Truly naïve Patients Rafael Esteban Mur, MD...

of 29 /29
Truly naïve Patients Rafael EstebanMur, MD (Spain)

Embed Size (px)

Transcript of Truly naïve Patients Rafael Esteban Mur, MD...

  • Truly naïve PatientsRafael Esteban‐Mur, MD (Spain) 

  • Current Treatment Hepatitis C

    SVR 70%

    Peginterferon-α +1000-1200 mg Ribavirin+ BOC o

    TVP 24-48 weeks

    Peginterferon-α+800 mg Ribavirin24 wks

    Genotype 1 Genotype 2/3

    HCV Genotype

    SVR 76-82%

  • SVR Rates With BOC or TVR in Genotype 1 Treatment‐Naive Patients

    0

    20

    40

    60

    80

    100

    SVR (%

    )

    PegIFN/RBV BOC or TVR + PegIFN/RBV

    38‐44

    63‐75

    Poordad F, et al. N Engl J Med. 2011;364:1195‐1206. Jacobson IM, et al. N Engl J Med. 2011;364:2405‐2416. 

  • Adverse Events of Triple Therapy

    Boceprevir TelaprevirSevere AEs 11% 7%Discontinuationsdue to AEs

    12% 14%

    Anemia 43‐49% 32%Rash 17% 55%

    Poordad F, et al. N Engl J Med. 2011;364:1195‐1206. Jacobson IM, et al. N Engl J Med. 2011;364:2405‐2416. Bacon BR, et al. N Engl J Med. 2011;364:1207‐1217. Zeuzem S, et al. N Engl J Med 011;364:2417  ‐2428. 

  • Predictors of Response to HCV Therapy• Pre‐treatment predictors

    – Race/ethnicity – Age– Low viral load– Absence of cirrhosis– IL‐28B genotype– HCV genotype 1a vs 1b, 2/3

  • SPRINT-2 (Boceprevir): SVR rates by baseline viral load

    SVR (%

    )

    n/N=

    BOC RGT

    41/54

    PR

    35/55

    PR

    102/308

    BOC 44/PR48

    197/313

    ≤800,000 >800,000

    Poordad F, et al. N Engl J Med 2011;364:1195–206SVR was defined as undetectable HCV RNA at the last available value in the period at or after follow‐up Week 24. If there was no such value, the follow‐up Week 12 value was carried forward

    BOC RGT

    192/314

    BOC 44/PR48

    45/53

  • PR48T12PRT8PR

    SVR by Advanced Fibrosis/Cirrhosis in Patients Receiving TVR + PegIFN/RBV

    • Recommendation: All cirrhotic patients receiving TVR + PR may benefit from 48 weeks of therapy[1,2]

    1. Telaprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Jacobson IM, et al. AASLD 2010. Abstract 211. 4. Jacobson IM, et al. NEJM. 2011;364:2405-2416.

    78

    62

    73

    5347

    33

    0

    20

    40

    60

    80

    100

    No, Minimal, or Portal Fibrosis Bridging Fibrosis or Cirrhosis

    SVR (%

    )[3,4]

    134/288

    n/N =

    226/290

    205/279

    24/73

    45/73

    45/85

  • SVR by Advanced Fibrosis/Cirrhosis in Patients Receiving BOC + PegIFN/RBV

    Subgroup Analysis of SPRINT-2[3]

    PR48BOC RGTBOC/PR48

    1. Boceprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Poordad F, et al. NEJM. 2011;364:1195-1206. 4. Bacon BR, et al. NEJM. 2011;364:1207-1217.

    F3/4

    100

    80

    60

    40

    20

    0

    SV

    R (%

    )

    F0/1/2

    38

    67

    213/319

    n/N=

    38

    9/24

    52

    22/42

    41

    14/34

    211/313

    67

    F3/4

    100

    80

    60

    40

    20

    0

    SV

    R (%

    )

    F0/1/2

    23

    66

    77/117

    132/15

    68

    21/31

    44

    14/32

    81/119

    68

    Subgroup Analysis of RESPOND-2[4]

    123/328

    n/N=

    14/61

  • BOC RGT

    63/77

    SVR in relation to IL28bSprint 2 Study

    RVS (%

    )

    PR48

    50/64n/N=

    CC TT

    BOC44/PR48 

    44/55

    CT

    PR48

    33/116

    BOC44/PR48 

    82/115

    BOC RGT

    67/103

    PR48

    10/37

    BOC44/PR48 

    26/44

    BOC RGT

    23/42Samples were available for 653/1048 (62%) patients enrolled in SPRINT‐2; SVR was defined as undetectable HCV RNA at the last available value in 

    the period at or after follow‐up Week 24. If there was no such value, the follow‐up Week 12 value was carried forwardBoceprevir EU SmPC

  • IL28B Genotype Predicts Likelihood of Shortened Therapy With BOC or TVR

    1. Poordad F, et al. EASL 2011. Abstract 12. 2. Jacobson IM, et al. EASL 2011. Abstract 1369. 

    Eligibility fo

    r Sho

    rten

    ed 

    Therap

    y (%

    )

    118/132

    158/304

    CC       CT/TT

    89

    52

    Eligibility fo

    r Sho

    rten

    ed 

    Therap

    y (%

    )

    39/50

    39/68

    10/22

    78

    5745

    SPRINT‐2: BOC + PR[1] ADVANCE*: T12PR[2]

    *IL28B testing in ADVANCE was in white pts only.

    80

    60

    40

    20

    0

    n/N =

    CC     CT     TT 

    100

    80

    60

    40

    20

    0

    n/N =

    100

  • Predictors of Response to HCV Therapy

    • On‐treatment predictors– Lead In–eRVR–Week 8 response– Week 12

  • Therapy with Boceprevir

  • SVR by Week 4 PR Lead-In Response

    52

    82 82

    5

    2939

    0

    20

    40

    60

    80

    100

    48 P/R BOC RGT BOC/PR48

    Non-Black Patients Black Patients

    ≥1 log 10 HCV RNA decline from baseline

  • SVR in Poor IFN Responders Based on TW8 Response (Log Decline in VL Compared to BL

    VL) (BOC Arms Combined)

    0

    38

    21

    50

    91

    09

    33

    48

    79

    0

    16

    30

    49

    83

    0

    20

    40

    60

    80

    100

    % S

    VR

    RESPOND-2 SPRINT-2 CombinedStudies

    5

    016

    38

    628

    1020

    1011

    028

    223

    2370

    1531

    2329

    5 5

    044

    531

    2998

    2551

    3340

    Bacon BR, et al. AASLD 2011

  • Predictors of SVR when Lead‐in Response is Considered

    RESPOND-2 (effect) Odds Ratio (95% CI) p-value

    BOC/PR48 vs PR48 11.4 (4.6 to 28.0)

  • SPRINT-2: undetectable HCV RNA at Week 8 and Weeks 8 to 24

    Patie

    nts w

    ith und

    etectable 

    HCV

     RNA (%

    )

    PR48

    60/363

    BOC44/PR48

    204/366n/N=

    Week 81 Weeks 8 to 242

    BOC RGT

    208/368

    BOC44/PR48 

    161/366

    BOC RGT

    162/368

    Patients eligible to receive 28 weeks of total treatment

    1. Boceprevir EU SmPC2. Poordad F, et al. N Engl J Med 2011;364:1195–206

    PR48 

    43/363

  • SPRINT‐2: SVR rates and treatment duration

    96

    72

    15

    96

    75

    0

    20

    40

    60

    80

    100SV

    R (%

    )

    Poordad F, et al. N Engl J Med 2011;364:1195–206 Bronowicki J‐P, et al. Hepatology 2010;52(Suppl.):881A 

    Undetectable Weeks 8–24

  • Response Guided Therapy with Telaprevir

  • No eRVR; PegIFN + RBV

    Genotype 1 naïve PatientsRGT with Telaprevir + PegIFN/Ribavirin

    TVR + PegIFN + RBV

    Wks 480 24124

    eRVR; stop at week 24, f/u 24 wksPegIFN + RBV

    *Quantificacion  HCV RNA  LLD ≤ 25 IU/mL.Telaprevir [package insert]. May 2011.

    HCV-RNA TVR + PegIFN/RBV

    PegIFN/RBV Total Duration

    Undetectable * wks 4 and 12 12 weeks 12 additionalweeks

    24 wks

    Detectable (but ≤ 1000 IU/mL) wks 4 and/or 12

    12 weeks 36 Additionalweeks

    48 wks

    F/u 24  wks

  • Response‐Guided Approach With TVR in Tx‐Naive Patients Supported by 2 Studies

    • 65% of patients eligible for shortened therapy[1]

    92 88

    ILLUMINATE: Response-Guided TVR + PegIFN/RBV in

    Treatment-Naive Genotype 1

    T12PR24 T12PR48

    SVR

    in P

    ts A

    chie

    ving

    eR

    VR (%

    )

    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

    • 58% of patients eligible for shortened therapy[2]

    8997

    T12PR24 PR

    SVR

    in P

    ts A

    chie

    ving

    eR

    VR (%

    )

    100

    80

    60

    40

    20

    0

    189/212

    28/29

    n/N=

  • Stopping rules during boceprevir dosing period

    0 48Weeks 284 8 24 3612

    If ≥100 IU/mLat Week 12

    If detectable at Week 24

    Stop all drugs

    Boceprevir EU SmPC

  • Stopping rules during telaprevir dosing period

    Telaprevir EU SmPC

    0Weeks 4 8 12

    If >1000 IU/mL at Week 4 or 12:stop all drugs*

    *In prior null responders, consideration should be given to conduct an additional HCV RNA test between Weeks 4 and 12. If the HCV RNA concentration is >1000 IU/mL, telaprevir and PR should be discontinued

  • Optimize Study

    Less frequent dosing

    + food + food + food

    + food + food

    24/48

    PRT + PR

    120

    Weeks

    Response Guided Therapyat week 4

  • 74 73

    0

    20

    40

    60

    80

    100

    OPTIMIZE SVR rates: telaprevir bid was non-inferior to q8h

    Full analysis populationCI: confidence interval Buti M, et al. Poster presented at AASLD 2012:LB-8

    SVR

    12(%

    )

    270/371274/369

    T12(q8h)/PRT12(bid)/PR

    Difference 1.5% (95% CI: –4.9%, 12.0%)

  • OPTIMIZE: a similar proportion of patients achieved RVR

    At Week 4, RVR determined total treatment duration– For patients achieving RVR, total treatment duration was 24 weeks, otherwise

    total treatment duration was 48 weeks

    RVR: rapid virologic response, undetectable HCV RNA at Week 4 Buti M, et al. Poster presented at AASLD 2012:LB-8

    69

    86

    67

    85

    0

    20

    40

    60

    80

    100

    RVR SVR in RVR+ SVR in RVR+RVR

    Patie

    nts

    (%)

    T12(bid)/PR (N=369) T12(q8h)/PR (N=371)

  • 77

    51

    78

    54

    77

    49

    0

    20

    40

    60

    80

    100

    246/321

    491/636

    29/54

    24/49

    245/315

    53/103

    CirrhosisNo cirrhosis

    OPTIMIZE: SVR12 by cirrhosis status

    One patient did not have a baseline fibrosis assessment and was excluded from this analysis Horsmans Y, et al. EASL 2013; Abstract 826

    TVR bid

    Allpatients

    TVR q8h

    TVR bid

    All patients

    TVR q8h

    SVR

    12(%

    )

  • 6979

    0

    20

    40

    60

    80

    100

    95% adherent (%)>85% adherent (%)

    TVP BID7490

    TVP 8h6487

  • CONCISE study: 12 weeks of Treatmenyresults of interim analysis*

    *128 patients were followed for 16 or more weeks; 66% (N=85) were randomized at Week 12, respectively: 57 in T12PR12 and 28 in T12PR24 armsRVR: Week 4 HCV RNA< 25 IU/mL, target not detected. PR: Peg-IFN alfa-2a (180 µg/week) and ribavirin (1000–1200 mg/day) Nelson DR et al. EASL 2013; Abstract 881

    PR

    Randomization 2:1in patients with RVR who continued

    all study drugs through Week 12

    T (1125 mg BID) + PR

    weeks0 124 24

    Follow-up

    IL28B CC non F4:

    Naïves

    Relapsers

    N=128 SVR4: 96% (47/49)SVR12: 89% (16/18)

  • IL28B CC

    F0-F2

    CC F3-4 TripleTherapy: Peg-RBV + TVP o BOC

    Peg-RBV

    24 wksRVR

    VL < 400.000 y F0-F1

    48 wksVL > 400.00 o F2

    No RVR

    Stop (*)

    48 wks

    < 1 log10

    > 1 log10

    * An IP (F2) could be added but it seems better to wait for new drugs

    Spanish Management of Hepatitis C Genotype 1 in naive patients

    IL28B CT/TT

    ≥ F2: Triple Therapy: Peg-RBV + TVP o BOC

    Document treball SCD (M Bruguera, R Esteban, X Forns, R Planas, J Quer, R Solà, M Vergara)

    IL28B CT/TT

    F0-F1Wait for new treatments