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36 year old HCV+ woman, Risk factor: occasional IVDU 15 years ago

Case study. 36 year old HCV+ woman, Risk factor: occasional IVDU 15 years ago First treatment with PEG-IFN/RBV in 2002 only qualitative PCR available : positive at W12 and W24 Treatment stopped after 24 weeks Weight: 65 kg, BMI: 23 No comorbidity, no medications

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36 year old HCV+ woman, Risk factor: occasional IVDU 15 years ago

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  1. Case study • 36 year old HCV+ woman, • Risk factor: occasional IVDU 15 years ago • First treatment with PEG-IFN/RBV in 2002 • only qualitative PCR available : positive at W12 and W24 • Treatment stopped after 24 weeks • Weight: 65 kg, BMI: 23 • No comorbidity, no medications • Genotype 1a, viral load 6.1 log10 • Fibroscan: 7.5 KPa • Fibrotest: 0.47 (Fibrosis  F1-F2)

  2. Case study • She complains about fatigue • She wants to be treated because of this fatigue. • No biological or clinical contraindication for the treatment

  3. Would you treat this patient ? • No, • because of no significant fibrosis • Would wait 2d wave PI • Yes, • because she is really motivated

  4. Would you perform an IL28B genotyping in this patient ? • Yes, • because the IL28B polymorphism can influence the treatment strategy • No

  5. Boceprevir in treatment experienced patients: SVR rates by IL28B genotype % SVR 6 13 22 28 17 22 5 29 38 62 48 66 5 10 6 11 13 18 Poordad F, et al. J Hepatol 2011;54(Suppl.):S6

  6. Telaprevir in treatment experienced patients: SVR Rates by IL28B Genotype and Prior Response TT TT TT CC CT CC CT CC CT n/N= 4/12 100/117 3/10 5/8 1/5 2/10 10/14 4/10 27/92 1/15 51/58 6/30 29/34 33/57 0/5 1/18 10/32 Prior relapsers Prior partial responders Prior null responders Pooled T12/PR48 (n=134) Pbo/PR48 (n=33) Pooled T12/PR48 (n=209) Pbo/PR48 (n=52) Pooled T12/PR48 (n=79) Pbo/PR48 (n=20) Patients achieving SVR (%) n/a Younossi Z et al. Gastroenterology 2011;

  7. Impact of IL28B polymorphisms on SVR in naïve patients CC CT TT CC CT TT 100 100 90 82 80 78 80 73 80 71 71 65 64 59 55 60 60 RVS (%) RVS (%) 40 40 28 27 25 23 20 20 0 0 PR4820/80 T12PR 48/68 PR4835/55 T12PR 45/50 PR486/26 T12PR16/22 PR48 50/64 BOC RGT 63/77 BOC44/PR48 44/55 PR48 33/116 BOC RGT 67/103 BOC44/PR48 82/115 PR48 10/37 BOC RGT 23/42 n/N= BOC44/PR48 26/44 n/N= Poordad F, et al. J Hepatol 2011;54(Suppl.):S6 Jacobson IM, et al. J Hepatol 2011;54(Suppl.):S542

  8. Impact of IL28B polymorphisms on SVR in naïve patient CC CT TT CC CT TT 100 100 90 82 80 78 80 73 80 71 71 65 64 59 55 60 60 RVS (%) RVS (%) 40 40 28 27 25 23 20 20 89 % of CC patients treated with BOC/PR were eligible for shorter therapy 80 % of CC patients treated with BOC/PR were eligible for shorter therapy 0 0 PR4820/80 T12PR 48/68 PR4835/55 T12PR 45/50 PR486/26 T12PR16/22 PR48 50/64 BOC RGT 63/77 BOC44/PR48 44/55 PR48 33/116 BOC RGT 67/103 BOC44/PR48 82/115 PR48 10/37 BOC RGT 23/42 n/N= BOC44/PR48 26/44 n/N= Poordad F, et al. J Hepatol 2011;54(Suppl.):S6 Jacobson IM, et al. J Hepatol 2011;54(Suppl.):S542

  9. SVR in patients with a favorable IL28B polymorphism and a RVR (rs8099917) NS p <0.001 99 97 95 100 24 week. 80 70 48 week. 60 SVR in patients with RVR (%) 40 20 0 IL28B rs 8099917 TTVL ≥ 600,000 IU/mL IL28B rs 8099917 TTVL < 600,000 IU/mL Liu CH, AASLD 2011, # 414

  10. Would you propose a lead-in in this patient ? • Yes, regardless the PI • because it will help to define the responsiveness to interferon of this patient • Yes but only in case of BOC prescription

  11. Case study • Day 1: start of antiviral therapy • Peginterferon -2b 1.5 ug/kg/week • Ribavirin: 300 mg BID • Week 4: • Side effect: fatigue • Viral load: 5.2 log10 (vs 6.1 log10 at D1)

  12. Will you add a protease inhibitor ? • No, because of <1 log10 decline. • Probability of SVR is very low. • Probability of resistance very high. • Yes, despite <1 log10 decline. • Probability of SVR remains significant

  13. 100 100 79 73 80 80 60 60 SVR (%) SVR (%) 34 33 40 40 25 20 20 0 17 0 80 15 90 15 _ _ _ _ _ _ 0 0 67 12 110 46 114 44 PR48 BOC RGT BOC/PR48 PR48 BOC RGT BOC/PR48 SVR according to the response during the lead –in: boceprevir <1 log10 HCV RNA reduction at Week 4 ≥1 log10 HCV RNA reduction at Week 4 Bacon BR., et al. N Engl J Med 2011; 364:1207-1217.

  14. Predictive Value of Week 4 Response in Prior Relapsers, Partial and Null Responders Prior relapsers Prior null responders Prior partial responders Patients achieving SVR (%) ≥1 log10 HCV RNA reduction at Week 4 <1 log10 HCV RNA reduction at Week 4 Prior treatment response provides a more granular prediction of SVRthan < or ≥ 1 log response after 4 weeks of Peg/RBV lead-in phase Lawitz EJ et al. Gastroenterology 2011

  15. Lead-in Predicts SVR and Resistance • Boceprevir resistance-associated variants: • - ≥1 log10 decline: • BOC RGT: 4% (10/232) • BOC/PR48: 6% (13/231) • - <1 log10 decline: • BOC RGT: 52% (49/95) • BOC/PR48: 40% (38/94) Poordad F. N Engl J Med. 2011; 364:1195-1206. 15

  16. ↓ viral load 0.9 log in this patient Variability of Taqman Roche: 0.3-0.5 log

  17. Case study • Start boceprevir 800 mg/8h (12 pills/day) at Week 4. • Week 8. • Side effects:  fatigue, dysgeusia, no rash. • Hb: 10.5 g/dL (vs 13 g/dL at Day 1). • HCV RNA: 3.4 log IU/ml (6.1 log at baseline) 17

  18. What will be your attitude ? • Stop all treatment • Because the probability of SVR = 0 • Continue the triple therapy and check again the viral response at W12 (W12 stopping rule) • Stop BOC and continue PEG-IFN/RBV

  19. Boceprevir : SVR according to viral response at week 8 in patient poorly responsive to PEG-IFN 17 100 91 83 79 80 60 50 49 48 SVR (%) 38 40 33 30 21 16 20 016 028 044 9 38 628 1020 10 11 223 2370 1531 2329 531 2998 2551 3340 0 0 0 0 < 3 3-4 4-5 > 5 < 3 3-4 4-5 > 5 < 3 3-4 4-5 > 5 Undetectable Undetectable Undetectable RESPOND 2 SPRINT 2 Combined studies Bacon BR, AASLD 2011, 33 actualisé

  20. Impact of TW12 stopping rules in naive patients Jacobson, AASLD 2011, #954

  21. Impact of TW12 stopping rules in treatment experienced patients Jacobson, AASLD 2011, #954

  22. Stop rules Stop rules for boceprevir Weeks 0 4 8 12 24 28 36 48 RNA detectable ↕B and PR RNA ≥100 UI/ml ↕ 3 B and PR Stop rules for telaprevir Weeks 0 4 8 12 24 36 48 RNA detectable ↕PR RNA > 1000 UI/ml ↕ T and PR

  23. Case study • All the drugs stopped at this point….

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