HEPATITIS C. Mitchell L. Shiffman, MD, FACG Director. Liver Institute of Virginia. Richmond and Newport News, VA

Transcription

1 NEW TREATMENTS FOR HEPATITIS C Mitchell L. Shiffman, MD, FACG Director Liver Institute of Virginia Bon Secours Health System Richmond and Newport News, VA Liver Institute of Virginia Education, Research and Treatment for Patients with Liver Disease Bon Secours Health System HCV LIFE CYCLE PLACES TO INTERVENE Packaging Cell Entry Uncoating Translation NS5A Protease NS3-4 Replication Polymerase NS5B Copyright 2015 American College of Gastroenterology 1

2 HCV TREATMENT DAA COMBINATIONS FOR GT1 Protease Replication Polymerase Inhibitor Complex Inhibitor Inhibitor NS3-4A NS5A NS5B Telaprevir Boceprevir Simeprevir Sofosbuvir Ledipasvir i Sofosbuvir Parataprevir Ombitasvir Dacabevir Grazaprevir Elbasvir Daclatasvir Sofosbuvir SIMEPREVIR GENOTYPE 1 Simeprevir protease inhibitor Once daily No anemia FDA approved for use with PEGINF/RBV in 11/2013 Pre-existing mutation Q80K in patients with genotype 1A reduced efficacy with PEGINF/RBV Most commonly used with sofosbuvir as the first all oral DAA combination for genotype 1 Copyright 2015 American College of Gastroenterology 2

3 SOFOSBUVIR/SIMEPREVIR GENOTYPE 1 Cohort 1: Non-cirrhosis: Null responders Cohort t2: Cirrhosis: i Treatment tnaive and dnull-responders llr Cohort: 1 2 SOF/SMV SOF/SMV + RBV SOF/SMV N=24+30 N=15+16 N=27+27 SOF/SMV + RBV N=14+14 N= Weeks of Treatment E Lawitz et al. Lancet 2014; 384: SOFOSBUVIR/SIMEPREVIR NON-RESPONSE AND CIRRHOSIS 12 weeks 24 weeks No RBV RBV No RBV RBV All patients 26/28 (93%) 51/54 (94%) 30/31 (97%) 47/50 (94%) GT1A Q80K (+) 8/9 (89%) 15/17 (88%) 7/8 (88%) 19/20 (95%) GT 1A Q80K (-) 11/12 (92%) 25/26 (96%) 16/16 (100%) 18/20 (90%) GT 1B 7/7 (100%) 11/11 (100%) 7/7 (100%) 10/10 (100%) E Lawitz et al. Lancet 2014; 384: Copyright 2015 American College of Gastroenterology 3

4 SOFOSBUVIR/SIMEPREVIR NO RBV ARMS Weeks E Lawitz et al. Lancet 2014; 384: SIMEPREVIR ADVERSE EVENTS Rash especially with sun exposure Itching associated with the rash Elevation in indirect bilirubin Grade 1: ( ) 27% Grade 2: ( ) 18% Grade 3: ( ) 4% Worse in patients with cirrhosis and elevated TBILI No greater anemia compared to PEGINF/RBV Copyright 2015 American College of Gastroenterology 4

5 SOFOSBUVIR/LEDIPASVIR TREATMENT OF GENOTYPE 1 SOF/LDV + RBV SOF/LDV SOF/LDV + RBV SOF/LDV SOF/LDV + RBV SOF/LDV Treatment Naïve N=647 No cirrhosis Treatment naïve N=865 Prior PEGINF/RBV Failure N= Weeks of Treatment SOFOSBUVIR/LEDIPASVIR GT 1 TREATMENT NAIVE Ribavirin: K Kowdley et al. N Engl J Med. 2014; 370: N Afdhal et al. N Engl J Med. 2104; 370: Copyright 2015 American College of Gastroenterology 5

6 SOFOSBUVIR/LEDIPASVIR GT 1 TREATMENT NAIVE SVR RELAPSE Weeks of Treatment: K Kowdley et al. N Engl J Med. 2014; 370: SOFOSBUVIR/LEDIPASVIR GT1 TREATMENT NAÏVE: CIRRHOSIS Cirrhosis: RBV 12 WEEKS N Afdhal et al. N Engl J Med. 2014; 370: RBV 24 WEEKS Copyright 2015 American College of Gastroenterology 6

7 SOFOSBUVIR/LEDIPASVIR GT1 PRIOR TREATMENT FAILURE Ribavirin: N Afdhal et al. N Engl J Med. 2014; 370: SOFOSBUVIR/LEDIPASVIR GT1 PRIOR TREATMENT FAILURE Prior Treatment: N Afdhal et al. N Engl J Med. 2014; 370: Copyright 2015 American College of Gastroenterology 7

8 SOFOSBUVIR/LEDIPASVIR GT1 PRIOR TREATMENT CIRRHOSIS Cirrhosis: RBV 12 WEEKS N Afdhal et al. N Engl J Med. 2014; 370: RBV 24 WEEKS SOFOSBUVIR+LEDIPASVIR SIDE EFFECTS Placebo SOF+RBV SOF+LDV Stop due to AE 4% 2% <1% SAE 3% 5% <1% Fatigue 24% 44% 21% Nausea 18% 22% 7% Headache 20% 21% 14% Rash 8% 9% 1% Arthralgia 1% 8% 4% Cough 3% 5% 1% Anemia 0% 13% 1% IM Jacobson et al. N Engl J Med 2013; 368: K Kowdley et al. N Engl J Med. 2014; 370: Copyright 2015 American College of Gastroenterology 8

9 PARITAPREVIR/r/OMBITASVIR/DASABUVIR GENOTYPE 1 PTV/rtv/OBV/DBV/RBV Placebo PTV/rtv/OBV/DBV/RBV Placebo PTV/rtv/OBV/DBV/RBV PTV/rtv/OBV/DBV PTV/rtv/OBV/DBV/RBV PTV/rtv/OBV/DBV/RBV Treatment Naive N = 631 Treatment Experienced N = 394 Treatment naïve No Cirrhosis N = 419 Cirrhosis N = Weeks of Treatment PRV/rtv/OBV/DSV GENOTYPE 1 NO CIRRHOSIS Ribavirin: PEGINF/RBV J Feld et al. N Engl J Med. 2104; 370: S Zeuzem et al. N Engl J Med 2014; 370: P Ferenci et al. N Engl J Med 2014; 370; Copyright 2015 American College of Gastroenterology 9

10 PRV/rtv/OBV/DSV GENOTYPE 1 NO CIRRHOSIS Ribavirin: GENOTYPE P Ferenci et al. N Engl J Med 2014; 370; PRV/rtv/OBV/DSV/RBV GENOTYPE 1 NO CIRRHOSIS S Zeuzem et al. N Engl J Med 2014; 370: PRIOR TREATMENT WITH PEGINF/RVN Copyright 2015 American College of Gastroenterology 10

11 PRV/rtv/OBV/DSV/RBV GENOTYPE 1 CIRRHOSIS Weeks of Treatment: PRIOR TREATMENT RESPONSE F Poordad et al. N Engl J Med. 2104; 370: PRV/rtv/OBS/DSV/RBV GENOTYPE 1 CIRRHOSIS Weeks of Treatment: GENOTYPE F Poordad et al. N Engl J Med. 2104; 370: Copyright 2015 American College of Gastroenterology 11

12 PTV/rtv/OBV/DSV/RBV SIDE EFFECTS Placebo PTV/rtv OBV/DSV PTV/rtv OBV/DSV RBV PTV/rtv OBV/DSV RBV No Cirrhosis Cirrhosis Stop due to AE 1% 2% 1% 2% Fatigue 28% 29% 35% 39% Headache 27% 25% 33% 29% Itching 4% 6% 17% 19% Rash 6% 0% 11% 13% Anemia 0% 0% 6% 9% J Feld et al. N Engl J Med. 2104; 370: S Zeuzem et al. N Engl J Med 2014; 370: P Ferenci et al. N Engl J Med 2014; 370; HCV TREATMENT SELECTED DRUG INTERACTIONS LDV+SOF PRV/rtv+OBV+DSV SOF+SMV Antiseizure Carbamazapine, Phenytoin, Phenobarbitol Statins Antihyperlipidemic Rosuvastatin Lovostatin, Simvistatin Gemfibrozil Herbals St Johns Wart St Johns Wart St Johns Wart HIV Some Efavirenz Many Antimicrobial Rifampin Rifampin Rifampin Erythromycin Clarithromycin Antifungal Voriconazole Ketoconazole Fluconazole Contraceptives Ethinyl estradiol Immune suppression Tacrolimus Cyclosporin Cyclosporin Cardiac Amiodarone PPI High dose Copyright 2015 American College of Gastroenterology 12

13 SUMMARY FOR GENOTYPE 1 FDA RECOMMENDATIONS LDV+SOF PRV/rtv+OBV+DSV SOF+SMV NAME Harvoni Veikira Ribavirin Not needed Sometimes needed Not needed Prior Treatment PEGINF + PI PEGINF PEGINF No Cirrhosis: Treatment Naïve: HCV RNA < 6M IU/ml Treatment Naïve or Prior Treatment: 8 weeks 12 weeks 12 weeks GT1A 12 weeks w/rbv GT1B 12 weeks No RBV Cirrhosis: 24 weeks Treatment Naïve 12 weeks Treatment Experienced 24 weeks GT1A 12 weeks w/rbv GT1B 24 weeks w/rbv GRAZOPREVIR/ELBASVIR GENOTYPE 1 GZR/EBR Placebo GZR/EBR PGZR/EBR/RBV GZR/EBR GZR/EBR/RBV GBR/EBR/RBV Treatment Naive N = 421 Treatment Experienced PEGINF/RBV N = 420 DAA/PEGINF/RBV N = Weeks of Treatment Copyright 2015 American College of Gastroenterology 13

14 GRAZOPREVIR/ELBASVIR GENOTYPE 1: TREATMENT NAIVE CIRRHOSIS S Zeuzem et al. EASL 2015 GRAZOPREVIR/ELBASVIR GENOTYPE 1: PRIOR PEGINF/RBV Weeks of Treatment: CIRRHOSIS P Kwo et al. EASL 2015 Copyright 2015 American College of Gastroenterology 14

15 TREATMENT FAILURES GENOTYPE 1 Very UNCOMMON up to 5% Higher in patients with cirrhosis Especially in advanced cirrhosis (Child class B-C) What to do for patients who failed DAA: Assess for non-compliance Resistance to NS5A Most commonly resistance is to NS5A Resistance to sofosbuvir is very rare SOF-SMV + RBV 12 vs 24 weeks? HCV GENOTYPE DISTRIBUTION Liver Institute of Virginia HCV Database 2015 Copyright 2015 American College of Gastroenterology 15

16 GENOTYPE 3 SOFOSBUVIR Cirrhosis: SOFOSBUVIR+RBV E Lawitz et al. AASLD 2013 S Zeuzem et al. AASLD 2013 IM Jacobson et al. N Engl J Med 2013; 368: SOF+RBV + PEGINF DACLATASVIR/SOFOSBUVIR GENOTYPE 3 Naïve = 101 Prior PEGINF/RBV = 51 Null response: 14% Relapse: 61% Cirrhosis = 19-25% All patients treated 12 weeks PRIOR TX CIRRHOSIS K Kowdley et al. EASL 2015 Copyright 2015 American College of Gastroenterology 16

17 LDV or DCV/SOFOSBUVIR GENOTYPE 3 G Foster et al. EASL 2015 RBV RBV SOF DCV/SOF+RBV TREATMENT OF HCV SUMMARY Genotype 1 Harvoni for 8, 12 or 24 weeks Viekira Pak for 12 or 24 weeks with RBV for GT1A and cirrhosis Sofosbuvir + Simeprevir 12 or 24 weeks 2 Sofosbuvir + RBV 12 weeks 3 Sofosbuvir + RBV for 24 weeks Sofosbuvir + RBV + PEGINF for 12 weeks* Sofosbuvir + Daclatasvir for weeks** 4 Harvonir for 12 weeks Viekira Pak + RBV for 12 weeks 5 Sofosbuvir + PEGINF/RBV 6 Sofosbuvir + PEGINF/RBV Copyright 2015 American College of Gastroenterology 17