Treating HCV After Liver Transplantation: What are the Treatment Options?

Transcription

1 4 th OPTIMIZE WORKSHOP USING DAAs IN PATIENTS WITH CIRRHOSIS AND LIVER RECIPIENTS Treating HCV After Liver Transplantation: What are the Treatment Options? Maria Carlota Londoño, MD Liver Unit, Hospital Clínic Barcelona

2 Agenda Antiviral options. Treatment of patients with mild hepatitis C recurrence or compensated cirrhosis. Treatment of patients with decompensated cirrhosis after liver transplant. Treatment of patients with fibrosing cholestatic hepatitis. Treatment of patients with DAA failures.

3 Hepatitis C and Liver Transplantation Patient survival Years after transplantation Prieto et al, Hepatology 1999

4 Direct-Antiviral Agents DAA ADVANCED LIVER DISEASE CP-B CP-C ESRD (GFR<3) SOF OK OK Not recommended LDV/SOF OK OK Not recommended SMV Caution Not recommended OK OK OK CsA Not recommended DCV OK OK OK OK OK 3D/2D Not recommended Not recommended GZV/EBV Caution Not recommended VEL/SOF OK OK Not recommended OK OK Dose adjustment Not recommended OK DDI Tac OK OK OK Dose adjustment OK OK

5 Agenda Antiviral options. Treatment of patients with mild hepatitis C recurrence or compensated cirrhosis. Treatment of patients with decompensated cirrhosis after liver transplant. Treatment of patients with fibrosing cholestatic hepatitis. Treatment of patients with DAA failures.

6 Mild Fibrosis-Compensated Cirrhosis SIMEPREVIR + SOFOSBUVIR HCV-RNA undetectable (%) weeks 119 w/o RBV 58% G1a 8% PI failure 12 weeks 98 w/o RBV 6% G1a 12% PI failure 37 F3-F or 24 weeks 81% G1 14% PI failure or 24 weeks Randomized w or w/o RBV Time 4.5y / 151 5/ 54 83/ 97 47/ 57 83/ 97 12/ 12 32/ 35 43/ 53 25/ 27 HCV-TARGET Mayo Clinic Canadian GALAXY Overall F-F2 F3-F4 G1a-F3/4 Brown et al. Liver Transpl 216, Pungpapong et al. Hepatology 215, Faisal et al Transplantation 216, O Leary et al, EASL 216

7 Mild Fibrosis-Compensated Cirrhosis ALLY-1: DACLATASVIR + SOFOSBUVIR 12 F=6/ F1=1/ F2=7/ F3=13/ F4=16 Starting RBV dose 6 mg/d HCV-RNA undetectable (%) /53 3/31 9/1 1/11 Overall G1a G1b G3 Poordad, Hepatology 216

8 Mild Fibrosis-Compensated Cirrhosis CORAL-1: OMBITASVIR + PARITAPREVIR/r + DASABUVIR + RIBAVIRIN Mild-Moderate fibrosis (F-F2) n=34 G1a 85% HCV-RNA undetectable (%) Anemia 17% 8 Rejection 6 Renal Impairement 4 Early Discontinuation 3% 2 SAEs 6% Deaths w4 EOT SVR4 SVR12 CNI adjustment (Tac.5mg/w and CyA 1/5 of previous dose) Kwo P, NEJM 214

9 Mild Fibrosis-Compensated Cirrhosis CORAL-1 (Cohort 2): OMBITASVIR + PARITAPREVIR/r + DASABUVIR ± RIBAVIRIN Mild-Moderate fibrosis (F-F3) n=4 W W 12 W 24 W 48 W 72 OMV/PRV/r/DSV + RBV G1a or G1b non-responders OMV/PRV/r/DSV G1b naïve or relapsers SVR12 SVR12 Variable RBV (n=27) No RBV (n=13) Genotype 1a/1b 21 (78%)/6 (22%) 13 (%) Post-LT treatment Naïve Relapser Non-responder 15 (56%) 12(44%) 8 (62%) 5 (38%) Fibrosis F-1/F2/F3 16(62%)/ 9(35%) / 1(3%) 8/62%)/2 (15%)/3(23%) Tac/CsA 21 (78%)/6 (22%) 5 (38%)/8 (62%) Mantry P, AASLD 215

10 Mild Fibrosis-Compensated Cirrhosis CORAL-1 (Cohort 2): OMBITASVIR + PARITAPREVIR/r + DASABUVIR ± RIBAVIRIN Mild-Moderate fibrosis (F-F3) n=4 HCV-RNA undetectable (%) /4 26/27 13/13 Overall RBV No RBV Anemia 3% of patients with RBV Rejection 1 Renal Impairement Hyperbilirrubinemia 1 SAEs 1 Deaths Mantry P, AASLD 215

11 Mild Fibrosis-Compensated Cirrhosis SOLAR 1 AND SOLAR 2: LEDIPASVIR/SOFOSBUVIR + RIBAVIRIN W W 12 W 24 W 48 W 72 SOF/LDV+ RBV SVR12 SOF/LDV + RBV SVR12 Genotype 1 or 4, F-F3, CP-A, RBV adjusted by weight Variable F-F3/CP-A (n=33) Genotype 1a/1b 19 (6%)/111 (34%) Genotype 4 22 (7%) Previous treatment 27 (82%) Cirrhosis 118 (36%) Gane E. AASLD 215, Charlon M. Gastroenterology 215, Manns M. Lancet 216

12 Mild Fibrosis-Compensated Cirrhosis SOLAR 1 AND SOLAR 2: LEDIPASVIR/SOFOSBUVIR + RIBAVIRIN Weight-based RBV HCV-RNA undetectable (%) /17 14/15 58/6 56/58 F-F3 CP-A 12 weeks 24 weeks Gane E. AASLD 215, Charlon M. Gastroenterology 215, Manns M. Lancet 216

13 Agenda Antiviral options. Treatment of patients with mild hepatitis C recurrence or compensated cirrhosis. Treatment of patients with decompensated cirrhosis after liver transplant. Treatment of patients with fibrosing cholestatic hepatitis. Treatment of patients with DAA failures.

14 Decompensated Cirrhosis SOLAR 1 AND SOLAR 2: LEDIPASVIR/SOFOSBUVIR + RIBAVIRIN Starting RBV dose 6mg/d 9 94 HCV-RNA undetectable (%) /48 46/49 4/8 7/ CP-B CP-C 12 weeks 24 weeks Gane E. AASLD 215, Charlon M. Gastroenterology 215, Manns M. Lancet 216

15 Decompensated Cirrhosis DACLATASVIR COMPASSIONATE USE HCV-RNA undetectable (%) DCV+SOF 77 DCV+SMV 18 39% G1a 49% CP-B or CP-C MELD 13 RBV 35% EOT SVR12 DCV+SOF DCV+SMV Fontana R. Liver Transplant 216

16 Agenda Antiviral options. Treatment of patients with mild hepatitis C recurrence or compensated cirrhosis. Treatment of patients with decompensated cirrhosis after liver transplant. Treatment of patients with fibrosing cholestatic hepatitis. Treatment of patients with DAA failures.

17 Fibrosing Cholestatic Hepatitis 96 HCV-RNA undetectable (%) /8 15/15 7/7 4/4 CULPIT: SOF+RBV±PEG CULPIT: DCV+SOF SOLAR 1/2: LDV/SOF+RBV 12W SOLAR 1/2: LDV/SOF+RBV 24W Leroy V. Clin Gastroenterol and Hepatol 215, Forns X. EASL 215, Gane E. AASLD 215

18 Agenda Antiviral options. Treatment of patients with mild hepatitis C recurrence or compensated cirrhosis. Treatment of patients with decompensated cirrhosis after liver transplant. Treatment of patients with fibrosing cholestatic hepatitis. Treatment of patients with DAA failures.

19 DAAs Failures Failed treatment Genotype LDV/SOF 3D 2D SOF+SMV SOF+DCV SOF+SMV 1 or 4 12w+RBV or 24w+RBV if F3 or F4 SOF+DCV or LDV/SOF 1 12w+RBV or 24w+RBV if F3 or F4 12w+RBV or 24w+RBV if F3 or F4 2 or 3 12w+RBV or 24w+RBV if F3 or F4 4 12w+RBV or 24w+RBV if F3 or F4 5 or 6 12w+RBV or 24w+RBV if F3 or F4 3D or 2D 1 or 4 12w+RBV or 24w+RBV if F3 or F4 12w+RBV or 24w+RBV if F3 or F4 12w+RBV or 24w+RBV if F3 or F4 12w+RBV or 24w+RBV if F3 or F4

20 DAAs Failures Deferral of treatment NS5A and NS3-associated RAVs testing - No NS5A RAVs LDV/SOF+RBV for 24 w - NS5A but no NS3 RAVs SMV+SOF+RBV for 24 w - Both 3D+SOF+RBV or GZV/EBV+SOF+RBV 12 or 24 weeks

21 DAAs Failures FAILURES TO SOF+SMV RETREATMENT WITH LDV/SOF Patients n=34 Average age, years (range) 59 (49 76) 96 Male, n (%) 28 (82) Non-white, n (%) 5 (15) GT 1a, n (%) 24 (71) IL28B CT/TT, n (%) 21 (88) SVR12, % * Metavir F3 F4, n (%) 27 (79) CTP Class B/C, n (%) 11 (32) Post-liver transplant, n (%) 1 (29) Median time since last dose of SMV+SOF, weeks (range) 23 (7 55) 2 25/ 26 Overall 5/ 5 LDV/SOF +RBV 12 weeks Overall LDV/SOF+RBV 12 weeks 2/ 3 LDV/SOF weeks 11/ 11 LDV/SOF +RBV 24 weeks LDV/SOF+RBV 24 weeks 7/ 7 LDV/SOF weeks Pungpapong AASLD 215

22 DAAs Failures FAILURES TO SOF+SMV RETREATMENT WITH LDV/SOF Patients n=31 Male, n (%) 24 (77) Median age, years (range) 58 (44 66) GT 1a, n (%) 29 (93) Compensated cirrhosis, n (%) 15 (48) Decompensated cirrhosis, n (%) 1 (32) Post-liver transplant, n (%) 3 (1) LDV/SOF 12 weeks, n (%) 1 (3) LDV/SOF+RBV 12 weeks, n (%) 11 (35) LDV/SOF 24 weeks, n (%) 16 (52) LDV/SOF+RBV 24 weeks, n (%) 3 (1) SVR12, % Overall 91 11/13 1/12 1/11 Cirrhotic patients 2 patients did not achieve SVR due to relapse 31% reported no AEs Most common AEs: fatigue, headache, insomnia, nausea, diarrhea 1 episode of decompensation with bleeding esophageal varices during treatment (patient on LDV/SOF 24 weeks who achieved SVR12) Gonzalez AASLD 215

23 DAAs Failures FAILURES TO LDV/SOF RETREATMENT WITH LDV/SOF SVR12 (%) /22 14/19 24/3 5/11 11/11 18/3 No Yes Yes 8 wks 12 wks No Yes Yes Cirrhosis Prior Treatment Baseline NS5A RAVs Duration Lawitz et al EASL 215

24 DAAs Failures 3D FAILURES RETREATMENT WITH 3D+SOF W W 12 W 24 W 48 W 72 n=14 G1a 3D+RBV+SOF SVR12 n=6 G1a 3D+RBV+SOF SVR12 n=2 G1b 3D+SOF SVR12 HCV-RNA undetectable (%) G1a 3D+RBv+SOF 12 G1a 3D+RBv+SOF 24 G1b 3D+RBV+SOF Poordad F. AASLD 215

25 DAAs Failures FAILURES TO GZV/EBV+SOF RETREATMENT WITH GZV/EBV+SOF+RBV n=23, 12 weeks, with RBV HCV-RNA undetectable (%) All Yes No 4 weeks 6-8 weeks Yes No Cirrhosis Duration RAVs Lawitz. AASLD 215

26 Conclusions After liver transplantation, antiviral therapy administered in patients with mild fibrosis stages achieve higher response rates as compared to patients with cirrhosis and decompensation. The election of antiviral regimen should be based on patients characteristics (liver function, immunosuppression, renal function). The need of RBV, the optimal treatment duration and the treatment of DAA failures need further studies.