Hepatology on the Nile 2016

Transcription

1 Todays options for the medical management of hepatitis C Hepatology on the Nile 2016 GM Dusheiko University College London School of Medicine Kings College Hospital, London, UK

2 EASL Recommendations on Treatment of Hepatitis C 2016 EASL HCV Recommendations Panel

3 Panel Coordinator: Jean-Michel Pawlotsky Panel: Alessio Aghemo David Back Geoffrey Dusheiko Xavier Forns Francesco Negro (EASL GB) Massimo Puoti Christoph Sarrazin

4 DAAs approved in 2016 Sofosbuvir/ Velpatasvir All genotypes Grazoprevir/ Elbasvir Genotypes 1, 4

5 IFN-Free treatment options Combination regimen GT1 GT2 GT3 GT4 GT5-6 SOF + RBV No Suboptimal Suboptimal No No SOF/LDV ± RBV Yes No No Yes Yes SOF/VEL ± RBV Yes Yes Yes Yes Yes OBV/PTV/r + DSV (3D) ± RBV Yes No No No No OBV/PTV/r (2D) ± RBV No No No Yes No GZR/EBR ± RBV Yes No No Yes No SOF + DCV ± RBV Yes Yes Yes Yes Yes SOF + SIM ± RBV Suboptimal No No Yes No

6 Genotype 1b Options Combination regimen No cirrhosis Compensated cirrhosis Rx-naïve Rx-exp d Rx-naïve Rx-exp d SOF/LDV ± RBV 8-12 wk 12 wk 12 wk 12 wk SOF/VEL ± RBV 12 wk 12 wk 12 wk 12 wk OBV/PTV/r + DSV (3D) ± RBV 8-12 wk 12 wk 12 wk 12 wk GZR/EBR ± RBV 12 wk 12 wk 12 wk 12 wk SOF + DCV ± RBV 12 wk 12 wk 12 wk 12 wk

7 8 weeks of OBV/PTV/r + DSV in Genotype 1b Treatment-Naïves % 90 SVR12 rate (%) GARNET study Genotype 1b Treatment-naïve No cirrhosis (F0-F3) SVR: 13/15 F3 patients 10 0 N=166 (Abbvie, presented at the EASL/AASLD Special Conference on Hepatitis C)

8 Genotype 1a Options Combination regimen No cirrhosis Compensated cirrhosis Rx-naïve Rx-exp d Rx-naïve Rx-exp d SOF/LDV ± RBV 8-12 wk 12 wk + RBV* 12 wk 12 wk + RBV* SOF/VEL ± RBV 12 wk 12 wk 12 wk 12 wk OBV/PTV/r + DSV (3D) ± RBV 12 wk + RBV 12 wk + RBV 24 wk + RBV 24 wk + RBV GZR/EBR ± RBV 12 wk if HCV RNA 800,000 or 16 wk + RBV if HCV RNA >800, wk if HCV RNA 800,000 or 16 wk + RBV if HCV RNA >800, wk if HCV RNA 800,000 or 16 wk + RBV if HCV RNA >800, wk if HCV RNA 800,000 or 16 wk + RBV if HCV RNA >800,000 SOF + DCV ± RBV 12 wk 12 wk + RBV* 12 wk 12 wk + RBV* *24 wk without RBV if RBV contraindicated or poorly tolerated Only if presence of NS5A RASs at baseline, if resistance testing available

9 SVR According to Baseline NS5A RASs GT1, SOF/LDV, guidelines-recommended With NS5A RASs No NS5A RASs Without cirrhosis With cirrhosis Rx-Naive Rx-Exp d Rx-Naive Rx-Exp d % 99% 99% 99% 90% 99% 96% 96% 100%100% 88% 100% 89% 96% 100% 87% 80 SVR12 (%) N=32 N=108 N=189 N=509 N=88 N=300 N=27 N=68 N=10 N=27 N=9 N=19 N=66 N=214 N=15 N=84 8 Wks* 12 Wks 12 Wks 12 Wks 12 Wks + RBV *HCV RNA < 6 million IU/mL 24 Wks 12 Wks + RBV 24 Wks (Zeuzem et al., AASLD 2015)

10 Sofosbuvir + Velpatasvir ASTRAL-1 Phase III, TN and TE (32%), Gt 1,2,4,5,6, 19% cirrhosis, 12 wks 99% 99% 99% 99% % SVR12 rate (%) N=624 N=501 N=121 N=423 N=201 0 Overall No Yes Naïve Experienced Cirrhosis Treatment history (Feld et al., N Engl J Med 2015;373: )

11 Grazoprevir/Elbasvir Pooled efficacy population-phase II and III trials, GT1a, 12 weeks, no RBV No NS5A RASs With NS5A RASs % 100% 97% 100% 97% SVR12 rate (%) % 29% N=119 N=624 N=273 N=21 N=14 N=69 N= ,000 IU/mL >800,000 IU/mL Treatment-naïve (Merck, communicated to the panel) 800,000 IU/mL >800,000 IU/mL Treatment-experienced

12 Direct-Acting Antiviral (DAA)-containing regimens recommended by EASL Genotype 3 Sofosbuvir + daclatasvir (+ ribavirin) weeks Sofosbuvir/velpatasvir (+ ribavirin) 12 weeks* Combination regimen No cirrhosis Compensated cirrhosis Rx-naïve Rx-exp d Rx-naïve Rx-exp d SOF/VEL ± RBV 12 wk 12 wk + RBV* 12 wk + RBV* 12 wk + RBV* SOF + DCV ± RBV 12 wk 12 wk + RBV* 24 wk + RBV 24 wk + RBV *24 wk without RBV if RBV contraindicated or poorly tolerated Only if presence of NS5A RAS Y93H at baseline, if resistance testing available

13 SOF/VEL Total, 12 weeks N=277 SOF + RBV 24 weeks SVR12 (%) /163 Treatment 141/156 Naïve, Non-cirrhotic 40/43 33/45 Treatment 31/34 Naïve, 22/31 Cirrhotic 33/37 22/38 Treatment Experienced, Non-cirrhotic Treatment Experienced, Cirrhotic Non-Cirrhotic Cirrhotic Non-Cirrhotic Cirrhotic Treatment-naïve Foster G, et al. N Engl J Med 2015;373: Treatment-experienced

14 Sofosbuvir + Velpatasvir ASTRAL-3 Phase III, TN and TE (26%), Gt 3, 30% cirrhosis, 12 weeks Resistance analysis (1% cutoff, deep sequencing) Total, n=274 97% SVR12 84% No BL NS5A RASs n=231 16% BL NS5A RASs n=43 88% SVR12 225/231 38/43 (Foster et al., N Engl J Med 2015;373: ) SVR12 was 84% (21/25) in patients with Y93H

15 Sofosbuvir/ledipasvir ADVANTAGES Single-tablet regimen for most GT1 and GT4 patients 8-week option in GT1 treatment-naive noncirrhotics Few interactions Can be retreated with a PI (SMV) + SOF + ribavirin if relapse DISADVANTAGES EASL does not recommend in GT2 and GT3 infection Slightly less efficacious in GT1 if BL NS5A RASs Not if egfr <30 ml/min Ribavirin should be added in cirrhosis NS5A resistance if non-svr

16 Paritaprevir/ombitasvir/ritonavir (+ dasabuvir) ADVANTAGES Dasabuvir (nonnucleotidic NS5B inhibitor; Exviera) not needed in GT4 infection Can be given in severe renal impairment (egfr <30 ml/min) DISADVANTAGES Only effective in GT 1 and 4 Dasabuvir dosed twice daily (GT1) Ribavirin must be added for GT1b cirrhosis, 1a and 4 24 weeks in GT1a and 4 cirrhosis Large pill burden Multiple drug-drug interactions (ritonavir) Contraindicated in CPT-B/C cirrhosis Complex resistance if non-svr

17 Grazoprevir/elbasvir ADVANTAGES Single-tablet regimen GT1 and GT4 Can be given in severe renal impairment (egfr <30 ml/min) DISADVANTAGES Baseline testing for EBRspecific RASs in GT1a Ribavirin, treatment prolongation to 16 weeks should be considered if BL EBR-specific RASs (GT1a) or viral load >800,000 IU/mL (GT1a and 4) Contraindicated in CPT-B/C Grazoprevir and elbasvir are substrates of CYP3A Complex resistance if non- SVR

18 Sofosbuvir/velpatasvir ADVANTAGES Pangenotypic efficacy Single-tablet regimen for most patient segments Few interactions Baseline NS5A resistance does not impact in GT1 Can be retreated with a PI (SMV) + SOF + ribavirin if relapse DISADVANTAGES 8 weeks not recommended Not if egfr <30 ml/min Ribavirin may be considered for cirrhotic GT3 patients to overcome the impact of baseline NS5A resistance Ribavirin should be added in decompensated liver disease NS5A resistance if non-svr * Epclusa to be included in EASL Treatment Guidelines

19 Not available Available, reliable, interpret able, understandable* *recommended for GZR/EBR for US patients with GT1a Optimize therapy to avoid treatment failure Presence of NS5As RASs conferring high-level resistance (pop seq or >15%) SOF/LDV, SOF/DCV, SOF/SIM: Add RBV in G1a TE SOF/VEL: Add RBV in G3 TE patients and cirrhotics GZR/EBR: use 16 weeks with RBV in GT1a Add ribavirin and/or increase treatment duration in patients with NS5A RASs

20 ABT-530 Antiviral Activity Across HCV GT1 6 In Vitro Compared With Other Inhibitors of NS5A Potency compared to GT1a: No loss <10-fold loss 10- to 100-fold loss >100-fold loss Data not available Replicon cell line EC 50 (pm) Compound 1a 1b 2a 2b 3a 4a 5a 6a ABT Ombitasvir Daclatasvir , Ledipasvir ,000 16, , ,100 Elbasvir , Velpatasvir Odalasvir ~150 Samatasvir Ng T, et al. Hepatology 2014; 60(suppl):1142A (poster presentation); 2. Wang C, et al. Antimicrob Agents Chemother 2014; 58: ; 3. Harvoni US Prescribing Information (accessed August 2015); 4. Lui R, et al. J Hepatol 2012; 56(Suppl):S334 S335 (poster presentation); 5. Cheng G, et al. J Hepatol 2013; 58(Suppl):S484 S485 (poster presentation); 6. Zhao Y, et al. J Hepatol 2012; 56(Suppl):S330 (poster presentation); 7. Dousson C, et al. J Hepatol 2011; 54(Suppl):S326 S327 (poster presentation).

21 ABT-493 Antiviral Activity Across HCV GT1 6 In Vitro Compared With Other Inhibitors of NS3/4A Potency compared to GT1a: No loss <10-fold loss 10- to 100-fold loss >100-fold loss Data not available Replicon cell line EC 50 (nm) Compound 1a 1b 2a 3a 4a 6a ABT Paritaprevir Grazoprevir Simeprevir 3, Asunaprevir , Ng T, et al. Hepatology 2014; 60(suppl):1142A (poster presentation); 2. AbbVie data on file; 3. Olysio US Prescribing Information (accessed August 2015); 4. Chase R, et al. IVHD 2013; Oral presentation; OA25; 5. McPhee F, et al. Antimicrob Agents Chemother 2012; 56:

22 SURVEYOR-II (Part 2): Phase 2, Treatment-Naive Patients with Cirrhosis (GT3, 12-Week Data) Baseline characteristics ABT ABT-530 N=24 ABT ABT RBV N=24 Male, n (%) 13 (54) 18 (75) White race, n (%) 23 (96) 22 (92) Age, mean (range), years 55 (36 68) 57 (30 65) BMI, mean (range), kg/m 2 27 (19 37) 27 (21 35) HCV RNA, mean (range), log 10 IU/mL 6.4 ( ) 6.3 ( ) ALT, median (range), U/L 100 (22 198) 116 (28 218) Platelets, median (range), 10 9 /L 140 (86 245) 157 ( ) Albumin, median (range), g/dl 4.1 ( ) 4.2 ( ) Child-Pugh score = 6, n (%) 5 (21) 3 (13) SVR12 (%) n N ABT ABT ABT ABT RBV Any NS3 or NS5A RAV at BL ABT ABT-530: 42% (10/24) ABT ABT RBV: 33% (8/24) BL = baseline. Kwo P, et al. J Hepatol 2016; 64(Suppl 2):S208 (oral presentation).

23 SOFOSBUVIR VELPATASVIR VOXILAPREVIR NS5B polymerase inhibitor Sofosbuvir (SOF) NS5A inhibitor Velpatasvir (VEL) Triple combination therapy To reduce treatment duration Or salvage therapy NS3/4A protease inhibitor GS-9587 Voxilaprevir (VOX)

24 Integrated Analysis* of SOF/VEL + VOX ± RBV in GT1 6- Infected, Treatment-Experienced Patients with or without Cirrhosis GT1 6, N=128 SOF/VEL + VOX Week 0 Week week follow-up 1 relapse in GT3-infected patient: 58 years old, cirrhosis, white female, NS5A at BL Presence of BL RAVs had no impact on SVR % BL RAVs (77/128) SVR12 (%) n N Overall GT1 GT2 GT3 GT4, % SVR12 (51/51) 40% No RAVs 20% NS5A 23% Multi-class 15% NS3 2% NS5B 99% SVR12 (76/77) * GS-US and GS-US Lawitz E, et al. J Hepatol 2016; 64(Suppl 2):S139 (oral presentation).

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26 NB:

27 Sofosbuvir + 3D in DAA Failures QUARTZ-I- Retreatment study, GT1, 12 weeks % 100% 100% 80 SVR12 rate (%) (Poordad et al., AASLD 2015) N=14 N=6 N=2 1a, no cirrhosis 12 wks + RBV 1a, cirrhosis 24 wks + RBV 1b 12 wks, no RBV

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