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Response Guided Therapy

Response Guided Therapy. Fabien Zoulim Hepatology Department & INSERM Unit 1052, Lyon University Lyon, France. Rationale for response guided therapy (RGT) ?. Potent and rapid viral suppression in patients receiving DAA based therapy

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Response Guided Therapy

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  1. ResponseGuidedTherapy Fabien Zoulim HepatologyDepartment & INSERM Unit 1052, Lyon University Lyon, France

  2. Rationale for responseguidedtherapy (RGT) ? • Potent and rapid viral suppression in patients receiving DAA basedtherapy • Can the duration of treatment be shortened in genotype 1-infected patients receiving DAA-based therapy? • Is the situation the same for naïve and treatment experienced patients ?

  3. Early viral load decline through Week 12 of telaprevir-based regimens Time (weeks) 8 0 3 12 2 4 1 0 –1 –2 –3 Median change from baseline(log10 HCV RNA) –4 –5 –6 –7 Non-responders to prior PR treatment who received T12/PR24 or T24/PR48 in PROVE3 (n=130) Relapsers after prior PR treatment who received T12/PR24 or T24/PR48 in PROVE3 (n=83) Null responders and partial responders to prior PR treatment who received T12/PR24 or T24/PR48 in roll-over Study 107 (n=79) Relapsers after prior PR treatment who received T12/PR24 or T24/PR48 in roll-over Study 107 (n=28) Treatment-naïve patients who received T12/PR in PROVE1 or PROVE2 (n=338) Poordad F, et al. J Hepatol 2010; 52(Suppl. 1):S121–S122

  4. Respond-2 Sprint-2 Kinetics of response to Boceprevirbasedtherapy (Sprint-2 & Respond2) Meeting FDA 27-28 avril 2011

  5. Can the duration of treatment be shortened in treatment-naïve, genotype 1-infected patients receiving DAA-based therapy?

  6. ADVANCE (telaprevir): study design (N=1088) SVR PR48 (control)(n=361) Pbo + PR PR Follow-up SVR eRVR+ Follow-up Follow-up T12PR(n=363) TVR + PR PR eRVR– SVR PR Follow-up SVR eRVR+ Follow-up Follow-up T8PR(n=364) TVR + PR Pbo + PR PR SVR eRVR– PR Follow-up 0 8 12 24 36 48 72 Weeks Peg-IFNalfa-2a dose: 180 µg/week; RBV dose: 1000 or 1200 mg/day eRVR: undetectable HCV RNA at Week 4 and 12 Jacobson IM, et al.N Engl J Med 2011;364:2405–16

  7. ILLUMINATE (telaprevir): study design (N=540) eRVR+ T12PR24 n=162 SVR 72 weeks PR Follow-up Follow-up T12PR PR Non-inferiority (NI) Randomized Treatments eRVR+ eRVR+ T12PR48n=160 SVR PR Follow-up Assigned Treatment eRVR– T12PR48 n=118 SVR eRVR– PR Follow-up 0 12 20 20 24 36 48 60 72 Weeks Patients discontinued for any reason before Week 20 randomization were categorized as ‘Other’ (N=100)Peg-IFNalfa-2a dose: 180 µg/week; RBV dose: 1000 or 1200 mg/dayeRVR: undetectable HCV RNA at Week 4 and 12 ShermanKE, et al. N Engl J Med 2011;365:1014–24

  8. SPRINT-2 (boceprevir): study design (N=1097) SVR SVR SVR SVR PR + Pbo PRlead-in PR48 Controln=363 Follow-up Follow-up Follow-up Follow-up Weeks 8–24 HCV RNA undetectable PR + BOC PRlead-in BOC RGT n=368 HCV RNA detectable at any time from Week 8 onwards, but Week 24 undetectable PR + Pbo PRlead-in PR + BOC BOC44/ PR48 n=366 24 28 0 4 8 48 72 Weeks Peg-IFN alfa-2b dose: 1.5 µg/kg/week RBV dose: 600–1400 mg/day in a divided daily dose Poordad F, et al. N Engl J Med 2011;364:1195–206

  9. ADVANCE and ILLUMINATE (telaprevir): undetectable HCV RNA at Weeks 4 and 12 Weeks 4 and 12 (eRVR) Week 4 (RVR) Patients eligible to receive 24 weeks of treatment in total Patients with undetectable HCV RNA (%) PR4834/361 T12PR635/903 PR4829/361 T12PR565/903 n/N= Adapted from Sherman KE, et al. CROI 2011. Abstract 957

  10. ILLUMINATE (telaprevir): SVR rates by treatment duration in patients treated with T12PR (N=540) Treatment duration according to eRVR status SVR rate  4.5% (2-sided 95% CI = –2.1% to +11.1%) <20 weeks 18% eRVR+* n=100 eRVR– 60%* 22% n=322 n=118 Eligible for 24 weeks and randomized to 24 or 48 weeks* 48 weeks <20 weeks (due to premature treatment discontinuation) eRVR+ T12PR24 149/162 eRVR+ T12PR48 140/160 eRVR– T12PR48 76/118 <20 weeks 23/100 *Patients who achieved eRVR (undetectable HCV RNA at Weeks 4 and 12) and completed the Week 20 visit were randomized to receive an additional 4 or 28 weeks of PR alone65% of patients achieved an eRVR (352/540); 322/352 were randomized and 30/352 patients discontinued before randomization at Week 20 ShermanKE, et al. N Engl J Med 2011;365:1014–24

  11. SPRINT-2 (boceprevir): undetectable HCV RNA at Week 8 and Weeks 8 to 24 Week 8 Weeks 8 to 24 Patients eligible to receive 28 weeks of total treatment Patients with undetectable HCV RNA (%) PR4860/363 BOC RGT208/368 BOC44/PR48204/366 BOC RGT162/368 BOC44/PR48 161/366 PR48 43/363 n/N= Adapted from Poordad F, et al. N Engl J Med 2011;364:1195–206

  12. <28 weeks 28 weeks 34% 44% n=124 n=162 48 weeks 22% SPRINT-2 (boceprevir): SVR rates and treatment duration in BOC arms n=82 Treatment duration in RGT arm SVR rates 28 weeks if undetectable HCV RNA from Weeks 8–24 48 weeks if detectable HCV RNA at least once between Weeks 8–24 but undetectable at Week 24 <28 weeks (discontinued because of detectable HCV RNA at Week 24, adverse events or non-medical reasons) BOC44/PR48 BOC RGT Undetectable Weeks 8–24 + 28 wks 156/162 – 48 wks 59/82 <28 wks 18/124 + 48 wks 155/161 – 48 wks 55/73 Poordad F, et al. N Engl J Med 2011;364:1195–206 Bronowicki J-P, et al. Hepatology 2010;52(Suppl.):881A

  13. Shorter duration of therapyis possible in naive patients whoachieve an eRVR

  14. Can the duration of treatment be shortened in treatment-experienced, genotype 1-infected patients receiving DAA-based therapy?

  15. REALIZE (telaprevir): study design (N=662) T12/PR48 TVR + Peg-IFN + RBV Pbo + Peg-IFN + RBV Peg-IFN + RBV Follow-up n=266 LI T12/PR48 Pbo + Peg-IFN + RBV TVR + Peg-IFN + RBV Peg-IFN + RBV Follow-up n=264 PR48 (control) Pbo + Peg-IFN + RBV Peg-IFN + RBV Follow-up n=132 72 4 0 12 16 48 8 Weeks SVR assessment Randomization was stratified by viral load and prior response category. Stopping rules applied for telaprevir (Weeks 4, 6, and 8 after telaprevir start) and PR (Weeks 12/16 [depending on treatment arm], 24, and 36)Peg-IFN alfa-2a: 180μg/week subcutaneously; RBV: 1000–1200mg/day; TVR: 750mg every 8 hours Zeuzem S, et al. N Engl J Med 2011;364:2417–28

  16. RESPOND-2 (boceprevir): study design (N=403) PR48 (control) BOC44/ PR48 Peg-IFN + RBV Peg-IFN + RBV Pbo + Peg-IFN + RBV BOC + Peg-IFN + RBV Follow-up Follow-up n=80 n=161 Week 8 and 12 undetectable HCV RNA Follow-up BOC RGT Peg-IFN + RBV BOC + Peg-IFN + RBV Week 8 detectable HCV RNA +Week 12 undetectable HCV RNA n=162 Pbo + Peg-IFN + RBV Follow-up 72 36 4 0 12 16 48 8 Weeks SVR assessment Patients with detectable HCV RNA at Week 12 were considered treatment failures and discontinued treatmentPeg-IFN alfa-2b: 1.5μg/kg/week; RBV: 600–1400mg/day; BOC: 800mg q7–9h Bacon BR, et al. N Engl J Med 2011;364:1207–17

  17. Telaprevir: SVR in prior relapsers eligible to receive 24 weeks of therapy SVR (%) Study 106 T12/PR24 25/28 Study 107 T12/PR2424/24 n/N = Patients with undetectable HCV RNA at Weeks 4 and 12 of subsequent telaprevir-based treatment INCIVO (telaprevir) EU SmPC 21

  18. RESPOND-2 (boceprevir): SVR by Week 8 HCV RNA levels* Undetectable HCV RNA at treatment week 8 Detectable HCV RNA at treatment week 8 Overall, 46% of patients eligible to receive 36 weeks of total treatment SVR (%) BOC RGT 29/72 PR487/7 BOC RGT 64/74 BOC44/PR48 74/84 PR48 8/65 BOC44/PR4830/70 n/N= *Some patients had missing values at Week 8 Bacon BR, et al. N Engl J Med 2011;364:1207–17; Bacon BR, et al. Hepatology 2010;52(Suppl.):430A 22

  19. Shorter duration of therapyis possible in relapsers/partial responderswhoachieve an eRVRduring DAA based triple therapy

  20. ResponseGuidedTherapy Can beapplied to: • Naive patients withoutcirrhosis • Relapsers • Partial responders Cannotbeapplied to: • Cirrhotics • Nullresponders • Blacks • IL28

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