Real lifeexperienceonhcv treatment, Simeprevir+Sofosbuvirat 2 University Hospitalsin Galicia.

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1 Real lifeexperienceonhcv treatment, Simeprevir+Sofosbuvirat 2 University Hospitalsin Galicia. Iria Rodríguez Osorio Clinical Virology Group, INIBIC-CHUAC Internal Medicine Service, CHUAC iria.rodriguez.osorio@sergas.es

2 SMV+SOF ON HCV TREATMENT o Clinical trials. o Real life cohorts. o GALICIA-Experience with Simeprevir+Sofosbuvir.

3 EVIDENCE IN CLINICAL TRIALS: COSMOS

4 EVIDENCE IN CLINICAL TRIALS: OPTIMIST 1

5 EVIDENCE IN CLINICAL TRIALS: OPTIMIST 2

6 SMV+SOF ON HCV TREATMENT o Clinical trials. o Real life cohorts. o GALICIA-Experience with Simeprevir+Sofosbuvir.

7 REAL LIFE COHORTS: SMV+SOF

8 REAL LIFE COHORTS: SMV+SOF

9 SMV+SOF ON HCV TREATMENT o Clinical trials. o Real life cohorts. o GALICIA-Experience with Simeprevir+Sofosbuvir.

10 Gaps in evidence: Real world data may be different than predicted by Phase III AIM studies There are major evidence gaps around effectiveness of HCV therapies: Some populations were not well-studied in registration trials True treatment harms/benefits (short and long-term) and side effects To acquire and analyze real world data from patients undergoing HCV treatment with Simeprevir+Sofosbuvir±RBV in two University Hospitals from Galicia

11 A 12 week combination of Simeprevir plus a high barrier-to-resistance NUC Polymerase Inhibitor shows: High activity and good safety profile in HCV G1 and G4 infected patients Responde irrespective from classical response predictors derived from the interferon era Is a safe and effective option for HIV-positive patients co-infected with G1 without cirrhosis or compesated cirrhosis

12 Basal characteristics of the study population

13 Hospital Universitario de A Coruña. CHUAC. (n=43) Hospital Universitario Álvaro Cunqueiro. Vigo. CHUVI (n=44)

14 Table1. Basal characteristicsof thestudypopulation. Pacients, n 87 Men, n (%) 57 (65.5) Age (years old), mean ± SD 54.5 ± 10,5 Genotype IL28B CT/TT, n (%) 35 (40.2) RNA HCV (log 10 UI/mL), median (range) 6.1 ( ) Naives, n (%) 38 (43.7) Previously treated, n (%) 49 (56.3) Previously treated, n (%) Relapser Parcial responders Null responders Unknown 12 (24.5) 21 (42.9) 14 (28.6) 2 (4)

15 Table 2. Basal characteristics of the study population. Pacientes, n 87 Fibrosis (Fibroscan), n (%) F0-F1 F2 F3 F4 Child-Pugh-Turcotte score A Child-Pugh-Turcotte score B Genotypo HCV, n (%) 1a 1b 4 2 (2.3) 7 (8) 6 (6.9) 72 (82.8) 73 (83.9) 14 (16.1) 30 (34.5) 40 (46.0) 17 (19.5) Polimorphism Q80K not present in GT1a, n (%) 27* (100) HIV, n (%) CD4/mm 3, median ± SD CV<20 cop/ml, n (%) ART, n (%): 27 (31) 411 ± (100) 27 (100) *3 patients: Q80K not performed

16 Alb < 3.5 g/dl Alb > 3.5 g/dl Basal Fibrosis: Mean=24,7 Kpa Median=21,7 Kpa Minimum= 14,6 Kpa Maximum= 74,5 Kpa 74% 26% Platelets <9x109/L Platelets >9x109/L 49% 51% Figure 1. Basal fibrosis of the study population. Figure 2. Basal characteristics of the study populatio

17 56,3 PI 1 Faldaprevir (Relapser) 3 Telaprevir (PR) >10 months since PI treatment (10-32) 43, ,4 2,3 4,6 Naives Previously treated Figure 3.HCV previoustreatment. IFN IFN+RBV Peg-IFN+RBV PI

18 28,8 23/80 71,4 71,3 5/7 57/80 12w With RBV Without RBV 28,6 2/7 24w Figure 4. HCV treatmentregimen.

19 w8 w12-24 EOT SVR12 Figure 5. HCV treatmentcurrentstatus.

20 Results

21 W2 W4 W8 W12 W24 UNDETECTABLE RNA-HCV 63,2 96,9 96,6 71,4 7,1 1/14 55/87 63/65 84/87 5/7 W2 W4 W8 W12 W24 Figure 6. Viral kinetics during HCV treatment.

22 ITT PP 89,7 98,7 37,9 41,8 33/87 33/79 78/87 78/79 SVR4 SVR12 Figure 7. Efficacy of HCV treatment.

23 1 FAILURE 51 yo monoinfected male. G1a, Q80K notpresent. F4 (FS: 63,9 kpa, CPT B8). Naive. Sofosbuvir+ Simeprevir+ Ribavirine(12 weeks). w2 RNA VHC > 15 UI/mL. W4 RNA VHC < 15 UI/mL. W8 and EOT: RNA-VHC undetectable.

24 Results by subgroups (ITT)

25 G1a G1b G ,5 94,1 GT1a: n=30 GT1b: n=40 GT4: n= ,2 12/30 14/40 7/17 27/30 35/40 16/17 SVR4 SVR12 Figure 8. SVR by genotype(itt).

26 Naive Previously treated 86,8 91,8 42,9 31,6 12/38 21/49 33/38 45/49 SVR4 SVR12 Figure 9. SVR by previous treatment(itt).

27 NR PR Relapser , ,9 42,9 50 6/14 9/21 6/12 14/14 20/21 9/12 SVR4 SVR12 Figure 10. SVR by previous response to treatment(itt).

28 IFN IFN+RBV Peg-IFN+RBV PI , ,3 25,9 7/27 1/2 9/16 4/4 23/27 2/2 16/16 4/4 RVS4 RVS12 Figure 11. SVR by previous treatment(itt).

29 RBV Without RBV GLOBAL 96,6 89, ,9 46,4 37,9 20/59 13/28 33/87 57/59 21/28 78/87 SVR4 SVR12 Figure 12. SVR byuse of ribavirine(itt).

30 RBV= 59 RBV adjustement= 21 (35.6%) Global with RBV RBV adjustement Without RBV adjustement 96,6 95,2 97,4 33,9 38,1 31,6 20/59 8/21 12/38 57/59 20/21 37/38 SVR4 SVR12 Figure 13. SVR by necesity of adjustment ribavirine(itt).

31 Cirrhosis: n=72 Without cirrhosis: n=15 Cirrhosis Without cirrhosis 91, ,3 26,7 29/72 66/72 12/15 4/15 RVS4 Figure 14. SVR by cirrhosis status (ITT). RVS12

32 Cirrhosis Alb < 3,5 g/dl Alb > 3,5 g/dl Plat < 9x109/L Plat > 9x109/L2 91,7 88,2 96,2 91,7 91,4 40,3 47,1 39,6 41,7 40 RVS4 RVS12 Figure 15. SVR by cirrhosis status (ITT).

33 Cirrhosis Cirrhosis and RBV Cirrhosis without RBV Cirrhosis+RBV: n=56 Cirrhosis No RBV: n=16 91,7 96, ,3 40,3 35,7 29/72 20/56 9/16 66/72 54/56 12/16 SVR4 SVR12 Figure 16. SVR by cirrhosis status and ribavirine use (ITT).

34 Cirrhosis + RBV: n=56 Cirrhosis adjustment of RBV: n=19 Cirrhosis No Ajustment of RBV=37 Cirrhosis+RBV Cirrhosis+RBV with adjustment Cirrhosis+RBV without adjustment 96,4 94,7 97,3 35,7 42,1 32,4 20/56 8/19 12/37 54/56 18/19 36/37 SVR4 SVR12 Figure 17. SVR by cirrhosis status and ribavirine use (ITT).

35 INF PEGINF+RBV IP Naives Previously treated F2 F4 7% 93% CPT A 78% CPT B GT4 22% 21% GT1a 42% GT1b 37% Figure 18. Coinfected patients, basal characteristics.

36 CV <20 (100%) VIH NO VIH VIH NO VIH 96,70% 70% 30% 81,50% 3,30% 18,50% 63% 37% 12 WEEKS 24 WEEKS RBV WITHOUT RBV Figure 19. Coinfected patients, type of treatment.

37 HIV coinfected HCV monoinfected 85,2 96,7 85,2 91,7 61,7 66,7 48,1 33,3 18/27 37/60 23/27 58/60 13/27 20/60 23/27 55/60 w4 EOT SVR4 SVR12 Figure 20. Viral kinetics during HCV treatment in mono and coinfected patients.

38 HIV coinfected HCV monoinfected 85,1 91,7 48,1 33,3 13/27 20/60 23/27 55/60 SVR4 Figure 21. SVR in coinfected patients (ITT). SVR12

39 Adverse events and security

40 Figure 22. Adverse events.

41 28,4% Nº PATIENTS 3,40% 2,30% Anemia Neurotropenia Thrombocytopenia Anemia: 25 patients(28.4%) 20 patients(80%) treated with RBV Grade 1-2: 100% 50% RBV adjustment 1 Transfusion Thrombocytopenias: 26 patients(29.5%) basal 2 patients(2.3%) (Grade1) Figure 23. Adverse events(ii).

42 Figure 24. Box-plot of bilirrubine levels during HCV treatment.

43 49 yo HIV coinfected female. G1b, F4 (FS: 21kPa, CPT B8). Relapser (IFN). Sofosbuvir + Simeprevir (24 weeks). w12 Liver decompesation. 50 yo HIV coinfected male. G1b, F4 (FS: 35kPa, CPT B7). Naive. Sofosbuvir + Simeprevir + Ribavirine (12 weeks). w2 STOP RBV. W6 Hiperbilirrubinemia grade 3, STOP study medication. Liver decompensation. Nowadays RVS 12.

44 SUMMARY High effectiveness in HCV G1/4. No significant differences were observed between mono and coinfected patients. When RBV adjustment was necessary, no influence in SVR was observed. SMV+SOF was well tolerate and a security regimen.