VIRAL LIVER DISEASE. OAG Post DDW Course Westin Prince, Toronto, June 13-14, 2015

Transcription

1 VIRAL LIVER DISEASE OAG Post DDW Course Westin Prince, Toronto, June 13-14, 2015

2 Financial Interest Disclosure (over the past 24 months) Dr. Paul Marotta Relationships related to this presentation! Research Contracts! Merck, Gilead Sciences, Bristol Myers Squibb! Advisory Boards! Merck, Bristol Myers Squibb, Gilead Sciences, Abbvie! Consultancy Agreements! Merck, Gilead Sciences, Bristol Myers Squibb

3 Program Name : OAG POST DDW REVIEW COURSE CanMEDS Roles Covered in this Session: " Medical Expert (as Medical Experts, physicians integrate all of the CanMEDS Roles, applying medical knowledge, clinical skills, and professional attitudes in their provision of patient-centered care. Medical Expert is the central physician Role in the CanMEDS framework.) Communicator (as Communicators, physicians effectively facilitate the doctor-patient relationship and the dynamic exchanges that occur before, during, and after the medical encounter.) Collaborator (as Collaborators, physicians effectively work within a healthcare team to achieve optimal patient care.) " " Manager (as Managers, physicians are integral participants in healthcare organizations, organizing sustainable practices, making decisions about allocating resources, and contributing to the effectiveness of the healthcare system.) Health Advocate (as Health Advocates, physicians responsibly use their expertise and influence to advance the health and well-being of individual patients, communities, and populations.) Scholar (as Scholars, physicians demonstrate a lifelong commitment to reflective learning, as well as the creation, dissemination, application and translation of medical knowledge.) Professional (as Professionals, physicians are committed to the health and well-being of individuals and society through ethical practice, profession-led regulation, and high personal standards of behaviour.)

4 Disclosures! Content of this presentation includes discussion of off- label/investigational use of medicine.

5 ! Review key clinical abstracts from the 2 major LIVER annual meetings.! AASLD : Boston Nov, 2014! EASL : Vienna, April, 2015! Abstracts that will affect your clinical practice

6 HCV G1 : 8 weeks Standard of Care 444 Follow Guidelines HCV Decompensated Liver Disease 44 Dramatic Change!! HCV Renal Failure 4 New effective Therapy (MRK) HCV HBV Next Phase of DAA s Long term treatment with NA * Global impact 44 Safety of long- term treatment

7 Background:! LDV/SOF (Harvoni) : Phase 3 trial : ION- 3 study showed that 8 weeks was non- inferior to 12 weeks in naïve GT1 patients without cirrhosis and Viral load of <6 million IU/mL.! In Ontario reimbursed accordingly (Public and Private) Aim:! Outcomes (SVR4) using LDV/SOF used for 8 weeks in real world clinical practice.

8 Methods:! 8 weeks of LDV/SOF in a single centre in Germany.! Report includes SVR4 for those reaching that time point. Results:! 45 had 8w treatment with LDV/SOF. No patient had ribavirin.! The genotype distribution was 49%, 47% GT1a, GT1b (2pts G4)! The METAVIR stage distribution! 37% (F0), 33% (F1), 24% (F2) 5% (F3)! No patient had HCV RNA 6 million IU/mL.! No discontinuations or relevant Adverse Drug Reactions! 42/42 (100%) SVR4, 3 not reached SVR4 timepoint

9 German Real- World LDV/SOF for 8 weeks in NC with HCV RNA < 6M, primarily TN GT 1 Effectiveness and Safety Virologic Response Safety Results Total cohort n=45 SVR4 N=42* Any AEs (Grades 3 & 4), n (%) 1 (2.2) Headache, n (%) 1 (2.2) AE related to LDV/SOF, n (%) 1 (2.2) AE leading to D/C, n (%) 0 Deaths, n (%) 0 *3 patients had no SVR4 data available at time of analysis LDV/SOF for 8 weeks resulted in high rates of SVR4 and was safe and well tolerated Buggisch, EASL, 2015, LP32

10 Conclusions:! 42/42 SVR- 4 (100%).! For those naïve, non- cirrhotic G1, <6million VL 8 weeks of Harvoni is suggested. Take Home:! Use 8 weeks in those that satisfy criteria.

11 Background:! Oral nucleos(t)ide analogues (NAs) suppress HBV and reduce hepatic events in HBV patients.! Early data suggest nucleotide analogues (Adefovir and Tenofovir) may cause renal and bone toxicity.! Those observations were based on small number of patients and heterogeneous populations (HIV).! Long- term data on these hard clinical outcomes are lacking.

12 Aim:! Cohort study using database which captures medical services at both in- patient and out- patient settings for 70 80% of the Hong Kong citizens.! Identified HBV patients diagnosed between 2000 and 2012.! Tracked relevant diagnoses, with special focus on renal failure and fracture, procedures, concomitant drugs, and laboratory parameters.! The primary outcome was the incidence of chronic renal failure and fractures.! A 3- year analysis, with follow- up up to 7 years, was used to evaluate the relative risk of primary outcome in patients with or without NA treatment.

13 Results:! 53,500 patients with HBV. 46,454 untreated and 7,046 treated with NA.! Median follow- up of 4.9 years

14 Results:! After propensity score weighting, NA therapy did not increase the risk of the events! Hazard ratios [HR] ranged from 0.79 to 1.31;! P values ranged from to 0.887! Exposure to nucleotide analogues, compared with nucleoside analogues was no different except hip fracture! HR = 4.71, 95% confidence interval , P=0.003)! Similar findings were observed when comparing nucleotide analogues with no treatment.! Male gender and age 50 years were associated with these events.

15 Conclusions:! NA treatment (Tenofovir/Adefovir) does not increase the risk of renal and bone events in general.! Risk of hip fracture may be real (men over 50 years), but the overall event rate is low (17 / 7,000 over 5 years) (0.2%). Take Home:! No need to worry about renal nor bone issues with Tenofovir / Adefovir (NA).

16 C- SURFER: GRAZOPREVIR PLUS ELBASVIR IN TREATMENT- NAIVE AND TREATMENT- EXPERIENCED PATIENTS WITH G1 AND CHRONIC KIDNEY DISEASE EASL# LP02 Roth D et al

17 Grazoprevir / Elbasvir Studies Study Name C-EDGE TN C-EDGE TE C-EDGE Coinfection C-SALVAGE C-SCAPE C-WORTHY C C-SWIFT C-SURFER Description 12 wks of grazoprevir/elbasvir in treatment-naive pts with GT1, 4, or 6 HCV infection 12 or 16 wks of grazoprevir/elbasvir ± RBV in pts with GT1, 4, or 6 HCV and previous failure of pegifn/rbv 12 wks of grazoprevir/elbasvir in HCV treatment-naive pts coinfected with HIV and GT1, 4, or 6 HCV 12 wks of grazoprevir/elbasvir + RBV in pts with GT1 HCV and previous failure of HCV PI + pegifn/rbv 12 wks of grazoprevir ± elbasvir ± RBV in treatment-naive, noncirrhotic pts with GT2, 4, 5, or 6 HCV 8 wks of grazoprevir/elbasvir ± RBV in treatment-naive, noncirrhotic pts with GT1b HCV Short-duration therapy with grazoprevir/elbasvir + sofosbuvir in treatmentnaive, GT1 or 3 HCV infected pts ± cirrhosis 12 wks of grazoprevir/elbasvir in pts with GT1 HCV infection and stage 4 or 5 CKD

18 C- SURFER: GRAZOPREVIR PLUS ELBASVIR IN TREATMENT- NAIVE AND TREATMENT- EXPERIENCED PATIENTS WITH G1 AND CHRONIC KIDNEY DISEASE EASL# LP02 Roth D et al Background! No all oral DAA currently indicated in renal failure.! Studies with SOF- based regimens in pts with egfr 30! Decreased excretion of metabolite GS ! AUC 400% : safety remains uncertain! Data for OMV/PTV/RTV + DSV ± RBV in hemodialysis pts! AEs remain a concern with RBV, even at low doses! CKD small but important unmet medical need! 2% of HCV, high direct/indirect costs

19 C- SURFER: GRAZOPREVIR PLUS ELBASVIR IN TREATMENT- NAIVE AND TREATMENT- EXPERIENCED PATIENTS WITH G1 AND CHRONIC KIDNEY DISEASE EASL# LP02 Roth D et al! This study evaluated Grazoprevir + Elbasvir in HCV- infected patients with CrCl <30 ml/min, including patients on hemodialysis! <1% of Grazoprevir and Elbasvir are renally excreted! Phase 1 trial demonstrated no need for dose adjustments in CKD

20 C- SURFER: GRAZOPREVIR PLUS ELBASVIR IN TREATMENT- NAIVE AND TREATMENT- EXPERIENCED PATIENTS WITH G1 AND CHRONIC KIDNEY DISEASE EASL# LP02 Roth D et al HCV NS3/4A inhibitor 100 mg once-daily, oral HCV NS5A inhibitor 50 mg, once-daily, oral Grazoprevir (MK-5172) Elbasvir (MK-8742)! Fixed-dose combination tablet Grazoprevir (100 mg) Elbasvir (50 mg)

21 C- SURFER: GRAZOPREVIR PLUS ELBASVIR IN TREATMENT- NAIVE AND TREATMENT- EXPERIENCED PATIENTS WITH G1 AND CHRONIC KIDNEY DISEASE EASL# LP02 Roth D et al! Multicenter, placebo- controlled, phase III trial Treatment Wk 12 Follow-up Wk 4 Follow-up Wk 16 GT1 HCV-infected pts with stage 4/5 CKD Grazoprevir/Elbasvir (n = 111) Open-label period (n = 224) Placebo Grazoprevir/Elbasvir (n = 113) (n = 113)! Pts split evenly by GT1a and 1b infection (52% for GT1a); 6% had compensated cirrhosis! 81% and 82% were CKD stage 5 (egfr < 15 ml/min/1.73 m 2, or on hemodialysis); 18% and 19% were CKD stage 4 (egfr ml/min/1.73 m 2 )

22 C- SURFER: GRAZOPREVIR PLUS ELBASVIR IN TREATMENT- NAIVE AND TREATMENT- EXPERIENCED PATIENTS WITH G1 AND CHRONIC KIDNEY DISEASE EASL# LP02 Roth D et al GZR/EBR 12 wks SVR12 (%) n/n = 0 115/ 116* Modified Full Analysis Set 115/ 122* Full Analysis Set 6/6 Cirrhotic 61/61 GT 1a HCV 54/55 GT 1b HCV 86/87 40/41 On Diabetic hemodialysis

23 C- SURFER: Adverse Events AE, % Grazoprevir/Elbasvir (Randomized Treatment) Placebo (n = 111) (n = 113) Serious AEs Discontinuation due to AE Death Common AEs* ! Headache ! Nausea ! Fatigue ! Insomnia ! Dizziness ! Diarrhea

24 C- SURFER: GRAZOPREVIR PLUS ELBASVIR IN TREATMENT- NAIVE AND TREATMENT- EXPERIENCED PATIENTS WITH G1 AND CHRONIC KIDNEY DISEASE EASL# LP02 Roth D et al Conclusions:! Once daily GZR/EBR for 12 weeks was highly effective for HCV GT1 patients with CKD stage 4/5, HD! SVR12 >95%! Efficacy is consistent across different subpopulations: GT1a and 1b, Diabetes, Hemodialysis! Trivial side effects Take Home:! Looking for Health Canada approval soon!

25 The pipeline of HCV DAAs continues! Drug Class Dosing Daclatasvir NS5A inhibitor 60 mg QD Elbasvir NS5A inhibitor 50 mg QD* Grazoprevir NS3/4A protease inhibitor 100 mg QD* GS-5816 NS5A inhibitor 100 mg QD GS-9451 NS3/4A protease inhibitor 80 mg QD GS-9857 NS3/4A protease inhibitor 100 mg QD GS-9669 NS5B nonnucleoside polymerase inhibitor 500 mg QD Ledipasvir NS5A inhibitor 90 mg QD Sofosbuvir NS5B nucleotide polymerase inhibitor 400 mg QD

26 Short- Duration Sofosbuvir/GS GS in GT1 HCV Pts EASL LP03 Gane EJ et al! Single- center, nonrandomized, open- label phase II trial Wk 4 Wk 6 Tx-naive noncirrhotic GT1 pts (N = 30) Tx-naive cirrhotic GT1 pts (N = 30) Tx-exp d GT1 pts ± cirrhosis (N = 30) Sofosbuvir/GS GS-9857 (n = 15) Sofosbuvir/GS GS-9857 (n = 15) Sofosbuvir/GS GS-9857 (n = 15) Sofosbuvir/GS GS-9857 (n = 30) Sofosbuvir/GS mg/100 mg FDC tablet QD; GS mg QD.

27 Short- Duration Sofosbuvir/GS GS in GT1 HCV Pts EASL LP03 Gane EJ et al SVR12, n/n (%) Treatment Naive, No Cirrhosis 4 wks 4/15 (27) Sofosbuvir/GS GS-9857 Treatment Naive, Cirrhosis Treatment Experienced ± Cirrhosis 6 wks 14/15 (93) 13/15 (87) 20/30 (67)

28 Safety and Efficacy of Sofosbuvir plus GS (RBV- Free) in Non- Cirrhotic Naïve G1-6! SVR12 in Pts Treated with SOF + GS-5816: HCV Genotype SOF 400mg + GS mg SOF 400mg + GS mg G1 96% (26/27) 100% (37/37) G2 91% (10/11)* 100% (13/13) G3 89% (24/27)* 93% (25/27)** G4 100% (7/7) 88% (8/9)* G5 100% (1/1) 100% (1/1) G6 100% (4/4) 100% (6/6) * One subject per group was lost to follow-up prior to post tx wk 4 ** One relapse, one proven re-infection Everson et al, EASL 2014, oral (O111)

29 SHORT- DURATION SOFOSBUVIR/GS GS IN GT1 HCV PTS EASL LP03 GANE EJ ET AL Conclusions:! No serious adverse events or discontinuations for toxicity! 4 weeks not enough!! 6 weeks for naïve cirrhotics (87%) Take Home:! More DAAs coming, shorter duration, pan- genotype

30 Direct Acting Antivirals For Decompensated Liver Disease WOW!! National Health Service of England (N = 467)! Solar 1, 2! London Experience

31 SOF + NS5A Inhibitors ± RBV in Pts With GT1/3 HCV and Decompensated Cirrhosis Foster G et al EASL #o002! Observational cohort study of National Health Service of England (N = 467)! At physician s discretion, pts received 12 wks SOF + LDV or DCV ± RBV Baseline Characteristic All Pts (N = 467) Genotype 1 (n = 235) Genotype 3 (n = 189) Other Genotypes (n = 43) CTP B, % CTP C, % Mean MELD score (range) Regimen, % of total population 11.9 (6-36) 11.3 (6-24) 12.6 (6-36) 11.9 (6-22) SOF + LDV + RBV SOF + DCV + RBV RBV-free regimen

32 SOF + NS5A Inhibitors ± RBV in Pts With GT1/3 HCV and Decompensated Cirrhosis Foster G et al EASL #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 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)

33 SOF + NS5A Inhibitors ± RBV in Pts With GT1/3 HCV and Decompensated Cirrhosis Foster G et al EASL #o002 SVR12, % (ITT) 12-wk SOF + LDV + RBV 12-wk SOF + LDV 12-wk SOF + DCV + RBV 12-wk SOF + DCV P < N = All GT1 GT3 SVR12 among pts with other HCV GTs: 89% (n = 27) with SOF + LDV + RBV; 85% (n = 13) with SOF + DCV + RBV; 100% (n = 3) SOF + DCV

34 LDV/SOF+RBV for 12 or 24 Weeks in 329 Decompensated and Post- Liver Transplant HCV GT 1 and GT 4 Patients Solar 2 : Manns EASL #G02 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 34

35 LDV/SOF+RBV for 12 or 24 Weeks in 329 Decompensated and Post- Liver Transplant HCV GT 1 and GT 4 Patients Solar 2 : Manns EASL #G02 Patients, n (%) 12 Weeks n=86 Post- Transplant F0 F3 + CTP A 24 Weeks n=82 12 Weeks n=78 Pre/Post- Transplant 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) Manns, EASL, 2015, GO2

36 LDV/SOF+RBV for 12 or 24 Weeks in 329 Decompensated and Post- Liver Transplant HCV GT 1 and GT 4 Patients Solar 2 : Manns EASL #G02 LDV/SOF + RBV 12 Weeks 24 Weeks SVR12 (%) 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 20/23 22/23 17/20 13/18 CTP B CTP C

37 LDV/SOF+RBV for 12 or 24 Weeks in 329 Decompensated and Post- Liver Transplant HCV GT 1 and GT 4 Patients Solar 2 : Manns EASL #G02 LDV/SOF + RBV 12 Weeks 24 Weeks GT 1 SVR12 (%) 72/75 57/58 F0-F3 & CTP A Post-Transplant 57/65 54/61 CTP B & C Pre- and Post-Transplant

38 LDV/SOF+RBV for 12 or 24 Weeks in 329 Decompensated and Post- Liver Transplant HCV GT 1 and GT 4 Patients Solar 2 : Manns EASL #G02 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 Change in MELD Score n=95 n=18 n=22 Follow- up Week 4 CTP A (5 6) 67 (96) 31 (35) 2 (5) 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 38

39 LHSC Experience (POST LTX) Sofosbuvir/Ledipasvir + Riba Baseline CPS Current CPS SVR Status Transplant Status wk Tx SVR 12 POST wk Tx SVR 8 POST wk Tx SVR 12 POST wk Tx SVR 12 POST wk Tx SVR 8 POST 100% SVR No Increases in MELD/CPT score : Most improved BR/ALB/Ascites

40 LHSC Experience (PRE- LTx) Sofosbuvir/Ledipasvir + Riba * Baseline CPS Current CPS SVR Status Transplant Status wk Tx SVR 12 DIED - EVB wk Tx SVR 12 LIST OFF wk Tx SVR 12 LIST OFF wk Tx SVR 12 LIST OFF wk Tx SVR 12 LIST OFF 100 % SVR 80% Removed from Wait LIST 75% in Wait listed HCV Patients!!

41 Direct Acting Antivirals For Decompensated Liver Disease WOW! Conclusions! SOF based therapy (+/- RIBA) ! SVR12 >85 % in very Advanced Decompensated Liver Disease.! MELDs drop, CPC drop, HVWP drops! Need for Liver Transplantation DROPS!! Historical trend Future trend with new therapies

42 HCV G1 : 8 weeks Standard of Care 444 Follow Guidelines HCV Decompensated Liver Disease 44 Dramatic Change!! HCV Renal Failure 4 New effective Therapy (MRK) HCV Next DAA * Global impact HBV Long term treatment with NA 44 Safety of long term treatment

43 HCV G1 : 8 weeks Standard of Care 444 Follow Guidelines HCV Decompensated Liver Disease 44 Dramatic Change!! HCV Renal Failure 4 New effective Therapy (MRK) HCV Next DAA * Global impact HBV Long term treatment with NA 44 Safety of long term treatment

44 VIRAL LIVER DISEASE OAG Post DDW Course Westin Prince, Toronto, June 13-14, 2015