Treatment of Patients with Decompensated Cirrhosis and Liver Transplant Recipients Paul Y. Kwo, MD, FACG Professor of Medicine Gastroenterology/Hepatology Division Stanford University email pkwo@stanford.edu HCV Management in Decompensated Cirrhosis: Current Therapies ACG 216 Southern Hepatitis School Copyright 216 American College of Gastroenterology Page 1 of 16
Childs Class Dose Adjustments in Cirrhosis PEG IFN alfa 2a, μg/wk PEG IFN alfa 2b, μg/kg/wk Ribavirin Daily A 18 1.5-12 mg/day B No No 6 mg C No No 6 mg Childs Class Sofosbuvir Simeprevir Ledipasvir/ sofosbuvir A 4 mg 15 mg 9 mg/4 mg PTV/OMB/DSB 75/5/12.5 mg + 25 mg B 4 mg No* 9 mg/4 mg No* C 4 mg No 9 mg/4 mg No Daclatasvir 6 mg 6 mg 6 mg Persons with CTP B/C are difficult to treat and the clinical benefit is debated NS3 inhibitors are not recommended and may cause drug-induced liver injury Paritaprevir/r (part of 3D) Grazoprevir (with elbasvir) Simeprevir SOF/NS5As (LDV or DAC) combinations may be used www.hcvguidelines.org ACG 216 Southern Hepatitis School Copyright 216 American College of Gastroenterology Page 2 of 16
LDV/SOF + RBV: Genotype 1 and 4 with Advanced Liver Disease Week Week 12 Week 24 Week 36 LDV/SOF + RBV SVR12 LDV/SOF + RBV SVR12 SOLAR-1 Treatment naïve or experienced CPT Class B CPT Class C Post liver transplantation SOLAR-2: (greater G4 population) Treatment naïve or experienced CPT Class B CPT Class C Post liver transplantation SOLAR-1 and SOLAR-2 Charlton M, et al. Gastroenterology, 215 [epub ahead of print] Reddy RT, et al. Presented at: AASLD; November 7-11, 214; Boston, MA. Abstract 8. Manns M, et al. Presented at: EASL; April 22-26, 215; Vienna, Austria. Abstract G2. LDV/SOF + RBV: SVR12 in Genotype 1 or 4 with Decompensated Cirrhosis Comparable efficacy between SOLAR-1 and SOLAR-2 studies LDV/SOF + RBV 12 weeks LDV/SOF + RBV 24 weeks SVR12 (%) 8 6 4 87 89 86 9 SVR12 (%) 8 6 4 87 96 85 72 2 n/n = 26/ 3 CTP B 24/ 27 19/ 22 CTP C 18/ 2 SOLAR-1: GT 1 and 4 [1.2] 2 n/n = CTP B CTP C AE, adverse event; CTP, Child-Turcotte-Pugh; LDV, ledipasvir; RBV, ribavirin; SAE, serious adverse event; SOF, sofosbuvir. 1. Charlton M, et al. Gastroenterology, 215 [epub ahead of print] 2. Flamm SL, et al. Presented at: AASLD; November 7-11, 214; Boston, MA. Abstract 239. 3. Manns M, et al. Presented at: EASL; April 22-26, 215; Vienna, Austria. Abstract G2. 2/ 23 22/ 23 17/ 2 SOLAR-2: GT 1 [3] 13/ 18 ACG 216 Southern Hepatitis School Copyright 216 American College of Gastroenterology Page 3 of 16
LDV/SOF + RBV: Safety in Advanced Liver Disease Pre OLT Safety Outcome, n (%) Pretransplant CPT B + C (n = 215) Grade 3/4 AE 51 (24) SAE 61 (28) Serious treatment-related AE 5 (2) AE leading to discontinuation of LDV/SOF 9 (4) > 2 patients HCC Sepsis 2 (<1) 2 (<1) Death 1 (5) Liver Transplantation 11 (5) Treatment-related serious adverse events (SAEs) mostly related to RBV No deaths or D/C attributed to treatment with study drug (LDV/SOF) Samuel D, et al. Presented at: EASL; April 22-26, 215; Vienna, Austria. Poster P774. SOLAR-1 and SOLAR-2 LDV/SOF + RBV: Change in MELD Score from Baseline to Follow-up Week 4 in CPT B or C Disease Change in MELD Score 4 2-2 -4-6 -8 Pre/Post-Transplantation (CPT B and C; n = 136)* n = 18 * (8) -1 ** (-17) (-11) *Missing FU-4: n = 24. Manns M, et al. Presented at: EASL; April 22-26, 215; Vienna, Austria. Abstract G2. SOLAR-2 ACG 216 Southern Hepatitis School Copyright 216 American College of Gastroenterology Page 4 of 16
Real-World Efficacy of SOF/SMV ± RBV & SOF/RBV Regimens in Cirrhosis Pts With MELD >1 HCV-Target Network: North America, Germany, Israel SOF + RBV (n = 12) SOF + SMV (n = 117) SOF + SMV + RBV (n = 34) MELD 1-15 MELD 16-21 MELD >21 SVR12 (%) 8 6 4 GT1 Naive 78 6 43 GT 1Exp d 72 68 57 GT 2 GT 3 81 39 55 73 68 63 7 67 2 n/n = 3/ 7 31/ 4 6/ 1 8/ 14 8/ 48/ 14 67 13/ 48/ 19 67 21/ 26 1/ 26 37/ 67 67/ 92 19/ 28 5/ 8 7/ 1 2/ 3 / 1 6/ 6 1/ 1 Reddy RK, et al. Presented at: EASL; April 22-26, 215; Vienna, Austria. Abstract O7. HCV TARGET HCV TARGET: SAEs, Death, Liver Transplantation SOF/RBV N=88 SOF/SMV N=114 SOF/SMV/ RBV N=32 Total N=234 Total patients with SAEs N (%) 27 (31) 8 (7) 9 (26) 44 (17) Hepatic decompensation* 1 (11) 2 (2) 4 (12) 16 (6) Infections 2 (2) 1 (3) 1 (4) Death 2 (2) 1 (3) 3 (1) Unspecified 1 (3) 1 (.4) Hepatic Failure 1 (1) () 1 (.4) Shock 1 (1) 1 (.4) Underwent OLT on treatment 4 (5) 3 (3) 5 (16) 12 (5) *Hepatic encephalopathy, variceal bleeding, hepatic failure, hepatic hydrothorax, bacterial peritonitis Reddy RK, et al. Presented at: EASL; April 22-26, 215; Vienna, Austria. Abstract O7. ACG 216 Southern Hepatitis School Copyright 216 American College of Gastroenterology Page 5 of 16
ALLY-1: SOF + DCV + RBV for 12 Weeks in Patients With Genotype 1 HCV and Cirrhosis SVR12, % Treatment naïve or treatment experienced adults with any HCV genotype DAA failures allowed, except NS5A 76 8 83 8 6 4 2 1a 1b 2 3 4 Genotype Child-Pugh score: A, B, or C MELD scores 8-4 Hepatocellular carcinoma allowed Poordad F, et al. Presented at: EASL; April 22-26, 215; Vienna, Austria. Abstract LO8. SVR12, % 8 6 4 2 All Genotypes 92 94 56 11/12 3/32 9/16 A B C Child-Pugh class ALLY-1 8 SVR12 by Baseline Disease Severity SVR12 by Child-Pugh Class Advanced cirrhosis cohort, all genotypes 92. 94. 95.7 97 91.3 9.9 89.2 83.7 78 76 75 75 73 SVR12, % 6 4 56. 56 2 A B C Child-Pugh class No Yes No Yes >3.5 2.8 <2.8 <1.71.7>2.3 <2. 2. >3. to 3.5 to 2.3 to 3. HE = hepatic encephalopathy Ascites HE Albumin, g/dl INR T bili, mg/dl 12 ACG 216 Southern Hepatitis School Copyright 216 American College of Gastroenterology Page 6 of 16
Treatment of Decompensated HCV Cirrhosis in Patients with Diverse Genotypes: 12 weeks Sofosbuvir and NS5A inhibitors With/Without Ribavirin Non-randomized observational cohort study of National Health Service of England (N = 467) Patients received 12 weeks SOF + LDV or DCV ± RBV at treating MD discretion (non-randomized) 12-wk SOF + LDV + RBV 12-wk SOF + LDV 12-wk SOF + DCV + RBV 12-wk SOF + DCV 89 86 P<.5 85 8 81 82 8 71 74 73 7 71 6 59 6 43 4 SVR12, % (ITT) 2 N = 252 28 172 15 164 21 45 5 61 7 114 7 27 13 3 All GT1 GT3 Other GT DCV, daclatasvir; GT, genotype; HCV, hepatitis C virus; ITT, intent to treat. Foster GR, et al. Presented at: EASL; April 22-26, 215; Vienna, Austria. Abstract O2. European Compassionate Use Program (CUP): SOF + DCV ± RBV for 24 Weeks 8 24-wk DCV + SOF 97 95 97 24-wk DCV + SOF + RBV 95 98 All patients SVR12, % 6 4 2 39/ 19/ 58/ 24/ 21/ 45/ 1/1 1/1 2/2 n/n = 4 2 6 24 22 46 A B C CP Score Treatment naive or treatment experienced CP Category: 57% CP A; 36% CP B; 6% CP C MELD Scores: >5% had MELD Scores 9 and <15 DCV dose determined by country; inclusion of RBV based on physician discretion Welzel TM, et al. Presented at: EASL; April 22-26, 215; Vienna, Austria. Abstract P772. ACG 216 Southern Hepatitis School Copyright 216 American College of Gastroenterology Page 7 of 16
Study Design ASTRAL-4 Childs B Cirrhosis Wk Wk 12 Wk 24 Wk 36 n=75 SOF/VEL SVR12 n=75 SOF/VEL + RBV SVR12 n=75 SOF/VEL SVR12 Open-label, randomized (1:1:1) US study GT 1-6 treatment-naïve or -experienced patients with CPT B cirrhosis Eligibility criteria: CrCL >5 ml/min, platelets >3, x 1 3 /μl; no HCC or liver transplant Weight-based RBV dosing ( or 12 mg/day) Results: SVR12 in GT 1 Patients ASTRAL-4 88 96 92 8 6 SVR-12 4 2 5 relapse 2 death 1 LTFU 1 relapse 2 deaths 3 relapse 3 LTFU 6/68 SOF/VEL 65/68 SOF/VEL+ RBV 65/71 SOF/VEL 12 week 12 week 24 week ACG 216 Southern Hepatitis School Copyright 216 American College of Gastroenterology Page 8 of 16
Results: SVR12 in GT 3 Patients ASTRAL-4 85 8 SVR 6 4 2 5 6 relapses 1 death 1 breakthrough 1 relapse 5 1 breakthrough 4 relapse 1 death 7/14 SOF/VEL 11/13 SOF/VEL+ RBV 6/12 SOF/VEL 12 week 12 week 24 week ACG 216 Southern Hepatitis School Copyright 216 American College of Gastroenterology Page 9 of 16
Solutions for patients with decompensated cirrhosis due hepatitis C 1. Observe closely for complications 2. Treat hepatitis C, observe for clinical improvement 3. Treat hepatitis C while listing for transplant 4. List for transplant, treat post OLT If we treat, will they improve clinically? ACG 216 Southern Hepatitis School Copyright 216 American College of Gastroenterology Page 1 of 16
Post liver transplant treatment of HCV infection Post transplant Drug interactions: DAAs as Culprits Medication Cyclosporine Tacrolimus Sirolimus Everolimus Cmax AUC Cmax AUC Cmax AUC Cmax AUC Ribavirin Ledipasvir ND ND ND ND ND ND Sofosbuvir 27% 9% ND ND ND ND Simeprevir 16% 19% 24% 17% ND ND ND ND Daclatasvir 4% 3% 5% ND ND ND ND 3D Regimen 1% 482% 299% 5613% Expected increase in both Cmax and AUC. Expected increase in both Cmax and AUC. HCV infection inhibits cytochrome P45 through direct and indirect mechanisms. SVR leads to lower CNI levels and risk of ACR. Dick TB, et al. Hepatology. 215. [Epub ahead of print] ACG 216 Southern Hepatitis School Copyright 216 American College of Gastroenterology Page 11 of 16
Post transplant Drug interactions: DAAs as Victims (CYA and TAC affect DAA metabolism or transport) Medication Daclatasvir Ledipasvir Sofosbuvir Simeprevir Cmax AUC Cmax AUC Cmax AUC Cmax AUC Cyclosporine 4% 4% ND ND 154% 353% 374% 481% Tacrolimus 7% 5% ND ND 3% 13% 79% 85% Dick TB, et al. Hepatology. 215. [Epub ahead of print] SOLAR-1: SVR12 Rates in OLT Patients Receiving LDV/SOF + RBV 96 98 96 96 85 83 6 67 8 12 wks LDV/SOF + RBV 24 wks LDV/SOF + RBV SVR12 (%) 6 4 2 n/n = 53/ 55 55/ 56 25/ 26 24/ 25 22/ 26 15/ 18 F-F3 CPT A CPT B CPT C 3/ 5 2/ 3 In the 24-week arm, 8 patients with CPT B and 1 patient with CPT C have not reached the follow-up week 12 visit MELD scores improved from baseline through follow-up Week 4 in 15/48 patients with CPT A and 8/41 patients with CPT B disease Reddy RT, et al. Hepatology. 214;6(suppl): Abstract 8. ACG 216 Southern Hepatitis School Copyright 216 American College of Gastroenterology Page 12 of 16
Solar-2: LDV/SOF + RBV: SVR12* in Genotype 1 or 4 Comparable efficacy between 12 and 24 week durations LDV/SOF + RBV 12 weeks LDV/SOF + RBV 24 weeks 96 98 88 89 91 86 SVR12 (%) 8 6 4 SVR12 (%) 8 6 4 57 2 n/n = 72/ 75 57/ 58 F-F3, CPT A 57/ 65 54/ 61 CTP B&C 2 n/n = 1/ 11 7/7 F-F3, CPT A 4/7 6/7 CTP B&C SOLAR-2: GT 1. Manns M, et al. Presented at: EASL; April 22-26, 215; Vienna, Austria. Abstract G2. SOLAR-2: GT 4 SOLAR-1: LDV/SOF + RBV in Post Transplant Change in MELD Score 4 2-2 -4 Change from Baseline to Follow-Up Week 4 CTP A Patients (n=48) 4 2-2 CTP B Patients (n=41) 12 Wk (n=23) 24 Wk (n=25) 12 Wk (n=21) 24 Wk (n=2) n=9 n=4 n=4 n=1-6 -8 Reddy, AASLD, 214, Oral #8 (-11) -4-6 Missing FU-4: n=3 CTP A 12 wk; n=5 CTP B 12 wk; n=5 CTP B 24 wk -8 ACG 216 Southern Hepatitis School Copyright 216 American College of Gastroenterology Page 13 of 16
Ally-1 : SOF +DCV+RBV 6 Post OLT SVR12 by HCV Genotype N = 53 94. 97 9 91 8 SVR12, % 6 4 2 5/53 3/31 9/1 Overall 1a 1b 1/11 1/1 3 6 Genotype Poordad F, et al. Presented at: EASL; April 22-26, 215; Vienna, Austria. Abstract LO8. SVR 12, % 8 6 4 2 SOF +DCV+RBV 6 Post OLT Interim SVR12 Results Post-transplant Cohort 89 24 27 DCV + SOF DCV + SOF + RBV All patients 91 89 91 1 1 Relapse, n=1 Deaths, n=2 25 28 6 6 3 33 GT 1 GT 3 All GT HCV genotype 1 1 31 34 NS5A sequencing (population-based) in relapse patient identified Y93S RAV ACG 216 Southern Hepatitis School Copyright 216 American College of Gastroenterology Page 14 of 16
CORAL-1: GT1 Patients After Liver Transplantation (F-F2) PTV/OMB/DSB + RBV (n=34) SVR12 Day Week 24 To Week 72 PTV/OMB/DSB: co-formulated paritaprevir/r/ombitasvir, 15 mg/ mg/25 mg QD; dasabuvir, 25 mg BID RBV: dosing was managed at the discretion of the investigator and closely monitored per protocol Tacrolimus.5 mg q 1-2 weeks, Cyclosporin reduced to 2% of daily dose Kwo PY, et al. N Engl J Med. 214;371(25):2375-2382. CORAL-1: SVR Rates in GT1 Liver Transplant Patients % 9% 8% 7% 6% 5% 4% 3% 2% 1% % % 97% 97% 97% EOTR SVR4 SVR12 SVR24 No patient had breakthrough One patient had a relapse (post-treatment day 3) At the time of relapse, this patient had R155K in NS3 protease, M28T+Q3R in NS5A, and G554S+G557R in NS5B, none of which were present at baseline Study now including F3-F4, 12 week duration ACG 216 Southern Hepatitis School Copyright 216 American College of Gastroenterology Page 15 of 16
HCV-TARGET Post Transplant HCV RNA Outcomes for SOF+SMV±RBV: Genotype 1 interim analysis 9% 87% 95% 88% 96% 88% 95% 9% 8% 8 6 SVR % 4 2 94/14 52/6 42/44 51/58 27/28 59/67 35/37 19/21 8/1 Overall Tx Experienced Yes No Genotype 1a 1b Cirrhotic Yes No MELD < 1 1 Summary Patients with decompensated cirrhosis may be treated successfully across all genotypes SVR rates are good, lower than compensated cirrhosis SOF/VEL/RBV, SOF/LDV ± RBV 12-24 weeks, SOF/DCV ± RBV 12-24 weeks Carefully consider who to treat in transplant setting to avoid MELD purgatory Post Liver Transplant: Do your drug interactions No graft should fail due to recurrent HCV across all genotypes 12 weeks of SOF/LDV/RBV or SOF/DCV/RBV 24 weeks of SOF/LDV or SOF/DCV 24 weeks of PTV/OMB/DSV±RBV SOF/VEL and GRZ/ELB will likely be effective, data pending ACG 216 Southern Hepatitis School Copyright 216 American College of Gastroenterology Page 16 of 16