New Therapy Reality. Pegylated interferon alpha will remain the platform for all hepatitis C therapy for the foreseeable future

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Hepatitis c choices in care l.jpg

Hepatitis C Choices in Care

Future of Western Management

of Hepatitis C

Robert Gish, MD


Slide2 l.jpg

New Therapy Reality

  • Pegylated interferon alpha will remain the platform for all hepatitis C therapy for the foreseeable future

  • No FDA approved small molecule therapy, without interferon base, for at least 3 years and maybe longer



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New Therapies

Oral drugs (known as direct-acting antivirals, or DAAs) that specifically target certain steps in the hepatitis C virus life cycle are in late-stage development.


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New Therapies

  • HCV-specific protease inhibitors will be the first DAA class available.

    • Protease inhibitors block cleaving of viral proteins


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New Therapies

  • Nucleoside and nucleotide polymerase inhibitors

  • Non-nucleoside polymerase inhibitors

  • NS5a inhibitors

  • Novel Interferons

  • OtherImmune Modulators

  • Anti-fibrotics

  • For a complete list of drugs in the HCV pipeline visit: http://www.treatmentactiongroup.org/publication.aspx?id=3798


Definitions of response to anti hcv therapy l.jpg
Definitions of Response to Anti-HCV Therapy

8

PEG IFN/RBV

7

Breakthrough

Relapse

Null Response

6

5

2-Log Decline

HCV RNA (IU/mL)

4

Partial Response

3

Limit of

Detection

2

SVR

1

0

-6

0

6

12

18

24

30

36

42

48

54

60

66

72

78

Week


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Definitions of Response to Anti-HCV Therapy

  • Relapse

    HCV RNA becomes and remains undetectable during treatment but reappears after treatment is stopped.

  • Non-response

    HCV RNA drops by two logs but never becomes undetectable

  • Null response

    HCV RNA drops less than one log after four weeks and less than two logs after 12 weeks of treatment

  • Viral breakthrough

    HCV RNA reemerges after it becomes undetectablewhile on treatment

Adapted from the Treatment Action Group 2010 Pipeline report


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Definitions of Response to Anti-HCV Therapy

  • Very rapid virological response (vRVR)

    HCV RNA becomes undetectable after 14 days of treatment

  • Rapid virological response (RVR)

    HCV RNA becomes undetectable after 4 weeks of treatment

  • Extended rapid virological response (eRVR)

    HCV RNA becomes undetectable after 4 weeks of treatment and remains undetectable at week 12

  • Partial early virological response (pEVR)

    HCV RNA drops by at least 2 logs at week 12

Adapted from the Treatment Action Group 2010 Pipeline report


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Definitions of Response to Anti-HCV Therapy

  • Complete early virological response (cEVR)

    HCV RNA remains undetectable after 12 weeks of treatment

  • End-of-treatment response (EOT)

    HCV RNA remains undetectable at the end of treatment

  • Slow Virologic response (SR)

    2 log drop at week 12 and HCV RNA negative at week 24

  • Sustained virological response (SVR)

    No HCV RNA detectable 6 months after completion of treatment - Cure

Adapted from the Treatment Action Group 2010 Pipeline report


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Looks at: safety & activity

Dose (what is maximum tolerated dose)

Phamacokinetics(how much drug gets in,

& how long it lasts)

Small & short-term (monotherapy for 2 days

to 2 weeks)

Phase Ia - Healthy volunteers

Phase Ib - People w/ HCV

Clinical Trial PHASE I


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Looks at: safety & efficacy (capacity to produce a

certain effect, such as SVR)

12- 48 weeks of treatment, plus follow up

Larger (>100 people)

Randomized

SVR is primary endpoint; RVR &/ or EVR are

co-primary endpoints

Often used to choose dose and duration

Not a good idea to leap to conclusions about results,

as these are too small--but can inform design of phase III

(example: 44% SVR rate in African Americans with SOC + an HCV protease inhibitor--based on 10% of study population--or 18/27 people)

Clinical Trial PHASE II


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Looks at: safety & efficacy

Effectiveness (a measure of the accuracy or success of a diagnostic or therapeutic technique when carried out in an average clinical environment)

Randomized

Surrogate (or clinical) endpoints

Large (can be 1000’s of people)

Used to license medications

Clinical Trial PHASE III


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post-approval;

Diverse populations

Long-term effectiveness & toxicities

Treatment strategies

Clinical Trial PHASE IV


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PHASE I: high-risk(toxicity, risk

of incorrect dose/resistance)

PHASE II: if you can take a risk, it might be a good idea

PHASE III: safer entry point; more is known about the drug & dose

Risks & Benefits of Trial Participation


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PROVE 1 Phase II: Response Rates (ITT)

PEG-IFN RBV 48 wk

100

TVR 12 wk PEG-IFN RBV 48 wk

90

TVR 12 wk PEG-IFNRBV 24 wk*

81

81

80

TVR 12 wk PEG-IFN RBV 12 wk*

67

70

61

59

60

50

Patients (%)

41

40

35

33

30

23

20

11

10

6

2

0

4 Wk Undetectable

SVR

Relapse

*Patients stopping therapy at 12 and 24 weeks had achieved a RVR; †P=0.001 vs control; ‡P=0.02 vs control

McHutchison JG, et al. N Engl J Med. 2009;360(18):1827-1838.


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Boceprevir: Phase IISustained Virologic Responsea

Part 1

Part 2

80

75e

80

60

40

20

0

67d

70

60

56c

54

50

50

38

36

% Patients HCV Negative

Patients HCV Negative (%)

40

30

20

10

n= 104

107

103

103

n= 16

59

103

0

P/R(Control)48 wks

P/R/B28 wksf

P/R 4 wks P/R/B 24 wks

P/R/B48 wks

P/R 4 wks  P/R/B44 wks

P/R/B48 wks

P/low-dose R/B48 wks

P=PEG-IFN alfa-2b; R=RBV; B=boceprevir

aRoche COBAS TaqMan LLD <15 IU/mL; bP=0.013; cP=0.005; dP<0.0001; eP<0.0001 compared to P/R Control; f1 late relapser after follow-up week 24, not included n SVR

Kwo PY, et al. (AASLD Abstract 1582). Hepatology. 2009;50(S4):1035A.


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SVR Influenced by IL28B Genotype

100

75

50

25

0

P<0.0001

P=0.002

P=0.004

P<0.0001

SVR (% of Patients)

Genotype:

T/T T/C C/C

T/T T/C C/C

T/T T/C C/C

T/T T/C C/C

European-

Americans

African-

Americans

Hispanics

Combined

Ge D, et al. Nature. 2009;461(7262):399-401.


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INFORM-1: No Inteferon !Antiviral Activity in HCV G1 Interferon-Naïve and Null Responders with a BID Regimen of RG7128 + RG7227

100

RG7128 1000 mg BID + RG7227 900 mg BID

88

90

7

80

6

TF - Nulls

70

63

Naïves

5

60

50

EOT HCV RNA <LLOQ or LLOD (%)

50

Median Log10 HCV RNA (IU/mL)

4

40

3

30

25

2

20

Limit of Detection

Naïves

Naïves

Nulls

Nulls

10

1

1

3

5

7

9

11

13

0

Days

LLOD: Lower limit of detection LLOQ: Lower limit of quantification

<LLOD

<LLOQ

GaneEJ, et al. (Abstract 193). Hepatology. 2009;50(S4):394A-395A.


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Vitamin D: Impact on virologic response

  • Randomized Study, 58 patients G1, treatment naïve

    • PEG-IFN-2b (1.5 mcg/kg) + RBV (1000-1200 mg) + Vit D (1000-4000 IU)(27 patients, median age 47, 50 % male, 55 % > F2)

    • PEG-IFN-2b (1.5 mcg/kg) + RBV (1000-1200 mg) + placebo(31 patients, median age 49, 60 % male, 18 % > F2)

HCV RNA undetectable(< 50 IU)

100

96 %

80

Placebo + PEG-IFN/RBV

60

48 %

44 %

%

Vitamin D + PEG-IFN/RBV

40

18 %

20

0

S4

S12

AASLD 2009 – Abu-Mouch S, Israël, Abstract LB20 actualisé


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Graveyard for HCV Compounds is Filling Up Quickly!

BILN 2061

(Protease)

ISIS 14803

(Antisense)

JTK-003

(Polymerase)

UT-231B

(Imino sugar)

Heptazyme

(Ribozyme)

HCV-796

(Polymerase)

VX-497

(IMPDH inhibitor)

Viramidine

(RBV analogue)

NM-283

(Polymerase)

R803

(Polymerase)

Idenix compounds

2010

ANA975

(TLR agonist)

R1626

(polymerase)

CPG 10101

(TLR agonist)

ACH-806/GS-9132

(NS4a)

R7025

(Interferon-alpha)

Courtesy of Nelson D.


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To Treat or not to Treat:

A Constellation of Considerations

Histologic stage

20%+ life time risk

Of cirrhosis

Duration of

infection

Genotype virus

Genotype Patient (IL28)

Age

Family and other

support

Personal plans

(marriage,

pregnancy)

ALT

Occupation

Patient

"mindset"

Extrahepatic

Features

(Fatigue, EMC, PCT)

HIV coinfection

Contraindications

& comorbidities

Insulin Resistance

PinKAALSD CME 2009


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HCV Therapy – the bottom line

  • No new agent before 2011

  • All new therapies will be used in combination with PEG-IFN for the foreseeable future (2015)

  • Ribavirin will still need to be used

  • Combination therapyrequired with new DAA due to rapid development of resistance


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HCV Therapy – the bottom line

Adherence is critical!

Successful HCV treatment must rapidly—and fully—suppress hepatitis C virus, & keep it completely suppressed throughout the course of treatment (12-72 weeks)


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For more information

Visit us on line at www.HepCChallenge.org

8: Western (Allopathic) Medicine

Section 4: Future of Allopathic Hepatitis C Treatment

http://www.hepcchallenge.org/choices/pdf/Chapter_08_04_OL.pdf


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