HCV Treatment: Why to Wait

Transcription

1 HCV Treatment: Why to Wait Prof. Jean-Michel Pawlotsky, MD, PhD National Reference Center for Viral Hepatitis B, C and delta Department of Virology & INSERM U955 Henri Mondor Hospital University of Paris-Est Créteil, France

2 I Current Treatments are Suboptimal

3 Standard-of-Care (EU label) Genotype 2,3 Genotype 4, 5, 6 PegIFNα + ribavirin 24 weeks PegIFNα + ribavirin 48 weeks

4 New Standard-of-Care for HCV Genotype 1 Boceprevir Telaprevir Pegylated IFN-α + Ribavirin

5 Telaprevir tid vs bid-optimize HCV genotype 1, treatment-naive 100 SVR12 rate (%) % 74% 270/ /369 T12 (q8h)/pr T12 (bid)/pr (Buti et al., AASLD 2012)

6 SVR According to Lead-in (SPRINT-2, non-black) 100 % of patients with SVR % 82% 39% 82% <1 log HCV RNA decrease 1 log HCV RNA decrease 10 0 BOC/RGT BOC/PR48 (Poordad et al., N Engl J Med 2011;364: )

7 REALIZE Rx-experienced, Gen 1, Telaprevir Patients With Undetectable HCV RNA (%) % 82% 62% 94% 56% 59% <1 log decrease 1 log decrease 54% 20 15% 0 Overall Prior relapse Prior partial response Prior null-response (Foster et al., EASL 2011)

8 Rash Grading Mild rash Moderate rash Severe rash Localized skin eruption and/or a skin eruption with limited distribution (up to several isolated sites on the body) Diffuse rash involving 50% of body surface area Extent of rash >50% of body surface area or with: Significant systemic symptoms Mucous membrane ulceration Target lesions Epidermal detachment 36.8% 13.8% 4.8% (Cacoub et al., J Hepatol 2012;56:455-63)

9 (Sulkowski et al., EASL 2011) Hb Shifts on Boceprevir

10 Clinical Trials vs Real World Telaprevir Boceprevir PegIFN/RBV 60 Clinical trials (including cirrhotics) Real world (cirrhotics only) Treatment-naïve Treatment-experienced Treatment-experienced 60 Patients with serious AEs (%) Patients with serious AEs (%) n=727 n=361 n=734 n=363 n=530 n=132 n=323 n= ADVANCE SPRINT-2 REALIZE RESPOND-2 0 n=269 n=159 French real-world (courtesy F. Poordad)

11 Medicines that are Contraindicated with Boceprevir and Telaprevir Drug class Contraindicated with boceprevir Contraindicated with telaprevir Alpha 1-adrenoreceptor antagonist Alfuzosin Alfuzosin Anticonvulsants Carbamazepine, phenobarbital, phenytoin N/A Antimycobacterials Rifampin Rifampin Antiretrovirals EFV, all RTV-boosted PIs DRV/RTV, FPV/RTV, LPV/RTV Ergot derivatives Dihydroergotamine, ergonovine, ergotamine, methylergonovine Dihydroergotamine, ergonovine, ergotamine, methylergonovine GI motility agents Cisapride Cisapride Herbal products Hypericum perforatum (St John s wort) Hypericum perforatum HMG CoA reductase inhibitors Lovastatin, simvastatin Lovastatin, simvastatin Oral contraceptives Drospirenone N/A Neuroleptic Pimozide Pimozide PDE5 inhibitor Sedatives/hypnotics Sildenafil or tadalafil when used for treatment of pulmonary arterial HTN Triazolam; orally administered midazolam (Boceprevir package insert; Telaprevir package insert) Sildenafil or tadalafil when used for treatment of pulmonary arterial HTN Orally administered midazolam, triazolam

12 Summary Treat now only patients who cannot wait for 1 year? 2 years? More? Tell the others better/safer treatments are coming

13 II Future Treatments are (over?)optimal

14 HCV Treatment Options Triple therapy with Peg-IFNα, ribavirin and a low barrier to resistance DAA Triple therapy with Peg-IFNα, ribavirin and a high barrier to resistance DAA/HTA Quadruple therapy with Peg-IFNα, ribavirin 2 DAAs/HTAs IFN-free regimens SVR strongly depends on the patient s responsiveness to IFN SVR partly depends on the patient s responsiveness to IFN SVR partly depends on the patient s responsiveness to IFN SVR depends on the potency and barrier to resistance of the combination

15 Triple combination with Peg-IFNα, ribavirin and a DAA/HTA

16 Future Triple Combinations Alisporivir a (Phase III) Mericitabine (Phase II) Simeprevir (Phase III) BI (Phase II) Sofosbuvir (Phase II) Telaprevir & boceprevir Faldaprevir( Phase III) Asunaprevir (Phase II) Daclatasvir (Phase III) Danoprevir (Phase II) (courtesy G.R. Foster)

17 Simeprevir-PILLAR Treatment-naive, Gen % 75% 81% 86% SVR24 rate (%) % N=78 75 mg 12w P/R N=75 75 mg 24w P/R N= mg 12w P/R N= mg 24w P/R N=77 Pbo P/R (Fried et al. AASLD 2012)

18 Simeprevir-PILLAR and ASPIRE Patients with F3/F4 100 Placebo (control) Simeprevir SVR24 rate (%) % 79% 56% (Poordad et al. AASLD 2012) 5/7 15/19 PILLAR Rx-Naïve, F3 4% 1/23 15/19 ASPIRE Rx-Experienced, F3/F4

19 Sofosbuvir/PegIFN/RBV-NEUTRINO Phase III, 12 weeks, Gen , Treatment-naive % 89% 97% 80% SVR12 rate (%) TOTAL (Gilead press release, February 4, 2013) N=327 N=292 N=35 N=56 Genotype 1 (89%) Genotype (11%) Cirrhosis (17%)

20 Quadruple combination with Peg- IFNα, ribavirin and 2 DAA/HTAs

21 Daclatasvir + Asunaprevir + Peg-IFNα + Ribavirin (Lok et al., EASL 2012)

22 Danoprevir/r + Mericitabine + Peg-IFNα + Ribavirin-MATTERHORN Partial and nullresponders, Gen 1, non-cirrhotic SVR12 rate (%) % 75% 96% 84% 73% 100% 10 0 (Feld et al. AASLD 2012) N=50 N=24 N=26 All Gen 1a Gen 1b PARTIAL RESPONDERS N=74 N=44 N=30 All Gen 1a Gen 1b NULL RESPONDERS

23 All-oral, IFN-free regimens

24 Available All-Oral Combinations Company NI PI NS5A NNI Cyclophilin Abbott BMS Gilead Vertex Boehringer -Ingelheim Roche Novartis Merck Janssen Achillion

25 All-oral, IFN-free regimens: NI-containing regimens

26 Sofosbuvir + RBV - FISSION Phase III, 12 weeks, Gen 2/3, Treatment-naive 100 SVR12 rate (%) Non-inferiority (95%CI: -7.5/+8.0%) 67% 67% (Gilead press release, February 4, 2013) N = 257 N = 243 Sofosbuvir + wb RBV 12 weeks PegIFNα + RBV 800 mg 24 weeks

27 Sofosbuvir + RBV - FISSION Phase III, 12 weeks, Gen 2/3, % Treatment-naive % SVR12 rate (%) % 63% SOF+RBV (Gilead press release, February 4, 2013) PegIFN+RBV SOF+RBV PegIFN+RBV Genotype 2 (28%) Genotype 3 (72%)

28 Sofosbuvir + RBV - FISSION Phase III, 12 weeks, Gen 2/3, Treatment-naive Compensated cirrhotics (20%) SVR12 rate (%) % 38% SOF+RBV PegIFN+RBV (Gilead press release, February 4, 2013)

29 Sofosbuvir + RBV - FUSION Phase III, 12 vs 16 weeks, Gen 2/3, Treatment-experienced SVR12 rate (%) % 73% (Gilead press release, February 19, 2013) N = 100 N = 95 Sofosbuvir + wb RBV 12 weeks Sofosbuvir + wb RBV 16 weeks

30 Sofosbuvir + RBV - FUSION Phase III, 12 vs 16 weeks, Gen 2/3, Treatment-experienced % 94% SVR12 rate (%) % 62% SOF/RBV 12 wk SOF/RBV 16 wk (Gilead press release, February 19, 2013) SOF/RBV 12 wk SOF/RBV 16 wk Genotype 2 (37%) Genotype 3 (63%)

31 Sofosbuvir + RBV - FUSION Phase III, 12 vs 16 weeks, Gen 2/3, Treatment-experienced 100 SVR12 rate (%) Compensated cirrhotics (34%) 31% 66% (Gilead press release, February 19, 2013) Sofosbuvir + wb RBV 12 weeks Sofosbuvir + wb RBV 16 weeks

32 Sofosbuvir + Ledipasvir ELECTRON (Gen 1) Week 0 Week 4 Week 8 Week 12 n = 25 n = 10 SOF + RBV (treatment-naïve) SOF + RBV (null responders) 84% SVR12 10% SVR12 (Gane et al., CROI 2013)

33 Sofosbuvir + Ledipasvir ELECTRON (Gen 1) Week 0 Week 4 Week 8 Week 12 n = 25 n = 10 SOF + RBV (treatment-naïve) SOF + RBV (null responders) 84% SVR12 10% SVR12 n = 25 n = 10 SOF + ledispavir + RBV (treatment-naïve) SOF + ledispavir + RBV (null responders) 100% SVR12 100% SVR12 (Gane et al., CROI 2013)

34 Sofosbuvir + Daclatasvir ± RBV Treatment-naive, Genotype 2, % 100% 93% 80 SVR24 rate (%) N=16 LI/SOF + DCV N=14 SOF + DCV N=14 SOF + DCV + RBV (Sulkowski et al., AASLD 2012)

35 Sofosbuvir + Simeprevir (PI) ± RBV COSMOS, Gen 1, null-responders % 96% 93% SVR8 rate (%) % 10 0 N=6 N=5 SOF+SIM+RBV 24 weeks SOF+SIM 24 weeks N=27 N=14 SOF+SIM+RBV 12 weeks SOF+SIM 12 weeks (Lawitz et al. CROI 2013: interim report, SVR8)

36 All-oral, IFN-free regimens: NI-free regimens

37 Faldaprevir (PI) + BI (NNI) SOUND-C2 Phase IIb Study 100 GT-1a GT-1b SVR 12 (%) ITT n/n BI dosing Duration (weeks) RBV ITT, intention-to-treat All groups received faldaprevir 120 mg QD for the same duration as BI (16, 28, or weeks) (Soriano et al., AASLD 2012) 13/34 35/47 14/32 33/48 16/34 24/43 13/30 41/48 2/18 16/28 TID 16 + TID 28 + TID + BID TID 28 -

38 ABT-450/r (PI) ± ABT-267 (NS5A) ± ABT-333 (NNI)-AVIATOR Treatment-naϊve Patients 97% 89% 90% 88% 85% Null Responders 89% 93% SVR12 rate (%) N=80 N=41 N=79 N=79 N=79 N=45 N=45 8 weeks 12 weeks 12 weeks ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-333 RBV ABT-450 ABT-267 RBV ABT-450 ABT-267 ABT-333 ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-267 RBV ABT-450 ABT-267 ABT-333 RBV (Kowdley et al., AASLD 2012)

39 III What About HIV- Coinfected patients

40 Triple Therapy with Boceprevir in HCV/HIV Coinfected Patients 100 PR B/PR % HCV RNA undetectable (Mallolas et al., EASL 2012) /34 3/64 5/34 27/64 8/34 38/64 11/34 47/64 10/34 42/64 9/34 37/ EOT SVR12 Treatment Week

41 Telaprevir in HIV-Coinfected Patients (SVR24) Patients With Undetectable HCV RNA (%) No ART EFV/TDF/FTC ATV/r+TDF+FTC/3TC TOTAL 80% 71% 74% 69% 50% 50% 45% 33% 0 n=7 n=16 n=15 n=38 n=6 n=8 n=8 n=22 T/PR PR48 (control) (Sulkowski et al., AASLD 2012)

42 BocepreVIH-ANRS HC27 Genotype 1, Rx-Experienced 100% 90% Relapse (n=20) Breakthrough (n=5) Partial (n=18) Null (n=21) HCV RNA <15 IU/mL (%) 80% 70% 60% 50% % 30% 20% 10% 0% W4 W6 W8 W12 W16 (Poizot-Martin et al., CROI 2013)

43 TelapreVIH-ANRS HC26 Genotype 1, Rx-Experienced (n=69) HCV RNA <15 IU/mL (%) % 74% 88% 88% 87% 88% 88% 88% 10 1% 0 Week 4 Week 8 Week 12 Week 16 (Cotte et al., CROI 2013) <15 IU/mL <15 IU/mL (undetected)

44 Simeprevir-Phase III C212 Study Treatment-experienced, Gen 1-SVR SVR4 SVR12 SVR4 and SVR12 (%) 100 Overall Naïve Relapsers /35 10/13 21/25 6/8 9/10 4/5 (Dieterich et al., CROI 2013)

45 Question Shall we wait for specific data in HIVcoinfected patients to treat these patients with IFN-free regimens?

46 Conclusion Achieving eradication of HCV infection is easily achievable without IFN, provided that: Potent antiviral drugs are used The combination has a high barrier to resistance Ribavirin is used to accelerate infected cell cure Treatment duration is sufficient to ensure definitive clearance or cure of HCV-infected cells Thus, let s wait and cure