DAAs in the era of decompensated liver disease. Piero L. Almasio University of Palermo

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1 DAAs in the era of decompensated liver disease Piero L. Almasio University of Palermo

2 HCV therapy in the era of interferon based therapy Priority Compensated cirrhosis Decompensated cirrhosis Efficacy Tolerability

3 Severity of Disease Increases Need for HCV Therapy but Also Impairs Response May not need immediate treatment BUT Easier to treat High likelihood of response Greater need for treatment BUT Response to current IFN-based therapy may be impaired Mild disease Advanced disease/ cirrhosis

4 Standard of Care (PEG IFN + RBV) in Decompensated Cirrhosis HCV-RNA Neg Author N Rx EOT SVR Iacobellis 66 Peg/RBV 49% 20% Forns 51 Peg/RBV 29% 20% Tekin 20 Peg/RBV 45% 30% Annichiarico 15 Peg/RBV 47% 20% Everson 124 IFN/RBV 46% 24% Forns 30 IFN/RBV 30% 20% Thomas 20 IFN 60% 20% Amarapukar 18 IFN/RBV 61% 38% Crippin 15 IFN/RBV 33% 0% TOTALS % 24% Mar$nez-Camacho A, Fortune BE, Everson GT. Trea$ng HCV Prior to Liver Transplanta$on. In Chronic Hepa$$s C: Advances in Treatment, Promise for the Future. ML Shiffman (ed) Springer Science-Business. NY.

5 CumulaPve survival aqer IFN and RBV treatment in papents with decompensated cirrhosis 1 Cumulative probability of survival 0,9 0,8 0,7 0,6 0,5 p= 0.07 SVR NonR Ctrl months Iacobellis A. et al, J Hepatol 2007

6 Safety and tolerability Deaths and AEs in the first 6 months of follow-up according to treatment or not OR 2.4 ( ) OR 0.7 OR 0.6 OR 2.9 OR 0.6 OR 0.9 OR 1.2 OR 1.9 Iacobellis A, et al. J Hepatol 2007

7 1 st Generation DAA

8 DAA in PNC-HCV G1 Cirrhosis awaiting LT Verna EC et al. High Early Response Rates with Protease Inhibitor Triple Therapy in a Multicenter Cohort of HCV-Infected Patients Awaiting Liver Transplantation. Triple therapy (PR + TPV or BOC) Mean duration 14 w Mean (range) initial UNOS MELD 9 (7-31) HCC 45% History of ascites or HE 20% N. Completed (4w) - (12 w) 90-70% Time from PI to <LOD 28 days Undetectable HCV-RNA W4 61% W12 86%

9 Verna EC et al. High Early Response Rates with Protease Inhibitor Triple Therapy in a Multicenter Cohort of HCV-Infected Patients Awaiting Liver Transplantation.

10 DAA in PNC-HCV G1 Cirrhosis awaiting LT Verna EC et al. High Early Response Rates with Protease Inhibitor Triple Therapy in a Multicenter Cohort of HCV-Infected Patients Awaiting Liver Transplantation. Triple therapy (PR + TPV or BOC) Time from PI to <LOD 28 days Breakthrough 0 1 NR Discontinuation 1 Rash 1 Neuritis 2 Decompensation (10%) 5 (25%)

11 HCV therapy in the era of interferon-free therapy

12 The paradox of new anp HCV drugs development Studies mainly in easy to treat populapons with the lower urgent need: HCV G1b Naives Non cirrho3cs HIV- Few studies in difficult to treat populapons with the most urgent need: Transplanted pa3ents Decompensated and compensated cirrhosis Null responders HCV G1a HIV+ Marke3ng of new an3 HCV drugs with high prices à cost effec3veness only in sickest pa3ents without enough data from phase III studies

13 Hepa-C Registry: TreaPng HCV in Advanced Liver Disease Retrospec3ve, observa3onal analysis of pts with cirrhosis who were not LT candidates or who were listed for LT but did not receive LT during or for 12 wks ajer HCV treatment CP A (n = 564; 7% with HCC) CP B/C (n = 175; 10% with HCC) Pts treated for 12 or 24 wks with IFN-free regimens, with or without RBV: SMV + SOF (45%) DCV + SOF (22%) LDV/SOF (16%) OBV/PTV/RTV + DSV (10%) Fernández-Carrillo C, et al. EASL Abstract GS01.

14 Hepa-C Registry: SVR, Safety, and Deaths With HCV Tx in Advanced Liver Disease SVR12 rate lower for CP B/C vs CP A (78% vs 94%; P <.001) SAE incidence higher for CP B/C vs CP A (50% vs 11.7%; P <.001) Death rate higher for CP B/C vs CP A (6.4 % vs 0.9%; P <.001) Predictor CP A vs B/ C MELD MELD 18 Platelets Platelets < 100,000 OR (95% CI) 2.16 ( ) 1.31 ( ) SAE Multiv. P Value.004 <.001 Death (On Study) OR (95% CI) 1.73 ( ) 1.34 ( ) Multiv. P Value.034 <.001 NR.171 NR < ( ) 2.94 ( ) ( ).151 <.001 NR Kaplan-Meier Survival Estimates 99% 99% 97% 92% 78% Time (days) 68% MELD < 18 MELD 18 P < Fernández-Carrillo C, et al. EASL Abstract GS01.

15 UK Expanded Access: SOF + (DCV or LDV) ± RBV in Decompensated Cirrhosis HCV Research UK Database of pts with decompensated cirrhosis Enrolled at/ajer EAP start and treated: n = 409 SVR12: 80.4% (329/409) Enrolled 6 mos before EAP start: n = 261 Subsequently treated ajer EAP start: n = 177 Lower rate of liver events in treated vs untreated pts Adverse Events in First 6 Mos, % Treated (n = 409) Untreated (n = 261) Total * Death DecompensaPon * New HCC Sepsis New OLT Hospital admission MELD worsening by > 2 points * *P <.05 for treated vs untreated. Cheung MCM, et al. EASL Abstract PS097.

16 SOF + (DCV or LDV) ± RBV in Decomp. Cirrhosis: AEs and Survival With SVR Survival (%) In pts with SVR, AEs most frequent during therapy and decreased with Pme HCV treatment benefit limited to pts with SVR Treated with SVR Treated without SVR Untreated 3 6 Mos AE-Free Survival at 15 Mos (%) AE-free survival significantly greater for CP B vs CP C n = 0 P < < BL MELD NS A B C BL CP P <.05 Cheung MCM, et al. EASL Abstract PS097.

17 HCC Risk Persists AQer DAA Therapy in Pts With HCV-Related Cirrhosis Retrospec3ve analysis of 344 HCV-infected pts with CP A or B cirrhosis treated with DAAs (SVR: 89%) Pts followed for wks ajer treatment comple3on No HCC at baseline, but previous HCC permiged Overall HCC incidence ajer DAA therapy: 7.6% In pts without previous HCC: 3.2% In pts with previous HCC: 29.0% More advanced liver disease and previous HCC significant risk factors for HCC aqer DAAs Factor No HCC (n = 318) HCC (n = 26) P Value CP class B, % Mean liver s3ffness, kpa Liver s3ffness, n.005 kpa < kpa > Mean platelets, x 1000/ mm Previous HCC, n.0001 Yes No Buonfiglioli F, et al. EASL Abstract LBP506.

18 Phase 2 Treatment Naïve and Treatment Experienced Ledipasvir-Sofosbuvir + RBV in HCV GT 1,4 SOLAR-1 (Decompensated Cirrhosis) Flamm SL, al. 65 th AASLD. 2014: Abstract 239.

19 Ledipasvir-Sofosbuvir + Ribavirin in HCV GT 1,4 SOLAR-1 (Decompensated Cirrhosis): Features SOLAR-1 (Decompensated Cirrhosis): Design Design: Phase 2, randomized, prospective, multicenter trial, using fixeddose combination of ledipasvir-sofosbuvir plus ribavirin for 12 or 24 weeks in treatment-naïve and treatment-experienced patients with GT1 or 4 HCV and decompensated liver disease who are awaiting liver transplantation Setting: multicenter in United States Entry Criteria - Adults with Chronic HCV Genotype 1 or 4 (n=108) - Treatment-naïve or treatment experienced - Child-Pugh-Turcotte Class B (score 7-9) and Class C (score 10-12) - Total bilirubin 10 mg/dl; Creatinine clearance 40 ml/min - Hemoglobin 10 g/dl; Platelet count > 30,000/mm 3 - Excluded if history of organ transplant or hepatocellular carcinoma Primary End-Point: SVR12 Source: Flamm SL, al. 65 th AASLD. 2014: Abstract 239.

20 Ledipasvir-Sofosbuvir + Ribavirin in HCV GT 1,4 SOLAR-1 (Decompensated Cirrhosis): Features Week n = 53 LDV-SOF +RBV SVR12 GT-1,4 CPT Class B & C n = 55 LDV-SOF + RBV SVR12 Abbreviations: LDV= ledipasvir; SOF = sofosbuvir; RBV = ribavirin Drug N Dosing =14 Ledipasvir-sofosbuvir (90/400 mg): fixed dose combination; one pill once daily Ribavirin: started at 600 mg/day and then escalated as tolerated up to maximum of 1200 mg/day Source: Flamm SL, al. 65 th AASLD. 2014: Abstract 239.

21 Ledipasvir-Sofosbuvir + Ribavirin in HCV GT 1,4 SOLAR-1 (Decompensated Cirrhosis): Features CTP B CTP C Baseline CharacterisPc 12-Weeks n=30 24-Weeks n=29 12-Weeks n=23 24-Weeks n=26 Median age, years (range) 60 (28-69) 58 (35-69) 58 (41-71) 59 (48-68) Male sex, n (%) 22 (73) 18 (62) 14 (61) 18 (69) White, n (%) 29 (97) 26 (90) 21 (97) 24 (92) BMI 30 kg/m 2, n (%) 10 (33) 10 (34) 13 (57) 9 (35) HCV RNA, log 10 IU/ml (median) IL28B non CC, n (%) 26 (87) 23/28 (82) 17 (74) 19 (73) HCV Genotype 1a, n (%) 19 (63) 22 (76) 15 (65) 18 (69) 4, n (%) 1 (3) 0 2 (9) 0 Prior Treatment 22 (73) 19 (65) 11 (48) 18 (69) Source: Flamm SL, al. 65 th AASLD. 2014: Abstract 239.

22 Ledipasvir-Sofosbuvir + Ribavirin in HCV GT 1,4 SOLAR-1 (Decompensated Cirrhosis): Baseline Liver Status CTP B CTP C Baseline Characteristic 12-Weeks n=30 24-Weeks n=29 12-Weeks n=23 24-Weeks n=26 Meld Score, n (%) <10 6 (20) 8 (28) (70) 16 (55) 16 (70) 13 (50) (10) 5 (17) 7 (30) 12 (46) (4) Median bilirubin, mg/dl (range) 2.0 ( ) 1.4 ( ) 2.9 ( ) 3.8 ( ) Median albumin, g/l (range) 2.9 ( ) 3.0 ( ) 2.6 ( ) 2.6 ( ) Median INR, (range) 1.3 ( ) 1.3 ( ) 1.4 ( ) 1.4 ( Median platelets, x 10 3 µl (range) 88 (36-212) 73 (30-154) 81 (39-177) 71 (32-179) Ascites, n (%) 17 (57) 17 (59) 22 (96) 25 (96) Encephalopathy, n (%) 20 (67) 16 (55) 21 (91) 23 (88) Source: Flamm SL, al. 65 th AASLD. 2014: Abstract 239.

23 Ledipasvir-Sofosbuvir + Ribavirin in HCV GT 1,4 SOLAR-1 (Decompensated Cirrhosis): Features SVR12 Overall and by CPT Class 45/52 42/47 26/30 24/27 19/22 18/20 6 subjects excluded because received transplant while on study: (2 CPT B/24 week; 1 CPT 2/12 week; 3 CPT C/24 week 3 subjects had not reached SVR12 timepoint Source: Flamm SL, al. 65 th AASLD. 2014: Abstract 239.

24 Expert Guidance for HCV Treatment in Pts With Decompensated Cirrhosis AASLD/IDSA [1] Refer to experienced HCV provider (ideally LT center) Avoid IFN, TVR, BOC, SMV, OBV/PTV/ RTV + DSV, EBR/GZR EASL [2] Pa3ents with decompensated (CP B or C) cirrhosis not listed for LT and w/o comorbidi3es that could decrease survival can be treated HCV GT Recommended Regimens HCV GT Recommended Regimens RBV eligible - 12 wks of: RBV eligible LDV/SOF + RBV* or 1, 4, 5, or 6 LDV/SOF + RBV for 12 wks 1 or 4 DCV + SOF + RBV* RBV ineligible - 24 wks of: LDV/SOF or DCV + SOF Previous SOF failure LDV/SOF + RBV* for 24 wks 2 or 3 DCV + SOF + RBV* for 12 wks *Ini3al dose: 600 mg/day, increased as tolerated. 1. AASLD/IDSA. HCV Guidance EASL. HCV Guidelines SOF + RBV for wks All DCV + SOF + RBV for 12 wks RBV ineligible 1, 4, 5, or 6 LDV/SOF for 24 wks All DCV + SOF for 24 wks

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