Hepatitis C: How sick can we treat? Robert S. Brown, Jr., MD, MPH Vice Chair, Transitions of Care Interim Chief, Division of

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1 Hepatitis C: How sick can we treat? Robert S. Brown, Jr., MD, MPH Vice Chair, Transitions of Care Interim Chief, Division of Gastroenterology & Hepatology

2 HCV in advanced disease In principle we would treat all HCV + patients f we had safe and effective Rx But efficacy declines as CPT increases And safety not well established Decompensated cirrhosis has high mortality and unless will substantially improve status HCV Rx unlikely to change outcome without transplant Thus therapy in advanced disease remains controversial 2

3 What does cure of HCV mean in decompensated disease? Decompensated cirrhosis: Is there a threshold where we cannot avoid a transplant? Should HCV+ patients defer and take a HCV+ organ? Will we put them in MELD purgatory with Rx?

4 NHS England Early Access Program (EAP) SOF+NS5A±RBV for 12 Weeks in 467 Patients with History of Decompensated Cirrhosis Foster, EASL, 2015, O002 GT 1 N=235 GT 3 N=189 Other GTs N=43 Total N=467 Mean age, years (range) 56.1 (29-76) 54 (36-75) 59 (36-81) 55.6 (29-81) Male gender, n (%) 174 (74.0) 131 (69.3) 32 (74.4) 337 (72.2) Treatment experienced, n (%) 107 (45.5) 88 (46.6) 25 (58.1) 220 (47.1) Liver transplanted, n (%) 27 (11.5) 15 (7.9) 5 (11.6) 47 (10.1) Past or present decompensated cirrhosis, n (%) 223 (94.9) 179 (94.7) 39 (90.7) 441 (94.4) CTP B, n (%) 161 (68.5) 121 (64.0) 27 (62.8) 309 (66.2) CTP C, n (%) 19 (8.1) 24 (12.7) 3 (7.0) 46 (9.9) MELD mean (range) 11.9 (6-36) 11.3 (6-24) 12.6 (6-36) 11.9 (6-36) Active ascites, n (%) 97 (41.3) 67 (35.4) 14 (32.6) 178 (38.1) Previous variceal bleed, n (%) 61 (26.0) 55 (29.1) 11 (25.6) 127 (27.2) Active encephalopathy, n (%) 41 (17.4) 34 (18.0) 5 (11.6) 80 (17.1) Treatment, n (%)* LDV/SOF+RBV SOF+DCV+RBV SOF+NS5A without RBV *Choice of therapy was at clinician's discretion 164 (35.1) 45 (9.6) 26 (5.6) 61 (13.1) 114 (24.4) 14 (3.0) 27 (5.8) 13 (2.8) 3 (0.6) 252 (54) 172 (36.8) 43 (9.2) 4

5 NHS England EAP: SOF+NS5A±RBV for 12 Weeks SVR12 in GT 1 Patients with History of Decompensated Cirrhosis 17/21 141/164 3/5 37/45 LDV/SOF LDV/SOF +RBV Majority of patients received RBV SOF+DCV SOF+DCV +RBV LDV/SOF±RBV for 12 weeks resulted in high SVR rates in GT 1 decompensated cirrhotics Foster, EASL, 2015, O002 5

6 NHS England EAP: SOF+NS5A±RBV for 12 Weeks SVR12 in GT 3 Patients with History of Decompensated Cirrhosis Foster, EASL, 2015, O002 3/7 36/61 5/7 80/114 LDV/SOF LDV/SOF +RBV Majority of patients received RBV SOF+DCV SOF+DCV +RBV SVR rates were comparable to those seen in other studies of SOF+NS5A±RBV for 12 weeks in decompensated cirrhotics 6

7 Changes in MELD Score NHS England EAP: SOF+NS5A±RBV for 12 Weeks MELD Improvement in GT 1 and 3 Patients with History of Decompensated Cirrhosis n = 131 Non-transplanted Transplanted on treatment Number of Patients n = 33 n = 53 Improvement of > 2 MELD scores was observed in 41% by FU Week 4 and 48% had no significant changes Foster, EASL, 2015, O002 Comparative MELD scores available for 217 patients 7

8 NHS England EAP: SOF+NS5A±RBV for 12 Weeks in Decompensated Cirrhosis Serious Adverse Events by Follow-Up Week 4 Number of events (% of total SAEs) Number of patients (% of total population) Total SAEs (25.5%) Likely related to liver disease and/or HCV treatment Likely unrelated to liver disease and/or HCV treatment 138 (78.9%) 100 (21.4%) 37 (21.1%) 37 (7.9%) Ascites 55 (31.4%) 38 (8.1%) Hepatic encephalopathy 28 (16%) 23 (4.9%) Variceal bleed 6 (3.4%) 6 (1.3%) Infection 26 (14.9%) 23 (4.9%) Liver transplantation 16 (3.4%) New HCC 7 (1.5%) Discontinuation of DAAs 42 (9%) Deaths 14 (3.0%) 12 weeks SOF+NS5A ± RBV was generally well tolerated Foster, EASL, 2015, O002 8

9 SOLAR-2 LDV/SOF+RBV for 12 or 24 Weeks in 329 Decompensated and Post-Liver Transplant HCV GT 1 and GT 4 Patients Week Pre-Transplant CTP B (7 9) CTP C (10 12) Fibrosis (F0 F3) LDV/SOF + RBV SVR12 CTP A (5 6) Post-Transplant CTP B (7 9) LDV/SOF + RBV SVR12 CTP C (10 12) FCH Broad inclusion criteria: No hepatocellular carcinoma (HCC) Total bilirubin 10 mg/dl, Hemoglobin 10 g/dl CrCl 40 ml/min, Platelets > 30,000/mL RBV dosing F0 F3 and CTP A cirrhosis: weight-based (< 75 kg = 1000 mg; 75 kg = 1200 mg) CTP B and C cirrhosis: dose escalation, mg/d Manns, EASL, 2015, GO2 9

10 SOLAR-2: LDV/SOF + RBV in Decompensated and Post-Liver Transplant Patients Demographics Post-Transplant Pre/Post-Transplant Patients, n (%) Manns, EASL, 2015, GO2 12 Weeks n=86 F0 F3 + CTP A 24 Weeks n=82 12 Weeks n=78 CTP B + CTP C 24 Weeks n=82 Median age, y (range) 58 (32 73) 60 (44 74) 58 (27 76) 58 (23 79) Male, n (%) 69 (80) 65 (79) 55 (71) 59 (72) Median HCV RNA, log 10 IU/mL (range) 6.5 ( ) 6.5 ( ) 6.0 ( ) 5.9 ( ) GT, n (%) 1a 41 (48) 42 (51) 38 (49) 38 (46) 1b 34 (40) 30 (37) 33 (42) 35 (43) 4 11 (13) 10 (12) 7 (9) 9 (11) IL28B non-cc, n (%) 74 (86) 65 (79) 62 (79) 61 (74) Prior HCV treatment, n (%) 72 (84) 65 (79) 58 (74) 66 (80) MELD > 15, n (%) (28) 19 (23) Median total bilirubin, mg/dl (range) 0.8 ( ) 0.8 ( ) 2.3 ( ) 2.3 ( ) Median albumin, g/dl (range) 4.0 ( ) 3.9 ( ) 2.8 ( ) 2.9 ( ) Median INR (range) 1.0 ( ) 1.0 ( ) 1.3 ( ) 1.3 ( ) Median platelets, x 10 3 /µl (range) 142 (35-434) 134 (48-331) 77 (27-237) 80 (28-211) Ascites, n (%) 3 (3) 2 (2) 51 (65) 64 (78) Encephalopathy, n (%) (47) 45 (55) 1 0

11 SVR12 (%) SOLAR-2: LDV/SOF + RBV in Decompensated and Post-Liver Transplant Patients Overall Efficacy Pre-Transplant in GT 1 LDV/SOF + RBV 12 Weeks 24 Weeks 20/23 22/23 17/20 13/18 CTP B CTP C SVR rates were similar with 12 or 24 weeks of LDV/SOF + RBV 27 subjects in the 24 week arm have not reached SVR12 7 subjects who were transplanted and 3 subjects did not meet inclusion criteria are excluded. Error bars represent 2-sided exact 90% confidence intervals. Manns, EASL, 2015, GO2 1 1

12 Change in MELD Score SOLAR-2: LDV/SOF + RBV in Decompensated and Post-Liver Transplant Patients Liver Function Change from Baseline to Follow-Up Week 4 MELD Score Change Pre/Post-Transplant (CTP B and C, n=136*) Change in CTP Class Baseline CTP (+8) A (5 6) n=73 B (7 9) n=100 C (10 12) n=54 n=95 n=18 A (5 6) 67 (96) 31 (35) 2 (5) n=22 Followup Week 4 CTP B (7 9) 3 (4) 57 (65) 20 (48) C (10 12) (48) no assessment: CTP A, n=3; CTP B, n=12; CTP C, n=12 (-11) (-17) *Missing FU-4: n=24 Majority of patients showed improvements in MELD and CTP scores Manns, EASL, 2015, GO2 1 2

13 SOLAR-2: LDV/SOF + RBV in Decompensated and Post-Liver Transplant Patients Overall Safety Summary Post-Transplant F0 F3 + CTP A Pre/Post-Transplant CTP B + CTP C Overall Safety Patients, n (%) 12 Weeks n=86 24 Weeks n=82 12 Weeks n=78 24 Weeks n=82 AE 79 (92) 78 (95) 74 (95) 77 (94) Grade 3 4 AE 16 (19) 20 (24) 15 (19) 25 (30) SAE 12 (14) 12 (15) 22 (28) 23 (28) Treatment-related SAEs* 0 3 (4) 2 (3) 4 (5) Treatment D/C due to AE 0 1 (1) 1 (1) 4 (5) Death 2 (2) 1 (1) 3 (4) 4 (5) *Fall, anemia (5), vomiting, diarrhea, hyperbilirubinemia; edema, dehydration, HCC (2), type 2 diabetes mellitus, hyperbilirubinemia. Regimen was safe and well tolerated with low D/C due to AE No deaths were considered treatment related Manns, EASL, 2015, GO2 1 3

14 SVR12 (%) Decompensated cirrhosis SOLAR 1 study Patients 108 GT 1 or 4 treatment naïve or experienced CPT class B or C Inclusion/exclusion Total bili <10 mg/dl Creatinine clearance >40 ml/min Platelets >30,000 x 10 3 /ul Design: RCT Regimen Ledipasvir + sofosbuvir Ribavirin 600 mg daily, titrated up if tolerated Duration: 12 or 24 weeks weeks 24 weeks CPT B CPT C Charlton M. Gastroenterology 2015.

15 What does cure of HCV mean? SOLAR study MELD scores Charlton M. Gastroenterology 2015.

16 When/Who to Treat with Advanced Disease Summary Will all patients be HCV RNA (-) going into OLT? Patients treated earlier with SVR who develop HCC HCC upgrades, LDLT-Definite CPT B, MELD <15-Mostly CPT C, high MELD-Not at the current time,? Soon Will lower MELD and decrease risk of early recurrence post OLT but has decreased SVR and no access to HCV + livers What remains open is which patients can be treated and avoid transplant