Treating HCV Prior to Liver Transplantation. What Are the Treatment Options? Xavier Forns Liver Unit Hospital Clinic, CIBEREHD, IDIBAPS Barcelona

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1 Treating HCV Prior to Liver Transplantation What Are the Treatment Options? Xavier Forns Liver Unit Hospital Clinic, CIBEREHD, IDIBAPS Barcelona

2 Disclosures Unrestricted Grant Support: Janssen and Abbvie Advisor: Gilead, Jansen and Abbvie

3 Treatment options in HCV-infected patients awaiting LT Which drug regimens are safe and efficacious? 1. Compensated cirrhosis (HCC) 2. Decompensated cirrhosis

4 Treatment options in HCV-infected patients awaiting LT Which drug regimens are safe and efficacious? 1. Compensated cirrhosis (HCC) 2. Decompensated cirrhosis

5 Safety and efficacy of DAA in decompensated cirrhosis Protease Inhibitors Simeprevir Paritaprevir Grazoprevir Membraneous Web NS5A inhibitors Daclatasvir Ledipasvir Ombitasvir Elbasvir Velpatasvir NS5B polymerase inhibitors Sofosbuvir (NI) Dasabuvir (NNI) From Bartenschlager et al. Nature Reviews 13

6 Sulkowski M Gastroenterolgy 15, Afdhal N NEJM 14, Bourlière M Lancet Infect Dis 15, Poordad F NEJM 14, Jacobson I AASLD 15, Feld J NEJM 15 Safety and efficacy of DAA in G1 (4) compensated cirrhosis 92% 94% 94% 99% 81% 6 SVR12 45/52 42/47 * 22/26 24/25 19/22 /23 SOF+SMV SOF+LDV+RBV P/r+O+D (+RBV) GZV+EBV (+RBV) SOF+VEL * The combination of SOF+DAC+RBV can also be used in G1 (G4) patients with cirrhosis

7 Safety and efficacy of DAA in G1 (4) compensated cirrhosis 6 SVR12 81% 45/52 42/47 SOF+SMV 96% 92% 99% Real world data 94% Large cohort of cirrhotics (n=491) Nearly half (45%) history of previous decompensation Most patients treated without RBV Similar results in OPTIMIST-2 (SOF+SMV no RBV in cirrhosis) Real world data (Spanish Cohort) 22/26 24/25 19/22 /23 Large cohort of cirrhotics (n=946), most G1b SVR12: 91% Sulkowski M Gastroenterology 15, Lawitz E Hepatology 15, Mariño Z EASL 16

8 Safety and efficacy of DAA in G1 (4) compensated cirrhosis 6 SVR12 92% 45/52 42/47 SOF+LDV+RBV SIRIUS French Study Cirrhotics who failed PI-based regimen (n=155) Randomized to 12 weeks with RBV vs 24 weeks without RBV 6 22/26 24/25 19/22 /23 SVR12 96% 97% SOF/LDV+ RBV (12w) SOF/LDV (24w) Afdhal N NEJM 14, Bourlière M Lancet Infect Dis 15

9 Safety and efficacy of DAA in G1 (4) compensated cirrhosis SVR % 45/52 42/47 P/r+O+D+RBV Turquoise III 6 cirrhotics G1b Naive or Experienced P/r+O+D 22/26 24/25 19/22 /23 6 SVR12 % P/r+O+D Poordad FJ NEJM 14, Feld J Hepatol 16

10 Safety and efficacy of DAA in G1 (4) compensated cirrhosis SVR % Lower response rates in G1a with baseline NS5A RAVs: Add RBV and extend to 16 weeks 45/52 42/47 GZV+EBV (+RBV) 22/26 24/25 19/22 /23 Zeuzem S Ann Intern Med 15, Lawitz E Lancet 15, Jacobson I AALSD 15

11 Safety and efficacy of DAA in G1 (4) compensated cirrhosis SVR % 1 of 121 cirrhotics achieved SVR12 72/73 G1 infected cirrhotics achieved SVR12 The remaining patients were G2, 4, 5 or 6 45/52 42/47 SOF+VEL 22/26 24/25 19/22 /23 Feld J NEJM 15

12 Safety and efficacy of DAA in G3 compensated cirrhosis 79% 88% 86% 91% 6 SVR12 45/52 42/47 SOF+RBV 24w 22/26 24/25 PR+SOF 12w 19/22 /23 SOF+DAC+RBV (12-16w) * SOF+VEL * SOF+DAC for 24 w. (no RBV) obtains similar SVR12 rates (French CUP) Foster GH Gastroenterology 15, Leroy V Hepatology 16, Hezode C AALSD 15, Foster GH NEJM 15

13 DAA in patients with Hepatocellular carcinoma (HCC) 58 patients with treated HCC (BCLC and A) on complete response, who underwent DAA therapy. Median time between HCC treatment and DAA initiation: 11 m (P ) Median time between last radiologic confirmation of complete response and DAA initiation: 1.7 m (P ) Tumor recurrence: 16 (27,6%) patients. Median follow-up after DAA therapy 3.5 m (1-8) Recurrence rate is significantly higher than the expected based on previous studies Reig M and Mariño Z J Hepatol 16

14 Treatment options in HCV-infected patients awaiting LT Which drug regimens are safe and efficacious in this group? 1. Compensated cirrhosis (HCC) 2. Decompensated cirrhosis

15 Safety and efficacy of DAA in decompensated cirrhosis Protease Inhibitors Simeprevir Paritaprevir Grazoprevir Membraneous Web NS5A inhibitors Daclatasvir Ledipasvir Ombitasvir Elbasvir Velpatasvir NS5B polymerase inhibitors Sofosbuvir (NI) Dasabuvir (NNI) Bartenschlager R Nature Reviews 13

16 Safety and efficacy of DAA in decompensated cirrhosis Protease Inhibitors Simeprevir Paritaprevir Grazoprevir? Membraneous Web NS5A inhibitors Daclatasvir Ledipasvir Ombitasvir Elbasvir? Velpatasvir NS5B polymerase inhibitors Sofosbuvir (NI) Dasabuvir (NNI) Bartenschlager R Nature Reviews 13

17 Safety and efficacy of DAA in decompensated cirrhosis SOF/LDV + RBV in G1 and G4 patients with decompensated cirrhosis 12 weeks 24 weeks 87% 89% 87% 89% 86% 87% Severe Adverse Events * 6 45/52 42/47 Overall 22/26 24/25 19/22 /23 CPT B CPT C 12w 24w CP-B 1% 34% CP-C 26% 42% Overall safety is good. Cases of severe bradycardia (if combined with amiodarone), a few cases of lactic acidosis and pulmonary hypertension have been reported postmarketing. Few safety data if CP > 12 Charlton M Gastroenterology 15

18 Safety and efficacy of DAA in decompensated cirrhosis SOF/LDV + RBV in G1 and G4 patients with decompensated cirrhosis 12 weeks 83% 86% 96% 84% 81% 76% 24 weeks Severe Adverse Events 6 39/47 43/5 Overall 22/26 24/25 17/21 19/25 CPT B CPT C 12w 24w CP-B 11% 21% CP-C 52% 35% Overall safety is good. Cases of severe bradycardia (if combined with amiodarone), a few cases of lactic acidosis and pulmonary hypertension have been reported postmarketing. Few safety data if CP > 12 Manns M Lancet Infectious Dis 16

19 Safety and efficacy of DAA in decompensated cirrhosis Patients with decompensated cirrhosis (CP 7) NHS England Expanded Access Program Treatment duration 12 w; most patients with RBV SVR % 92% 85% 61% Overall SOF/LDV SOF/DAC SOF/LDV G1 G3 73% 381/467 17/185 39/46 41/67 91/125 SOF/DAC SVR rates similar than in ALLY-1 study in Child B/C (82%) Foster GH J Hepatol 16, Poordad F Hepatology 16

20 Safety and efficacy of DAA in decompensated cirrhosis SOF and Velpatasvir (+/- RBV) in G1-G6 Child B decompensated cirrhosis SOF/VEL 12 wk SOF/VEL+RBV 12 wk SOF/VEL 24 wk SVR12 (%) / 9 82/ 87 77/ 9 6/ 68 65/ 68 65/ 71 Overall G1 G3 G2, 4, and 6 7/ 14 11/ 13 6/ 12 G2 4/4 G4 4/4 G2 4/4 G4 2/2 G2 3/4 G4 2/2 G6 1/1 Curry MP NEJM 15

21 Safety and efficacy of DAA in decompensated cirrhosis SOF and Velpatasvir (+/- RBV) in G1-G6 Child B decompensated cirrhosis SOF/VEL (12w) SOF/VEL+RBV (12 w) SOF/VEL (24 w) Discontinuation 1 (1) 4 (5) 4 (4) Deaths* 3 (3) 3 (3) 3 (3) SAEs 17 (19) 14 (16) 16 (18) Hb < 1 g/dl 7 (8) (23) 8 (9) Hepatic Encephalopathy 2 (2) 2 (2) 1 (1) Sepsis 1 (1) 3 (3) 1 (1) GI hemorrhage 3 (3) Sepsis and liver failure were the most common causes of death Curry MP NEJM 15

22 DDI in HCV-infected liver transplant recipients Drug Cefotaxime Seguril B-blockers Ca-antagonist Amiodarone Sof/LDV Simeprevir Daclatasvir P/r/O/D GZV/EBV Drug Atorvastatin Acenocumarol Metformin Fluconazol Omeprazol Sof/LDV Simeprevir Daclatasvir P/r/O/D GZV/EBV No interaction Potential interaction Drugs should not be coadministered

23 Treatment regimens in patients awaiting LT G1 and G4* SOF/LDV + RBV 12 w vs SOF/LDV 24 w. SOF/DAC+ RBV (12-24 weeks) SOF/VEL (12 weeks), consider RBV in decompensated patients G3 Sofosbuvir/Daclatasvir+ RBV (12-24 weeks) Sofosbuvir/Velpatasvir + RBV (12 weeks) * 3D or GZV/EBV (G1b) and 3D+RBV or GZV/EBV+RBV (G1a) in compensated cirrhosis awaiting LT for HCC

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