HCV treatment options in clinical practice. Current treatment options for HCV-G4

Transcription

1 HCV treatment options in clinical practice Current treatment options for HCV-G4 C. Triantos Gastroenterology Department University Hospital of Patras

2 Conflicts of interest Speaker and research/travel grants from MSD, Roche, Abbvie, Bristol-Myers Squibb, Bayer and Gilead Sciences.

3 Treatment of Chronic HCV Genotype 4 Background Initial Treatment Retreatment of Prior Non-responders Future Therapies Real Clinical Practice Data Recommendations Not included data on the management of CHC in patients with decompensated cirrhosis, HBV/HIV co-infections and patients with hemoglobinopathies

4 Global Distribution and Prevalence of Hepatitis C Virus Genotypes Genotype 4 Globally, approximately 20% of all hepatitis C infections, 34 million people are chronically infected with HCV-4 Dominant HCV genotype in Egypt, North Africa, and sub-saharan Africa. Its prevalence has increased in several European countries, which is considered to be largely a consequence of immigration and intravenous drug use Messina J, Hepatology 2015

5 Epidemiological changes in chronic hepatitis C infection in Greece Savvas, S, Journal of Viral Hepatitis, 2005 Raptopoulou M, Hippoktatia 2011

6 Prospective studies evaluating a fixed 48-wk treatment using a standard dose of pegylated interferon and ribavirin in patients with hepatitis C genotype 4 Predictors of response to antiviral treatment in patients with hepatitis C virus genotype 4 infection Papastergiou V, World J Clin Cases 2015

7 Genotype 4 HCV infection is difficult to cure with pegylated interferon and ribavirin. Results from a Greek Nationwide Cohort Study Anagnostou O, Hippokratia 2014

8 Genotype 4 HCV: Initial Treatment Ledipasvir-Sofosbuvir - NIAID Synergy Ombitasvir-Paritaprevir-Ritonavir - PEARL-I Sofosbuvir + Ribavirin - Egyptian Ancestry Sofosbuvir + Ribavirin + Peginterferon - NEUTRINO

9 Genotype 4 HCV: Initial Treatment IFN-based Regimens

10 Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 1,4,5,6 NEUTRINO Trial Drug Dosing Sofosbuvir: 400 mg once daily Peginterferon alfa-2a: 180 µg once weekly Ribavirin (weight-based and in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if 75 kg Lawitz E, N Engl J Med. 2013

11 Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 1,4,5,6 NEUTRINO Trial: Results Lawitz E, N Engl J Med. 2013

12 Patients (%) with SVR12 Simeprevir + Peginterferon + Ribavirin in Genotype 4 RESTORE trial, Moreno C, J Hepatology 2015 Open-label, phase 3, n = 107, 8 centres in France and Belgium TN (n = 35) or TE relapsers (n = 22) Experienced (Nonresponder): partial (n = 10), null (n = 40) METAVIR Fibrosis Stage: F4 = 29%; F3 = 14% lack of a control arm serious AEs were infrequent (4.7%) All Treatment-Naïve Relapsers Partial Null

13 High efficacy of a 12-week simeprevir plus peginterferon alfa 2a/ribavirin regimen in treatment-naïve patients with chronic HCV genotype 4 infection and mild-to-moderate fibrosis Phase-3, open-label study Europe and Saudi Arabia G4 patients who achieved HCV-RNA <25 IU/mL (detectable/undetectable in IL28B CC, undetectable in CT/TT) at Week 2, and undetectable at Weeks 4 and 8 (Roche COBAS Taqman ), stopped all treatments at Week 12 (12-week group). Otherwise, PR was continued to Week 24 (24-week group). The 24-week group also included patients discontinuing treatment early for any reason. 67, G4 patients were enrolled (male: 69%, white: 80%, G4a/d/other: 40/37/23%, METAVIR F0 1/F2: 81/18%) SVR12 rates were 97% (33/34) and 84% (21/25) for the 12-week and 24-week groups, respectively Asselah T, AASLD 2015

14 Daclatasvir + Peg/RBV in Treatment-Naïve Genotype 4, COMMAND-4 Study, Phase 3 randomized, placebo-controlled trial, United States and Europe HezodeC, ID Week. 2014

15 Genotype 4 HCV: Initial Treatment All-oral Regimens

16 Ledipasvir-Sofosbuvir in Genotype 4 F4, 33% single-site trial nonrandomised enrolment without ribavirin Kohli A, Lancet Infect Dis. 2015

17 LDV/SOF in GT 4 Patients Multicenter study in TN/TE GT 4 or 5 patients in France Open-label, single-arm study: 12 wks LDV/SOF 90/400 mg QD LDV/SOF for 12 weeks was highly effective and well tolerated, without the need for RBV Naïve n=22 Experienced n= SVR Mean age, years (range) 52 (21 69) 50 (30 62) Male, n (%) 11 (50) 17 (77) White, n (%) 19 (86) 17 (77) Cirrhosis, n (%) 1 (5) 9 (41) IL28B non-cc, n (%) 15 (68) 21 (95) Mean HCV RNA, log 10 IU/mL (range) 6.0 ( ) 6.3 ( ) GT 4a, n (%) 13 (59) 12 (55) GT 4d, n (%) 5 (23) 5 (23) GT 4b, 4f, 4m, 4o, 4r, n (%) 4 (18) 5 (23) /22 20/22 31/34 10/10 TN TE No Yes Treatment Status Cirrhosis Abergel EASL, 2015

18 Ombitasvir + Paritaprevir + Ritonavir +/- RBV in HCV GT4 PEARL-I: Baseline demographics and disease characteristics France, Hungary, Italy, Poland, Romania, Spain,Turkey, and USA large study lack of examination of a ribavirin-free regimen in treatment experienced patients. only non-cirrhotic patients Drug Dosing Ombitasvir (25 mg once daily), Paritaprevir (150 mg once daily), Ritonavir (100 mg once daily) Ribavirin (RBV): weight-based and divided bid (1000 mg/day if < 75kg or 1200 mg/day if 75kg) Hézode C, Lancet. 2015

19 Ombitasvir + Paritaprevir + Ritonavir +/- RBV in HCV GT4 PEARL-I: Results Hézode C, Lancet. 2015

20 Efficacy and Safety of Ombitasvir/Paritaprevir/Ritonavir Co-Administered with Ribavirin in Adults with Genotype 4 Chronic Hepatitis C Infection and Cirrhosis (AGATE-I) Canada, Europe and US Asselah T, AASLD 2015

21 Efficacy and Safety of Co-Formulated Ombitasvir/Paritaprevir/ Ritonavir with Ribavirin in Adults with Chronic HCV Genotype 4 Infection in Egypt (AGATE-II) Esmat G, ASLD 2015

22 Sofosbuvir and Ribavirin in HCV Genotype 4 Egyptian Ancestry Trial Drug Dosing Sofosbuvir: 400 mg once dailyweight-based Ribavirin (in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if 75 kg Ruane PJ, J Hepatol. 2015

23 Sofosbuvir and Ribavirin in HCV Genotype 4 Egyptian Ancestry Trial: Results absence of complete prior treatment histories in all patients small number of patients infected with non-4a HCV. Ruane PJ, J Hepatol. 2015

24 Sofosbuvir plus Ribavirin in the Treatment of Egyptian Patients with Chronic Genotype 4 HCV Infection An integrated analysis was conducted of data from treatment-naïve and treatmentexperienced patients enrolled in Study GS-US in the USA (n=60) and GS-US in Egypt (n=103). Doss W, AASLD 2015

25 Retreatment of GT4 Chronic HCV Ledipasvir-Sofosbuvir - NIAID Synergy (Genotype 4) Ombitasvir-Paritaprevir-Ritonavir - PEARL-I Sofosbuvir + Ribavirin - Egyptian Ancestry

26 Patients (%) with SVR12 Retreatment of GT4 Chronic HCV - IFN-based Regimens Simeprevir + Peginterferon + Ribavirin in Genotype 4 (RESTORE) All Treatment-Naïve Relapsers Partial Null Moreno C, J Hepatology 2015

27 Retreatment of GT4 Chronic HCV All-oral Regimens Kohli A, Lancet Infect Dis Abergel, EASL, 2015 Hézode C, Lancet Ruane PJ, J Hepatol. 2015

28 Treatment of Hepatitis C Genotype 4 patients with Simeprevir and Sofosbuvir: Preliminary Results from a Phase IIa, Partially Randomised, Open-label Trial conducted in Egypt (OSIRIS) SVR 12, 100 % independently of prior PR response or cirrhosis G. Van Dooren, AASLD 2015

29 Figure 1. Study Designs Advanced cirrhosis ALLY-1 c Post-liver transplant Treatment-naive ALLY-2 Treatment-experienced Sofosbuvir + Daclatasvir +RBV DCV 60 mg + SOF 400 mg + RBV DCV 60 mg + SOF 400 mg + RBV DCV 30/60/90 mg + SOF 400 mg SVR12 b Regimen Study SVR 12 DCV 30/60/90 mg + SOF 400 mg DCV 30/60/90 mg + SOF 400 mg DCV + SOF + RBV ALLY (4) (advanced cirrhosis) Treatment-naive ALLY-3 Treatment-experienced AI d GT 1 Treatment-naive GT 2/3 Treatment-naive DCV 60 mg +SOF 400 mg DCV 60 mg +SOF 400 mg A: SOF 7 d, then DCV 60 mg + SOF 400 mg C: DCV 60mg + SOF 400 mg E: DCV 60 mg + SOF 400 mg + RBV G: DCV 60 mg + SOF 400 mg H: DCV 60 mg + SOF 400 mg + RBV B: SOF 7 d, then DCV 60 mg + SOF 400 mg D: DCV 60 mg + SOF 400 mg F: DCV 60 mg + SOF 400 mg + RBV SVR12 b GT 1 PI failures I: DCV 60 mg + SOF 400 mg J: DCV 60 mg + SOF 400 mg + RBV Week 0 Week 8 Week 12 Week 24 Week 36

30 HCV genotype 4: SVR with different direct-acting antivirals (DAAs) (with or without IFN). Asselah T, Journal of Hepatology 2015

31 Future Regimens for GT-4

32 Future Regimens for GT-4 Daclatasvir and Asunaprevir Plus Peginterferon Alfa-2a and Ribavirin Daclatasvir, asunaprevir, and beclabuvir Sofosbuvir-Velpatasvir Grazoprevir-Elbasvir Ravidasvir (PPI-668) and Sofosbuvir

33 Daclatasvir and Asunaprevir Plus Peginterferon Alfa-2a and Ribavirin in Patients With HCV Genotype 1 or 4 Infection: Phase 3 HALLMARK-QUAD, Jensen IDWeek 2014

34 A randomized trial of daclatasvir in combination with asunaprevir and beclabuvir in patients with chronic hepatitis C virus genotype 4 infection RCT, 1:1 to receive a twice-daily oral regimen comprising of 75 mg or 150 mg of beclabuvir, each with daclatasvir (30 mg) and asunaprevir (200 mg), for 12 weeks with 48 weeks of post-treatment follow up. Patients with compensated cirrhosis were permitted although none were enrolled. Hassanein T, Journal of Hepatology 2015

35 ASTRAL-1, -2, -3, -4 Trials Sofosbuvir/ Velpatasvir FDC ± RBV in GT1-6 HCV Multicenter, randomized phase III trials in Tx-naive and Tx-experienced pts 12 wks 24 wks ASTRAL-1 [1] : GT 1, 2, 4, 5, or 6 HCV (N = 740) ASTRAL-2 [2] : GT2 HCV (N = 266) Sofosbuvir/Velpatasvir (n = 624) Placebo QD (n = 116) Sofosbuvir/Velpatasvir (n = 134) Sofosbuvir + RBV (n = 132) Gen 4, SVR % (116/116) ASTRAL-3 [3] : GT3 HCV (N = 552) ASTRAL-4 [4] : GT1-6 HCV and CTP B cirrhosis (N = 267) Sofosbuvir/Velpatasvir (n = 277) Sofosbuvir + RBV (n = 275) Sofosbuvir/Velpatasvir (n = 90) Sofosbuvir/Velpatasvir + RBV (n = 87) Sofosbuvir/Velpatasvir (n = 90) Sofosbuvir/velpatasvir 400/100 mg QD 1. Feld JJ, et al. NEJM Sulkowski MS, et al. AASLD Abstract Mangia A, et al. AASLD Abstract Charlton MR, et al. AASLD Abstract LB-13.

36 Grazoprevir/Elbasvir Studies: Overview C-EDGE TN C-EDGE TE C-EDGE Coinfection C-SALVAGE C-SCAPE C-WORTHY C C-SWIFT C-SURFER 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 treatment-naive, GT1 or 3 HCV infected pts ± cirrhosis 12 wks of grazoprevir/elbasvir in pts with GT1 HCV infection and stage 4 or 5 CKD

37 Grazoprevir/Elbasvir Studies: Overview C-EDGE TN C-EDGE TE C-SCAPE 12 wks of grazoprevir/elbasvir in treatment-naive pts with GT1, 4, or 6 HCV infection 22% cirrhotics, SVR12, 100% (18/18) 12 or 16 wks of grazoprevir/elbasvir ± RBV in pts with GT1, 4, or 6 HCV and previous failure of pegifn/rbv 34 % cirrhotics SVR 4, GZR/EBR - 78 % (7/9) - GZR/EBR+RBV 100 % (15/15) 12 wks of grazoprevir ± elbasvir ± RBV in treatment-naive, noncirrhotic pts with GT2, 4, 5, or 6 HCV N=20, SVR12 GZR/EBR 100 % - GZR/EBR+RBV 90 % C-EDGE CO-STAR (PWID) (+- cirrhosis), SVR12 92 % (11/12)

38 Grazoprevir/Elbasvir Studies: Overview C-EDGE TN C-EDGE TE C-SCAPE 12 wks of grazoprevir/elbasvir in treatment-naive pts with GT1, 4, or 6 HCV infection 22% cirrhotics, SVR12, 100% (18/18) 12 or 16 wks of grazoprevir/elbasvir ± RBV in pts with GT1, 4, or 6 HCV and previous failure of pegifn/rbv 34 % cirrhotics SVR 4, GZR/EBR - 78 % (7/9) - GZR/EBR+RBV 100 % (15/15) 12 wks of grazoprevir ± elbasvir ± RBV in treatment-naive, noncirrhotic pts with GT2, 4, 5, or 6 HCV N=20, SVR12 GZR/EBR 100 % - GZR/EBR+RBV 90 % C-EDGE CO-STAR (PWID) (+- cirrhosis), SVR12 92 % (11/12)

39 GT4 infected patients enrolled in the GZR/EBR phase 2/3 clinical program Asselah T, AASLD 2015 Child-Pugh A cirrhosis. SVR 12 (TE) - 76, 4% (13/17) (includes 13 pts treated for 12 wks and 4 pts treated for 16/18 wks). Jacobson IM, et al. AASLD 2015

40 High Virologic Response Rate in Egyptian HCV-Genotype 4 Patients Treated with Ravidasvir (PPI-668) and Sofosbuvir: Results of a Large Multicenter Phase 3 Registrational Trial Esmat G, AASLD 2015

41 Genotype 4 - Real Clinical Practice Data - 1 SOF/PEG/RBV IFN/RBV/SOF N=24 M.H.Wehmeyer GERMA NY Dig Liver Dis 2015 Cirrhosis, 23.1% TE, 50 % SVR % SOF/PEG/RBV SOF/PEG/RBV N=16 N=4 S. Alqahtani Cirrhosis, USA % EASL 2015 TE, Cirrhosis % % SVR12, TE, % -88 % SVR 4, 88% SOF/PEG/RBV N=11 K. Bichoupan USA EASL % had a FIB-4 score 3.25 NA SVR12, 82% SOF/PEG/RBV D.Ouzan FRANCE EASL 2015 Cirrhosis 77% TE 100 % SVR 12, 67 % SOF/RBV SOF/RBV N=2 K. Bichoupan USA EASL % had a FIB-4 NA SOF/RBV N=2 Cirrhosis, % TE, 59 score % 3.25 SVR12, % SVR12, 50% SOF/RBV M=45 Moutaz F. Derbala QATAR AASLD 2015 Cirrhosis, 34.3% TE 58.8% SVR4, 96%

42 Genotype 4 - Real Clinical Practice Data - 2 SOF/DCV SOF/DCV N=33 ANRS CO22 HEPATHER FRANCE EASL 2015 Cirrhosis 78,8 % TE 70,7 % SVR 12, 12 W 90 % SOF/DCV N=1 Cirrhosis, 78 % TE, 71 % SVR 12, 24 W 100 % SOF/DCV/RBV N=15 12 W 90 % ANRS CO22 FRANCE EASL Cirrhosis 86,7 % 24 TE W 66-% 100 % SVR 12, HEPATHER W 100 % SOF/DCV/RBV N= 2 Cirrhosis, % TE, % SVR 12, 24 W 100 % 12 W 100 % SOF/DCV/RBV D.OUZAN FRANCE EASL W 100 % Cirrhosis 77% TE 100 % SVR 12, 100 % SMV/DCV SMV/DCV N=47 SMV/DCV Mohamed Alzaabi N=2 UNITED ARAB Cirrhosis, AASLD % Cirrhosis, 72.3 TE, 56 % TE, 56.1% SVR12, 85 % SVR 4, 85% EMIRATES SMV/DCV N=47 E. Taleb UNITED ARAB EMIRATES AASLD 2015 Cirrhosis, 68,4 % TE 56.1% SVR12, 85 %

43 Genotype 4 - Real Clinical Practice Data - 3 SOF/SMV+/- RBV SOF/SMV+/- ribavirin SOF/SMV+/- RBV (G 1/4) SOF/SMV+/- RBV (G 1/4) N=73 C. Moreno BELGIUM AASLD 2015 Cirrhosis 56.2 % Te 78.8 % W12, 74 % N=108 Z. Kayali USA AASLD 2015 Cirrhosis 100 % TE 46% SVR12, 77% N=130 E. Nguyen-Khac FRANCE AASLD 2015 Cirrhosis 66.9%. TE 70 % SVR % SMV/SOF N=19 E. Taleb UAE AASLD 2015 Cirrhosis 68.4 TE 56.1% SVR12, 94% SOF/SIM N=6 Cirrhosis, % TE, % SVR 12, % SOF/SMV N=40 F. Derbala Qatar AASLD 2015 Cirrhosis 34.3% TE 58.8% SVR4 96% SOF/SIM/RBV N= 7 Cirrhosis, % TE, % SVR 12, % SOF/SIM N=6 S. Alqahtani USA EASL 2015 Cirrhosis 38% TE 50 % 100% SOF/SIM + RBV N=6 S. Alqahtani USA EASL 2015 Cirrhosis 33% TE 83 % 100% SOF/SIM N=32 A.M. Hefner USA EASL 2015 Cirrhosis 100 % TE 71% SVR 12, naive 80%, TE 81% SOF/SMV N=27 K. Bichoupan USA EASL % had a FIB-4 score 3.25, NA SVR12 81% SOF/SMV/RBV N=70 K. Bichoupan USA EASL % had a FIB-4 score 3.25, NA SVR12 86% SOF/SIM N=22, 12 w N=32 24 w ANRS CO22 HEPATHER FRANCE AASLD 2015 Cirrhosis 53 %, 12 w Cirrhosis 61 %, 24 w TE 73 % SVR 12, 12 W 84 % 24 W 100 % SOF/SIM/RBV N=24, 12 w N=32 24 w ANRS CO22 HEPATHER FRANCE AASLD 2015 Cirrhosis 67 %, 12 w Cirrhosis 89 %, 24 w TE 71 % SVR 12, 12 W 100 % 24 W 100 % SOF/SIM/RBV D.OUZAN FRANCE EASL 2015 Cirrhosis 77% TE 100 % SVR 12, 100 %

44 Real Clinical Practice Data in Greece, n=52 SVR12, % Pts 1/ 4 /0 4/ 20/ 4 4/ 0/ 0 6/ 0/ 3 1/ 5/ 0 Papatheodoridis G, ΠΓΣ 2015

45

46 Recommendations on Treatment of Hepatitis C Genotype 4 AASLD Treatment naïve ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) and weight-based RBV for 12 weeks sofosbuvir (400 mg) and weight-based RBV for 24 weeks Alternative regimen for patients eligible to receive interferon sofosbuvir (400 mg) and weight-based RBV plus weekly PEG-IFN for 12 week Prior treatment with PEG-IFN and RBV has failed ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) (PrO) and weight based RBV for 12 weeks sofosbuvir (400 mg) for 12 weeks and daily weight based RBV plus weekly PEG-IFN for 12 weeks sofosbuvir (400 mg) and weight-based RBV for 24 weeks.

47 Recommendations on Treatment of Hepatitis C Genotype 4 European Association for the Study of the Liver cirrhosis ΚΕ.ΕΛ.Π.ΝΟ 12 w SMV+PR / PR x12/12 ή 36 w 24 w SOF/LDV SOF/LDV + RBV x 12 w + PR x 24 ή 48 w x 12 w x 12 w Sof +DCV SOF+DCV +RBV x12 ή 24 w

48 Recommendations on Treatment of Hepatitis C Genotype 4 European Association for the Study of the Liver 96 % 83 % 96 % 100 % cirrhosis 100 % RWD 100 % RWD % 100 % 97 % 100 % RWD 100 % ΚΕ.ΕΛ.Π.ΝΟ 12 w SMV+PR / PR x12/12 ή 36 w 24 w SOF/LDV SOF/LDV + RBV x 12 w + PR x 24 ή 48 w x 12 w x 12 w Sof +DCV SOF+DCV +RBV x12 ή 24 w

49 Treatment recommendations for retreatment of HCV-monoinfected or HCV/HIV coinfected patients with chronic hepatitis C who failed to achieve an SVR on prior antiviral therapy containing one or several DAA(s) EASL - Genotype 4 Patients that failed SOF alone, in combination with RBV or in combination with PegIFN-α and RBV GT4 LDV/SOF + RBV 12 wk or 24 wk (if F3) OBV/PTV/R TV + RBV 12 wk or 24 wk (if F3) SOF + SMV + RBV 12 wk or 24 wk (if F3) SOF + DCV + RBV 12 wk or 24 wk (if F3) Patients that failed PegIFN-α, RBV and SMV or SOF and SMV GT1 or 4 LDV/SOF + RBV 12 wk SOF + DCV + RBV 12 wk or 24 wk (if F3) Patients that failed PegIFN-α, RBV and DCV GT4 SOF + SMV + RBV 12 wk or 24 wk (if F3) Patients that failed SOF and DCV or LDV/SOF GT4 SOF + SMV + RBV 12 wk or 24 wk (if F3) Patients that failed OBV/PTV/RTV and DSV (GT1) or OBV/PTV/RTV (GT4) GT4 LDV/SOF + RBV 12 wk or 24 wk (if F3) SOF + SMV + RBV 12 wk or 24 wk (if F3) SOF + DCV + RBV 12 wk or 24 wk (if F3)

50 Summary Genotype 4 hepatitis C virus infection is not common in the United States, but it is highly prevalent in the Middle East, Africa, and Southern Europe. HCV-G4 has been considered difficult to treat with pegylated interferon (PegIFN) and ribavirin (RBV) treatment, with sustained virological response (SVR) rates around 50% The main limitations on HCV-G4 are their small sample size and the relatively mild stage of liver diseases included in patients There are effective regimens There is optimism for patients with genotype 4 HCV infection, with several promising ongoing trials. With these excellent data, the next steps will be to improve screening and access to therapy

51