Treatment of HCV in 2016

Transcription

1 5/1/16 Treatment of HCV in 16 Graham R Foster Professor of Hepatology QMUL Conflicts of Interest Speaker and consultancy fees received from AbbVie, BI, BMS, Gilead, Janssen, Roche, Merck, Novartis, Springbank, Achillion, Idenix 1

2 5/1/16 Genotype 1 HCV in 16 A whistle stop tour Genotype 3 Who to treat first Genotype 1 HCV in 16 A whistle stop tour Genotype 3 Who to treat first 2

3 SVR12 (%) 5/1/16 Genotype 1 without Interferon Two strategies emerging:- Sofosbuvir + anything Potent protease + 1 or 2 other drugs All oral FDC LDV/SOF ± RBV for 12 or 24 weeks in treatment-naive G1 HCV patients: Phase 3 ION-1 study AIM: Evaluate LDV/SOF for 12 and 24 weeks in HCV treatment-naive G1 patients 865 patients randomized to LDV/SOF or LDV/SOF + RBV for 12 or 24 weeks 6 4 Presence vs absence of cirrhosis / 1 32/34 178/ /33 181/ /33 179/ /36 LDV/SOF LDV/SOF + RBV LDV/SOF LDV/SOF + RBV 12 weeks 24 weeks No cirrhosis Cirrhosis 99% SVR rate following LDV/SOF for 12 wks RBV and extended treatment did not improve efficacy RBV associated with higher rates of AEs Afdahl NEJM 14;37:1889 3

4 SVR12 (%) 5/1/16 Sofosbuvir/ledipasvir ± RBV for 8 weeks vs 12 weeks in treatment-naive non-cirrhotic G1 HCV-infected patients Wk Wk 8 Wk 12 Wk Wk 24 LDV/SOF n=215 LDV/SOF + RBV n=216 LDV/SOF n=216 Stratified by HCV subtype (1a or 1b) G1 treatment-naive patients without cirrhosis SVR12 G1 treatment naive Kowdley K.V, et al. NEJM 14;37:1879 SVR12 SVR12 2/215 1/216 6/216 LDV/SOF LDV/SOF + RBV LDV/SOF 8 weeks 12 weeks SVR12 8 weeks without RBV not statistically inferior Without cirrhosis 8 weeks is the right duration An Integrated Safety and Efficacy Analysis of >5 Patients with Compensated Cirrhosis Treated with LDV/SOF±RBV 513 patients with HCV GT 1, compensated cirrhosis Pooled data from Phase 2 and 3 LDV/SOF ± RBV studies LONESTAR, ELECTRON, ELECTRON-2, Japan phase 3 study, ION-1, ION-2, SIRIUS Primary efficacy endpoint: SVR12 Wk Wk 12 Wk 24 Wk 36 n=118 LDV/SOF SVR12 n=4 LDV/SOF + RBV SVR12 n=133 LDV/SOF SVR12 n=58 LDV/SOF + RBV SVR12 Bourliere, AASLD, 14, Oral #82 4

5 5/1/16 Results: SVR12 by Treatment Regimen Overall SVR12 Duration Regimen Duration/± RBV wk wk 24 wk LDV/SOF LDV/SOF + RBV LDV/SOF 12 wk LDV/SOF + RBV 12 wk LDV/SOF 24 wk LDV/SOF + RBV 24 wk Treatment Naïve 98% 97% 99% 96% 99% 96% 98% 97% % Treatment Experienced 95% 94% 98% 95% 96% 9% 96% 98% % Bourliere, AASLD, 14, Oral #82 Among TE cirrhotic patients, 12 weeks of LDV/SOF + RBV resulted in similar SVR rates to 24 weeks of LDV/SOF alone Results: SVR12 by Treatment Regimen Overall SVR12 Duration Regimen Duration/± RBV wk wk 24 wk LDV/SOF LDV/SOF + RBV LDV/SOF 12 wk LDV/SOF + RBV 12 wk LDV/SOF 24 wk LDV/SOF + RBV 24 wk Treatment Naïve 98% 97% 99% 96% 99% 96% 98% 97% % Treatment Experienced 95% 94% 98% 95% 96% 9% 96% 98% % Bourliere, AASLD, 14, Oral #82 Among TE cirrhotic patients, 12 weeks of LDV/SOF + RBV resulted in similar SVR rates to 24 weeks of LDV/SOF alone 5

6 5/1/16 Sofosbuvir + Ledipasvir A single tablet Cures most G1 in 8 weeks side effect free Cures cirrhosis in 12 weeks (needs ribavirin, some side effects) SVR achieved (n=251) Real-world experience from the TRIO Network: Effectiveness of 8 or 12 week LDV/SOF in treatment-naive patients with non-cirrhotic, G1 HCV Patient disposition TN, non-cirrhotic (n=895) SVR not achieved (n=3) *21 Patients were on 12 weeks of LDV/SOF+RBV wks LDV/SOF (n=263) SVR achieved (n=64) Curry M, et al. AASLD 15, San Francisco. # wks LDV/SOF ± RBV (n=632)* SVR12 by duration Relapse 9 Death LTFU 6 DC/ 3 Relapse 6 Death 2 LTFU 16 DC/ 4 251/263 64/632 8 weeks 12 weeks SVR not achieved (n=6) SVR12 by fibrosis F F1 F2 F3 SVR12 rates by baseline viral load <6MM 6MM+ 8 weeks 12 weeks / /456 8/8 162/17 6

7 5/1/16 SVR achieved (n=251) Real-world experience from the TRIO Network: Effectiveness of 8 or 12 week LDV/SOF in treatment-naive patients with non-cirrhotic, G1 HCV 8 wks LDV/SOF (n=263) Patient disposition TN, non-cirrhotic (n=895) SVR not achieved (n=3) *21 Patients were on 12 weeks of LDV/SOF+RBV 6 4 SVR achieved (n=64) Curry M, et al. AASLD 15, San Francisco. # wks LDV/SOF ± RBV (n=632)* SVR12 by duration Relapse 9 Death LTFU 6 DC/ 3 Relapse 6 Death 2 LTFU 16 DC/ 4 251/263 64/632 8 weeks 12 weeks SVR not achieved (n=6) SVR12 by fibrosis F F1 F2 F3 SVR12 rates by baseline viral load <6MM 6MM+ 8 weeks 12 weeks / /456 8/8 162/17 Protease based regimens Potent protease plus 1 or 2 drugs Two options:- Paritaprevir/Ombitasvir + Dasabuvir OR Grazoprevir/elbasvir 7

8 SVR12 (%) 5/1/16 SAPPHIRE-I: GT1 treatment-naive patients ABT-45/r/ABT-267 (ombitasvir) + ABT-333 (dasabuvir) + RBV HCV GT1, treatment-naive, non-cirrhotic (N=631) n=473 n=158 ABT-45/r/ombitasvir + dasabuvir + RBV Placebo ABT-45/r/ombitasvir + dasabuvir + RBV Study weeks ABT-45/r/ombitasvir = 15//25 mg QD co-formulated; dasabuvir = 25 mg BID; RBV = 1 mg weight-based BID. Feld JJ, et al NEJM 14:37:1594]. SAPPHIRE-I: GT1 treatment-naive patients SVR12 rates by HCV GT1 subtype Treatment-naive n N Overall GT1a GT1b Error bars: 95% CI. 8

9 SVR12/24 (%) 5/1/16 AbbVie Regimes For naïve 1a patients (+/- cirrhosis):- 12 weeks 3D with ribavirin For naïve 1b patients (- cirrhosis) 12 weeks 3D without ribavirin (add ribavirin for cirrhosis) For experienced patients with cirrhosis extend for 24 weeks in 1a non-responders 6 Real-world safety and effectiveness of OBV/PTV/r with DSV and/or RBV in the German hepatitis C Registry Effectiveness by cirrhosis or treatment history / 18/ 246/ 51/ 121/ 26/ 93/ 2/ / 268/ 46/ Total G1 G1a G1b G4 Total G1 G1a G1b G4 Naive Peg ± RBV TVR/BOC Without cirrhosis With cirrhosis + RBV Safety, n (%) 2D/3D -RBV (n=436) 2D/3D + RBV (n=353) 2D/3D -RBV (n=44) 2D/3D + RBV (n=184) Any AE 185 (42) 1 (57) (45) 119 (65) Any SAE 5 (1) 8 (2) 8 (4) RBV dose mod (7) - 18 (1) Death 2 (.5) D/C due to AE 2 (.5) 4 (1) 9 (5) Fatigue (18) 97 (27) 8 (18) 58 (32) Pruritus 33 (8) 4 (11) 2 (5) 26 (14) AEs in Headache 35 (8) 35 (1) 5 (11) 16 (9) 5%of Insomnia 17 (4) 29 (8) 18 (1) patients Nausea 16 (4) (6) 3 (7) 12 (7) Hinrichsen H, et Anemia al. EASL 16, Barcelona. 1 #GS7 (.2) 15 (4) (11) 9

10 UND HCV RNA (%) % SVR12 (95% CI) % SVR12 (95% CI) 5/1/16 Real-world safety and effectiveness of OBV/PTV/r with DSV and/or RBV in the German hepatitis C Registry Israeli experience: 3D ± RBV in G1 patients with advanced fibrosis Virologic response: G1 cirrhosis vs no cirrhosis / / / /253 EOT No cirrhosis SVR12 (mitt) Cirrhosis 3D ± RBV in real world: 95 % SVR G1/4, including cirrhosis Safety and tolerance good but impact of RBV Hinrichsen H, et al. EASL 16, Barcelona. #GS7; Zuckerman E, et al. EASL 16, Barcelona. #PS4 Premature discontinuation of treatment n (%) 3D ± RBV (n=23) Patient discretion 3 (.4) Serious adverse event* 12 (1.8) Liver decompensation 8 (1.2) *3 pts achieved SVR12; 4 pts achieved SVR12 Predictors of decompensation Age >75 years, p=.5 MELD score >1, p=.1 Previous decompensation, p<.1 Not recommended for CPB & C: Risk of decompensation C-EDGE CO-STAR: Efficacy of GZR + EBR in PWID receiving opioid agonist therapy (OAT) Phase 3, double-blind RCT in pts on OAT for >3 months Adherence >% of appointments G 1, 4, 6, or mixed ± HIV coinfection TN, % with cirrhosis 7% HIV coinfected 58% had positive DOA at Day 1 (excl. OAT) Efficacy: SVR12 (Full Analysis Set, FAS) All G1a G1b G4 G6 184/1 144/154 28/3 11/12 1/5 Relapse Reinfection LTFU or non-vf d/c Dore G, et al. AASLD 15, San Francisco. #4 EBR / GZR n=1 PBO n= Unblinding Unblinding Follow-up for 24 weeks EBR / GZR D1 Wk Efficacy: SVR12 (Modified FAS) Follow-up for 24 weeks All G1a G1b G4 G6 189/ /153 28/29 11/11 3/5 Failures Relapse d/c 2 2 Reinfection counted as success LTFU or non-vf discontinuation excluded from mfas analysis

11 Patients (%) SVR12 (%) 5/1/16 Integrated analysis of compensated cirrhotic G1, 4, or 6 pts treated with GZR/EBR 6 4 Treatment-naive 12 weeks no RBV < Biopsy APRI + fibrotest Fibroscan >25. Platelets Cirrhosis Fibroscan value (x1 3 cells/µl) determination method Treatment-experienced, preferred regimens Analysis of preferred regimens by platelet count G1 TE pts SVR12, % (n/n) 35/ 36 99/ 12 wks no RBV (n=47) 38/ 38 16/18 wks + RBV (n=44) Prior relapse (1/1) (11/11) Prior nonresponder 91.9 (34/37) (33/33) 6 4 Relapsers may require only 12 wks of therapy Prior nonresponders appear to benefit from prolongation of therapy Jacobson IM, et al. AASLD 15, San Francisco. #42 8/ 8 89/ 91 25/ 25 Platelets < x 1³ cells/µl Platelets x 1³ cells/µl / 21 45/ 45 G1b 12 wks, no RBV 3/ 31 21/ 22 65/ 66 G1a/4/6 TN/prior relapse 12 wks, no RBV 6/ 6 7/ 7 28/ 29 / G1a/4/6 Prior nonresponders 16/18 wks, +RBV Genotype 1 CURED! All patients with Genotype 1 can be cured with current therapies 11

12 5/1/16 Genotype 1 CURED! All patients with Genotype 1 can be cured with current therapies BUT It is not quite as simple as it seems Avoid PPIs with ledipasvir Extend therapy to 24 weeks with experienced G1a with Paritaprevir based regimens Consider looking for RAVs with G1a receiving Gras/Elb Genotype 1 HCV in 16 A whistle stop tour Genotype 3 Who to treat first 12

13 Patients achieving SVR (%) 5/1/16 Genotype 3 A tricky customer Non-cirrhotic is easy to cure (even cheap IFN/Riba works) Cirrhotic is hard to cure Genotype 3 PegIFN + Ribavirin S Asian n=317 Non-Asian n=322 >4 years n=437 <4 years n=1 Cirrhosis n=161 No cirrhosis n=436 Patient subgroup (n=639) Data are from an audit of 639 patients tretated with PegIFN/RBV; Shoeb D, et al. Eur J Gastroenterol Hepatol 11;23:

14 Patients achieving SVR (%) 5/1/16 Genotype 3 PegIFN + Ribavirin S Asian n=317 Non-Asian n=322 >4 years n=437 <4 years n=1 Cirrhosis n=161 No cirrhosis n=436 Patient subgroup (n=639) Data are from an audit of 639 patients tretated with PegIFN/RBV; Shoeb D, et al. Eur J Gastroenterol Hepatol 11;23: Not quite so potent Sofosbuvir in G3 Needs a good friend 14

15 SVR12 (%) 5/1/16 Results: SVR12 in GT 3 SOF + RBV 16 weeks SOF + RBV 24 weeks SOF + PEG/RBV 12 weeks intervals /112 83/ 1/11 No Cirrhosis Cirrhosis Naïve Experienced Treatment History G3 Without Interferon Treatmentnaive Treatmentexperienced Treatmentnaive Treatmentexperienced SVR12, % a Absent Present Absent Present F-F F F-F3 5 8 F4 Cirrhosis b FibroTest c a HCV RNA < LLOQ (25 IU/mL); error bars reflect 95% confidence intervals. b Cirrhosis determined by liver biopsy (METAVIR > F3), FibroScan (> 14.6 kpa), or FibroTest score.75 and aspartate aminotransferase to platelet ratio index > 2. c FibroTest assessments could have been performed up to Day 1 (baseline). 3 15

16 HCV RNA <LLOQ TD/TND (%) HCV RNA <LLOQ TD/TND (%) 5/1/16 ALLY-3+ Phase 3 Study: All-oral treatment with DCV + SOF + RBV for 12 or 16 weeks in HCV G3-infected patients with advanced fibrosis or cirrhosis 6 4 SVR12 by prior treatment Treatment history: Treatment-experienced: All patients Cirrhotic patients Naive Experienced Overall weeks weeks 22 Efficacious (9% SVR12) for G3 patients with advanced fibrosis or compensated cirrhosis, a population in urgent need of treatment Comparable SVR12 for 12- (88%) and 16-weeks (92%) No on-treatment VFs; two relapses in each treatment arm % SVR12 among patients with advanced fibrosis, 86% among patients with cirrhosis Leroy V, et al. AASLD 15, San Francisco. #LB-3 Genotype 3 Not quite there yet Current regimens not quite good enough What about future regimens? 16

17 5/1/16 ASTRAL-3 Phase 3 Study: SOF/VEL FDC for 12 weeks compared to SOF + RBV for 24 weeks in G3 HCV infected patients Week n=25 n=25 SOF/VEL SOF + RBV SVR12 95% SVR12 % p<.1 Foster GR, et al. NEJM 15 SOF/VEL 12 weeks n=277 SOF + RBV 24 weeks n=275 Mean age, y (range) 49 (21 76) 5 (19 74) Male, n (%) 17 (61) 174 (63) White, n (%) 25 (9) 239 (87) Mean BMI, kg/m 2 (range) 26 (17 48) 27 (17 56) Cirrhosis, n (%) (29) 83 (3) Treatment experienced, n (%) 71 (26) 71 (26) IL28B CC, n (%) 15 (38) 111 (4) HCV RNA, log 1 IU/mL (range) 6.2 ( ) 6.3 ( ) ASTRAL-3 Phase 3 Study: SOF/VEL FDC for 12 weeks compared to SOF + RBV for 24 weeks in G3 HCV infected patients SVR12 by cirrhosis and treatment history Cirrhosis No Yes No Yes Treatment-naive Treatment-experienced SOF/VEL SOF + RBV Foster GR, et al. NEJM 15 17

18 5/1/16 ASTRAL-3 Phase 3 Study: SOF/VEL FDC for 12 weeks compared to SOF + RBV for 24 weeks in G3 HCV infected patients SVR12 by cirrhosis and treatment history Cirrhosis No Yes No Yes Treatment-naive Treatment-experienced SOF/VEL SOF + RBV Foster GR, et al. NEJM 15 ABT ABT-53 for 8 Weeks in Treatment-Naive HCV GT3-Infected Patients Without Cirrhosis: SURVEYOR-II Study to explore shorter treatment duration of 8 weeks with ABT ABT-53 in treatment-naive GT3-infected patients without cirrhosis (part of SURVEYOR-II Part 2 study) Patient demographics N = 29 Male, n (%) 15 (52) White race, n (%) 26 (9) Age, mean years (range) 42 (27 66) BMI, mean kg/m 2, ± SD 26 ± 3.8 HCV RNA, mean log 1 IU/mL (range) 6.5 (5. 7.5) HCV GT3a*, n (%) 25 (86) Baseline fibrosis stage, n (%) F F1 (69) F2 2 (7) F3 7 (24) Targets with Baseline Variants N = 28 Any variants n (%) 13 (46) Both NS3 and NS5A variants, n 1 NS3 only, n 2 8-week treatment in GT3 NS5A only, n 1 *Subgenotype was not determined for 3 patients; Sequencing results pending for 1 patient; 1 patient withdrew consent after treatment week 6 due to intolerance of blood draws and had undetectable HCV RNA at the time of d/c. Muir AJ, et al. J Hepatol 16; 64(Suppl 2):S186 (oral presentation). SVR12, % Patients SVR12 ITT mitt SVR12 18

19 SVR12 (%) 5/1/16 ABT ABT-53 ± RBV for 12 Weeks in Treatment- Naive HCV GT3-Infected Patients With Cirrhosis: SURVEYOR-II Part of SURVEYOR-II, an open-label, multicenter phase 2 trial evaluating the safety and efficacy of co-administered ABT-493 and ABT-53 ± RBV for GT3 infection in treatment-naive patients with compensated cirrhosis (12 weeks) weeks n N GT3 With Cirrhosis ABT ABT ABT ABT-53 + RBV * Tibia fracture on PT Day 15 (assessed as unrelated to study drug); Anemia on Day 3 (assessed as possibly related to RBV); delusional disorder on PT Day 3 (assessed as possibly related to ABT-493, ABT-53 and RBV following admitted amphetamine and alcohol use the same day); Patient with elevated baseline bilirubin had grade 3 total bilirubin elevation on Day 44 that resolved post treatment. Event ABT ABT-53 (N = 24) ABT ABT-53 + RBV (N = 24) Serious AE, n (%) 1 (4)* 2 (8) AE leading to study d/c, n ALT, grade 2 (> 3 x ULN), n AST, grade 2 (> 3 x ULN), n Total bilirubin, n Grade Grade 3 1 Hemoglobin, n Grade 2 1 No ALT elevations Kwo P, et al. J Hepatol 16; 64(Suppl 2):S8 (oral presentation). G3 Cirrhosis Still a problem with nucleotides Sofosbuvir + NS5A inhibitors are not perfect in G3 cirrhosis New protease based regimens may be required 19

20 5/1/16 Genotype 1 HCV in 16 A whistle stop tour Genotype 3 Who to treat first We can t treat everyone now! There needs to be some prioritisation For now it is easy prioritise the sick Once we have treated the sick.

21 5/1/16 English Early Access Programme Long term follow up HCV Research UK Database EAP treated (1 April Nov 14) N = 467 Untreated - enrolled with decompensated cirrhosis 6 months before EAP start N = 261 Extrahepatic disease N = 14 Baseline liver transplant N = 44 Decompensated cirrhosis N = 49 Subsequently treated on EAP after 1 April 14 N = 177 SVR12 achieved N = 329 Adverse Events Over Time for Virological Responders- 15 months Adverse events were most frequent during treatment and decreased with time 21

22 5/1/16 Adverse Events Over Time for Virological Responders- 15 months Overall in 329 patients over 15 months: Decompensation 21.3% (n=7) HCC 6.4% (21) Liver transplant 12.2% (4) Deaths 4.9% (16) Survival - Improved in SVR patients over non-svr Survival over time % survival Treated with SVR Treated without SVR Untreated Time in months 22

23 % of patients 5/1/16 Which Patients Benefit from Viral Clearance? Adverse event free survival at 15 months 6 * NS * 4 N= MELD <15 MELD >/= 15 CPA CPB CPC Baseline liver disease * p<.5 Impact of focussed HCV programme 23

24 5/1/16 Who to treat next Once the cirrhotics have been treated who is next in line.. HCV Therapy in 16 Most patients can be cured Therapy is not quite as easy as it appears The challenge now is to deliver 24