Hepa%%s C elimina%on needs involvement of all turn the page. Graham R Foster Professor of Hepatology Queen Mary University of London

Transcription

1 Hepa%%s C elimina%on needs involvement of all turn the page Graham R Foster Professor of Hepatology Queen Mary University of London

2 Conflicts of Interest Speaker and consultancy fees received from AbbVie, BI, BMS, Gilead, Janssen, Roche, Merck, NovarJs, Springbank, Achillion, Idenix

3 HCV The disease and its impact Viro- babble The polijcs

4 HCV The disease and its impact Viro- babble The polijcs

5 HCV causes slowly progressive liver fibrosis Percent of patients with cirrhosis Asian Genotype 3 Caucasians >70 Age of patients (years) Adapted from D Souza. Clin Gastroenterol Hepatol 2005;3:910 17

6 HCV causes slowly progressive liver fibrosis Percent of patients with cirrhosis Cirrhosis leads to HCC in 5% per year >70 Age of patients (years) Adapted from D Souza. Clin Gastroenterol Hepatol 2005;3:910 17

7 PaJents with chronic HCV feel unwell Physical functioning Social Role - Role - Mental functioning Physical Emotional health Foster et al Hepatology 1998 Energy and fatigue Controls Pain General health perception Mild disease' Severe' disease

8 HCV Makes people sick Then it kills them

9 Where we started Have HCV get a liver biopsy (not very nice) If very severe disease die quietly (not very nice) If moderate disease get up to 18 months injecjons and tablets for a 70% chance of a cure (not very nice)

10 Where we are today Get a scan Take some tablets for a few weeks Get cured (All very nice)

11 HCV The disease and its impact Viro- babble The polijcs

12 We now have highly efficacious DAAs that target different stages in the HCV lifecycle Receptor binding and endocytosis Transport and release Fusion and uncoating Virion assembly Translation and polyprotein processing (+) RNA LD ER lumen LD NS5A inhibitors Membranous web ER lumen LD RNA replication NS3 protease inhibitors Non-NA NS5B inhibitors NA NS5B inhibitors 3680/ 3826 Lindenbach BD, Rice CM. Nature 2005;436(Suppl):933 8; Liang J, Ghany MG. N Engl J Med 2014;370: DAA: direct- acjng anjviral agent; ER: endoplasmic rejculum; GT: genotype; IFN: interferon; LD: luminal domain; NA: nucleos(t)ide analogue; NS: non- structural protein; SVR: sustained virological response

13 SVR achieved (n=251) Real- world experience from the TRIO Network: EffecJveness of 8 or 12 week LDV/SOF in treatment- naive pajents with non- cirrhojc, G1 HCV 8 wks LDV/SOF (n=263) Pa%ent disposi%on TN, non- cirrhojc (n=895) SVR not achieved (n=3) *21 PaJents were on 12 weeks of LDV/SOF+RBV SVR achieved (n=604) Curry M, et al. AASLD 2015, San Francisco. # wks LDV/SOF ± RBV (n=632)* SVR12 by dura%on Relapse 9 Death 0 LTFU 6 DC/ 3 Relapse 6 Death 2 LTFU 16 DC/ 4 251/ /632 8 weeks 12 weeks SVR not achieved (n=6) SVR12 by fibrosis F0 F1 F2 F3 <6MM 6MM+ 8 weeks 12 weeks SVR12 rates by baseline viral load / /456 8/8 162/170

14 SVR12/24 (%) 100 Real- world safety and effecjveness of OBV/PTV/r with DSV and/ or RBV in the German hepa%%s C Registry Effec%veness by cirrhosis or treatment history / 378 Safety, n (%) 108/ / 254 Total G1 G1a G1b G4 Total G1 G1a G1b G4 Naive Peg ± Without cirrhosis With cirrhosis RBV Hinrichsen H, et al. EASL 2016, Barcelona. #GS07 51/ / / 28 93/ 97 2/ 2 200/ / / 48 TVR/BOC + RBV 2D/3D - RBV (n=436) 2D/3D + RBV (n=353) 2D/3D - RBV (n=44) 2D/3D + RBV (n=184) Any AE 185 (42) 201 (57) 20 (45) 119 (65) Any SAE 5 (1) 8 (2) 0 8 (4) RBV dose mod (7) - 18 (10) Death 2 (0.5) D/C due to AE 2 (0.5) 4 (1) 0 9 (5) FaJgue 80 (18) 97 (27) 8 (18) 58 (32) Pruritus 33 (8) 40 (11) 2 (5) 26 (14) AEs in Headache 35 (8) 35 (10) 5 (11) 16 (9) 5%of Insomnia 17 (4) 29 (8) 0 18 (10) pajents Nausea 16 (4) 20 (6) 3 (7) 12 (7) Anemia 1 (0.2) 15 (4) 0 20 (11)

15 Elbasvir and grazoprevir: Pooled Efficacy in HCV GT1a Infected PaJents ZEPATIER 12 weeks ZEPATIER + RBV 16 weeks 100% 90% 93% 95% 97% 100% 100% 98% 100% 91% 94% Subjects Achieving SVR 80% 70% 60% 50% 40% 30% 20% 10% 0% n N Overall SVR Without NS5A Resistance Associated Polymorphisms b,c 53% With NS5A Resistance Associated Polymorphisms b,c Baseline HCV RNA 800,000 IU/mL Baseline HCV RNA >800,000 IU/mL

16 ASTRAL- 3 Phase 3 Study: SOF/VEL FDC for 12 weeks compared to SOF + RBV for 24 weeks in G3 HCV infected pajents SVR12 by cirrhosis and treatment history Cirrhosis No Yes No Yes Treatment- naive Treatment- experienced SOF/VEL SOF + RBV Foster GR, et al. NEJM 2015

17 Phase 3 evaluajon of SOF/VEL FDC for 12 weeks in Tx- naive and - experienced G1, 2, 4, 5, and 6 pajents with and without cirrhosis: ASTRAL- 1 study SVR12* (%) / 206/ 117/ 104/ 116/ 34/ 41/ Overall G1a G1b G2 G4 G5 G6 *HCV RNA <15 IU/mL No pts in the PBO group had HCV RNA <15 IU/mL at any Jmepoint Virologic failure, n (%) On- treatment failure 0 Post- treatment relapse 2 (<1) Other reasons for classifica%on as failure to achieve SVR 12, n (%) Lost to follow- up 2 (<1) Withdrew consent 1 (<1) Death 1 (<1) Feld JJ, et al. AASLD 2015, San Francisco. #LB- 2 Feld JJ, et al. N Engl J Med Nov 16. [Epub ahead of print]

18 What is coming next? We have great opjons available What can we expect in the future?

19 Two drugs good, three drugs bever Sofosbuvir based regimens Triple therapy with:- NucleoJde NS5A inhibitor Protease inhibitor

20 100 A randomized Phase 3 trial of SOF/VEL/VOX for 8 weeks compared to SOF/VEL for 12 weeks in DAA- naive G1 6 pajents: The POLARIS- 2 study SVR12, % / / / / / / / 63 57/ 59 61/ 63 53/ 53 91/ 92 86/ 89 58/ 63 56/ 57 17/ / 30 9/ 9 2/ of 2 pajents (100%) with G1 other achieved SVR12 (1 each in SOV/ VEL/VOX and SOF/VEL arms) SOF/VEL/VOX 8 wks, n=501 Jacobson IM, et al. AASLD 2016, Boston. #LB- 12

21 SVR12 (%) ENDURANCE- 1: Efficacy and safety of 8- vs 12- week treatment with Glecaprevir/Pibrentasvir in G1 pajents , , */ / / / 334 Overall ITT Mono- infected Coinfected SOF- experienced 15/ 15 18/ 18 1/ 1 2/ 2 ITT popula%on: All pts receiving study drug; none excluded 8- wk *1 pt in the 8- wk Tx arm experienced on- treatment virologic failure; 1 pt in the 8- wk tx arm d/c in Week 2 due to non- compliance; 2 pts, 1 in each tx arm, are missing SVR12 data All- oral, RBV- free G/P regimen can yield high SVR12 rates in 8 weeks for non- cirrhojc G1 pajents, including those with HIV- 1 coinfecjon Zeuzem S, et al. AASLD 2016, Boston. #253

22 Next generajon regimes Expected soon 2 or 3 drug 8 week regimens for all genotypes Sof/led OR G/P for G1 Sof/vel/vox OR G/P for all others

23 HCV a dead virus We can cure ALL pajents with HCV with simple tablet based, side effect free regimens

24 HCV The disease and its impact Viro- babble The polijcs

25 HCV - PoliJcs The drugs are expensive (but ge{ng cheaper) Some people are more difficult to treat than others

26 HCV - PoliJcs The drugs are expensive (but ge{ng cheaper) Some people are more difficult to treat than others Where do acjve injectors sit on the treatment list?

27 Trial of Grazoprevir/Elbasvir in InjecJng drug users % SVR12 (95% CI) ,5 96,1 96,6 100,0 60,0 20 Failures 0 All GT GT1a* GT1b GT4 GT6 189/ /153 28/29 11/11 3/5 Relapse Discon%nua%on Reinfec%on counted as success LTFU or discon%nued unrelated to Virologic Failure excluded from mfas analysis *Includes one subject with mixed infecjon (GT1a and GT1b) who achieved SVR12 AASLD 2015

28 Incidence of reinfecjon Through FW12 Through >FW48 5 reinfec%ons Through FW24 1 reinfec%on 2 reinfec%ons 8 reinfec%ons 4.0 reinfec+ons per 100 person years From End of Treatment Through Observa%on Visit 1 8 reinfec%ons person years 4.0 reinfec%ons per 100 person years (95% CI: 1.7, 8.0) From End of Treatment Through Observa%on Visit 1 (Includes only those pa%ents with persistent HCV RNA) 5 reinfec%ons person years 2.5 reinfec%ons per 100 person years (95% CI: 0.8, 5.9)

29 HCV in Drug Users HCV is common in those who use drugs Therapy is effecjve in drug users The benefits of treajng drug users may be huge

30 200% Empirical social network of PWID SVR JD35 8,100% SVR Rolls DA, et al. J Theor Biol 2012;297:73 87 Slide thanks to John Dillon

31 Hawthorne Effect Benefits of engaging with health care systems goes beyond the treated disease

32 TreaJng acjve drug users Drug users should be a priority for treatment Are they

33 Transplant waijng lists in the USA If you have kidney failure You wait 7 years for a kidney (7 weeks if you will accept an HCV +ve kidney)

34 In summary We have fantasjc curajve therapies for HCV TreaJng drug users is the most effecjve way to use these wonderful drugs What is stopping us?