Nowe możliwości leczenia pwzw C co się zmieniło w ciągu roku Krzysztof Tomasiewicz Klinika Chorób Zakaźnych i Hepatologii Uniwersytet Medyczny w Lublinie Forum Wirusologiczne 218 Łódź
Wykład powstał przy wsparciu firmy Gilead Sciences Poland Sp. z o.o., ul. Postępu 17A, 2-676 Warszawa. Zawarte w wykładzie wytyczne mogą zawierać wskazania do terapii i schematy leczenia wykraczające poza zapisy rejestracyjne poszczególnych leków.
Disclosures Krzysztof Tomasiewicz: Consultancy/Advisory Board/Speaker: AbbVie, Alfa Wasserman, BMS, Gilead, Janssen, MSD, Roche; Grant/Research: AbbVie, BMS, Gilead, Janssen, MSD, Roche
Co się wydarzyło w 217 roku Liczba leczonych w programach terapeutycznych przekroczyła 12 Kwalifikacja pacjentów bez względu na stopień zaawansowania włóknienia i inne czynniki (mniejsze znaczenie priorytetów leczenia) Dostępność wszystkich terapii, z wyjątkiem pangenotypowych (Maviret, Epclusa i Vosevi).
EpiTer-2 Zaawansowanie włóknienia u pacjentów leczonych Polska 215-216 Polska 217 (do 19-9-217) 1% 1% 9% 8% 7% 6% 5% 4% 3% 2% 1% % 44% 15% 14% 21% 1% 5% n=2879 9% 8% 7% 6% 5% 4% 3% 2% 1% % 32% 19% 14% 3% 4% 1% N=74 F4 F3 F2 F1 F UKN Dzięki uprzejmości Prof. R. Flisiaka 5
SVR12, % (PP) TRIO Real-World Cohort Real-World Experience LDV/SOF i SOF/VEL u pacjentów GT1 SVR12 1 8 weeks LDV/SOF 12 weeks LDV/SOF 12 weeks SOF/VEL 97 98 97 97 98 99 1 95 97 98 1 1 98 97 98 1 1 96 98 9 91 8 6 4 2 189 195 382 389 29 3 147 282 151 288 23 24 39 41 91 92 5 5 177 183 255 259 Overall GT 1a GT 1b F-3 F4 TN TE 2 2 12 12 12 122 9 1 183 321 189 327 19 19 6 6 61 62 1 11 Wysoki SVR12 w schemacie 8 i 12 tyg LDV/SOF oraz 12 tyg SOF/VEL, niezależnie od genotypu/subtypu, zaawansowania włóknienia lub historii leczenia Tsai, EASL 217, SAT-244 6
TRIO Real-World Cohort Real-World Experience SOF/VEL ± RBV w HCV GT 2 Treatment uptake SVR12 (PP) 1H 216 (n=366) Prior to SOF/VEL Approval 2H 216 (n=485) After SOF/VEL Approval 1% SOF+RBV SOF/VEL±RBV 94% 97% 88% 95% 95% 97% 94% 95% 96% 97% 77% 18% 2% 81% 11% 7% 8% 15% 1% 6% SOF/VEL ± RBV SOF+RBV DCV+SOF ± RBV LDV/SOF ± RBV EBR/GZR ± RBV Other Baseline Demographics SOF + RBV (n=337) SOF/VEL ± RBV (n=394) 12 week schedule, n (%) 28 (83) 386 (98) Other schedule, n (%)* 53 (16) 7 (2) + RBV, n (%) 337 (1) 22 (6) Age - mean (range) 59 (24-85) 61 (21-86) Male, n (%) 195 (58) 226 (58) TE, n (%) 45 (13) 82 (21) F4, n (%) 68 (21) 85 (22) CKD, n (%) 14 (32) 156 (41) Diabetes, n (%) 41 (13) 56 (15) 4% 2% % 238 252 91 94 3 34 21 22 28 218 7 72 48 51 21 22 188 196 All TE TN F4 F-3 7 72 Potwierdzenie wysokiego odsetka SVR12 u pts z GT2 leczonych SOF/VEL *A small fraction of patients were indicated for schedules other than those shown Curry, EASL 217, PS-12 7
TRIO Real-World Cohort Real-World Experience SOF/VEL ± RBV w HCV GT 4 6 1H 216 (n=168) Prior to SOF/VEL Approval Treatment uptake 2H 216 (n=16) After SOF/VEL Approval 14% 1% LDV/SOF±RBV SVR12 (PP) SOF/VEL±RBV 94% 91% 1% 93% 91% 1% 9% 97% 9% 9% 7% 5% 36% 8% 6% SOF/VEL ± RBV SOF + RBV DCV+SOF ± RBV EBR/GZR ± RBV LDV/SOF ± RBV Other Baseline Demographics 4% LDV/SOF ± RBV SOF/VEL ± RBV (n=24) (n=38) 12 week schedule, n(%) 191 (94) 38 (1) Other schedule, n(%)* 4 (2) + RBV, n(%) 5 (2) 2 (5) Age - mean (range) 63 (21-87) n=182 62 (24-82) n=37 Male - no. (%) 19 (53) 23 (61) HIV coinfection, n(%) 3 (2) TE, n(%) 37 (18) 6 (16) F4, n(%) 64 (32) 6 (16) CKD, n(%) 7 (35) 12 (32) Diabetes, n(%) 3 (15) 8 (21) 2% % 127 135 1 11 17 17 11 118 1 11 37 41 All TE TN F4 F-3 1 1 9 93 Potwierdzenie wysokiego odsetka SVR12 u pts z GT4-6 leczonych SOF/VEL 9 1 *A small fraction of patients were indicated for schedules other than those shown Curry, EASL 217, PS-12 8
Genotyp 3 Skuteczność i tolerancja dotychczasowych schematów Terapia All patients No cirrhosis (F-F3) cirrhosis (F4) N SVR (%), ITT* SVR (%), mitt** N SVR (%), ITT* SVR (%), mitt** 84 91 94 114 8 83 SOF+PegIFN+RBV, 12 wks SOF+RBV, 24 wks 43 24 98 79 98 86 56 47 91 68 91 73 No cirrhosis (F-F3) cirrhosis (F4) N Modyfikacja Przerwanie N Modyfikacj Przerwa PegIFN+RBV, 24 wks 16 88 88 2 a SOF+DCV+RBV, 24 wks 1 1 1 9 89 1 All patients 84 8 (9.5%) 3 (3.6%) 114 16 (14%) 4 (3.5%) SOF+PegIFN+RBV,12 wks 43 2 (4.6%) 1 (2.3%) 56 7 (12.5%) SOF+RBV, 24 wks 24 3 (12.5%) 2 (8.3%) 47 7 (14.9%) 2 (4.2%) PegIFN+RBV, 24 wks 16 3 (18.7%) 2 SOF+DCV+RBV, 24 wks 1 9 2 (22.2%) 2 (22.2%) Zarębska-Michaluk D, et al. J Interf Cyt Res 218
TRIO Real-World Cohort Real-World Experience of SOF/VEL ± RBV w HCV GT 3 1H 216 (n=366) Prior to SOF/VEL Approval Treatment uptake 2% 2H 216 (n=485) After SOF/VEL Approval 5% 1% SVR12 (PP) SOF+DCV±RBV SOF/VEL±RBV 97% 97% 98% 96% 93% 92% 93% 93% 98% 1% 86% 12% 74% 22% 8% Curry, EASL 217, PS-12 Baseline Demographics SOF+DCV ± RBV SOF/VEL ± RBV (n=392) (n=244) 12 week schedule, n (%) 37 (78) 238 (98) Other schedule, n (%)* 82 (21) 6 (2) + RBV, n (%) 78 (2) 35 (14) Age - mean (range) 54 (22-81) 52 (21-83) Male, n (%) 224 (57) 14 (57) HIV coinfection, n (%) 7 (2) 5 (4) TE, n (%) 82 (21) 54 (22) F4, n (%) 11 (29) 69 (29) CKD, n (%) 99 (26) 64 (27) Diabetes, n (%) 46 (13) 33 (14) 4% SOF/VEL ± RBV SOF + RBV DCV+SOF ± RBV LDV/SOF ± RBV EBR/GZR ± RBV Other *A small fraction of patients were indicated for schedules other than those shown 6% 4% 2% % 266 276 66 68 52 56 11 12 214 22 55 56 67 72 14 15 196 21 All TE TN F4 F-3 52 52 Wysokie odsetki SVR12 u pts z GT3 leczonych SOF/VEL 1
SVR12, % German ifi Institute SOF/VEL±RBV: Niemieckie doświadczenia Real-World u pacjentów z GT 3 Safety and efficacy of patients receiving SOF/VEL±RBV in clinical practice BUGGISCH, AASLD 217, 16 Baseline Demographics GT 3 N=122 Median age (range), years 47 (26 73) Males, n (%) 97 (8) White, n (%) 113 (93) Metavir score, % F / F1 / F2 / F3 / F4 23 / 12 / 12 / 11 / 41 TN, n (%) 14 (85) TE, n (%) 18 (15) Prior DAA therapy, n (%) 4 (22) Prior NS5A and/or SOF, n (%) 4 (1) No prior DAA therapy 14 (78) HIV coinfection, n (%) 4 (3) 1 8 6 4 2 SVR12 (PP) 1 56/56 GT 3 1 (.8%) AE led to D/C No grade 3/4 AEs and no deaths Wszyscy pacjenci z GT3, którzy skończyli leczenie osiągnęli SVR12
Efficacy and Safety of Glecaprevir / Pibrentasvir in Patients Infected with HCV GT1 3 by Renal Impairment Status: A Pooled Analysis of Two Phase 3 Japanese Trials Rozwiązanie w terapii pacjentów z Genotypem 3 i niewydolnością nerek? Overall ITT SVR = 98%
Pacjenci z (zaawansowaną) marskością/dekompensacją Real world data
SVR12, % HCV-TARGET Real-World Experience SOF/VEL (bez RBV) u pts z HCV GT 1 6 47 pacjentów leczonych SOF/VEL w ramach HCV-TARGET początek Lipiec 216 Luty 217) Baseline Demographics SOF/VEL n=47 Male, n (%) 228 (56) Age 6, n (%) 164 (4) HCV GT, % 1 / 2 / 3 / Other 17 / 39 / 38 / 6 Treatment duration 12 weeks, n (%) 33 (81) Other, n (%) 39 (1) Ongoing 38 (9) Cirrhosis, n (%) 113 (28) History of DC, n (%) 3 (7) TE*, n (%) 67 (17) Liver transplant, n (%) 8 (2) 1 8 6 4 2 97 232/ 239 94 29/ 31 SVR12 (PP) 98 98 99 93/ 95 95/ 97 196/ 199 9 98 94 93 Overall GT 1 GT 2 GT 3 TN TE NC CC DC 36/ 4 168/ 171 5/ 53 14/ 15 * 21 (5%) were DAA treatment failures (per abstract only). Landis, AASLD 217, Poster 196 TN=treatment-naïve TE=treatment-experienced NC=non-cirrhotic CC=compensated cirrhotic DC=decompensated cirrhotic 14
SVR12, % HCV-TARGET Real-World Experience of SOF/VEL+RBV u pacjentów z HCV GT 1 6 113 pacjentów leczonych SOF/VEL+RBV w ramach HCV-TARGET początek Lipiec 216 Luty 217) Baseline Demographics Landis, AASLD 217, Poster 196 SOF/VEL+RBV n=113 Male, n (%) 83 (74) Age 6, n (%) 49 (43) HCV GT, % 1 / 2 / 3 / Other 34 / 14 / 46 / 6 Treatment duration 12 weeks, n (%) 85 (75) Other, n (%) 22 (2) Ongoing 6 (5) Cirrhosis, n (%) 81 (72) History of DC, n (%) 57 (5) TE*, n (%) 66 (58) Liver transplant, n (%) 14 (12) * 54 (45%) were DAA treatment failures (per abstract only) 1 8 6 4 2 93 62/ 67 88 14/ 16 1 13/ 13 SVR12 (PP) 91 31/ 34 97 3/ 31 89 9 94 93 Overall GT 1 GT 2 GT 3 TN TE NC CC DC 32/ 36 17/ 19 17/ 18 15 28/ 3 TN=treatment-naïve TE=treatment-experienced NC=non-cirrhotic CC=compensated cirrhotic DC=decompensated cirrhotic
SVR12, % GECCO Impact of RAS or RBV Use on Treatment Success of SOF/VEL±RBV for 12 Weeks in HCV GT3 Patients Prospective multicenter cohort from Germany Baseline Demographics Christensen, AASLD 217, Oral 63 N=232 Male, n (%) 161 (69) Age, years 47 (38 54) HIV/HCV, % 11 TE, % 26 Cirrhosis (%) 22 Child Pugh A / B / C, % 9 / 1 / Baseline NS5A RAS available, n (%) Baseline NS5A RAS positive (A3K/Y93H/A3T) 177 (76) 16 (9%) (8/7/1) +RBV, n (%) 32 (14) 1 8 6 4 2 SVR12 (PP) 99 1 14/ 141 Overall 13/ 13 Cirrhosis, +RBV 1% SVR in patients with baseline RASs A3K (n=5) Y93H (n=5) One relapser 94 16/ 17 Cirrhosis, -RBV SVR12 for SOF/VEL ± RBV in this real-world cohort of GT 3 patients with and without baseline RASs was similar to registrational Phase 3 studies 16
Leczenie po przeszczepie wątroby EASL 218 HCV Guidelines
SOF/VEL Post-Liver Transplant SOF/VEL przez 12 Tyg po przeszczepie wątroby HCV GT 1-4 Single-arm, open-label phase 2 study conducted in Europe Baseline Demographics N=79 Mean age, y (range) 62 (45 81) Male, n (%) 64 (81) Mean time since transplant, y (range) 8.7 (.3 23.9) HCV GT, % 1a / 1b / 2 / 3 / 4 19 / 28 / 4 / 44 / 5 Protocol-defined Cirrhosis, n (%) 7 (9) TE, n (%) 47 (6) DAA ± PEG + RBV* 4 (5) IFN/PEG ± RBV 43 (54) Immunosuppression use, n (%) Tacrolimus Cyclosporine Sirolimus Everolimus Mycophenolate Azathioprine Prednisolone 56 (71) 11 (14) 8 (1) 5 (6) 19 (24) 9 (11) 1 (1) * DAA regimens: SOF + RBV, boceprevir + PegIFN + RBV, and telaprevir + PegIFN + RBV Agarwal, AASLD 217, Poster 169 18
SVR12, % SOF/VEL Post-Liver Transplant SOF/VEL przez 12 Tyg po przeszczepie wątroby HCV GT 1-4 SVR12 1 96 95 93 96 1 97 1 1 94 1 95 8 6 4 2 76 79 Total 35 37 14 15 21 22 3 patients did not achieve SVR: one early D/C and 2 relapses 4/4 patients with baseline Y93H RASs (3 GT 3 and 1 GT 1b) achieved SVR12 No changes in immunosuppression were needed for rejection or suspected drug-drug interactions 3 3 34 35 GT 1 GT 1a GT 1b GT 2 GT 3 GT 4 4 4 1 1 33 35 Safety 11 11 Patients, n (%) n=79 AEs 62 (78) Grade 3 4 AE 3 (4) Serious AE 3 (4) Treatment D/C due to AE 1 (1) 2 21 F F1 F2 F3 F4 Wysoka skuteczność SOF/VEL przez 12 tygodni u pacjentów po przeszczepie wątroby Agarwal, AASLD 217, Poster 169 19
Pacjenci po nieskutecznym leczeniu DAA
Retreatment study: SOF/VEL + RBV in prior NS5A failure - Phase II Schemat Open-label W24 > 18 years Failure to SOF/VEL or SOF/VEL + VOX (LEPTON study) Any genotype Compensated cirrhosis allowed No HBV or HIV co-infection N = 69 SOF/VEL + RBV SVR 12 SOF/VEL: 4/1 mg FDC QD ; RBV: weight based in twice daily dose (1 mg/day if < 75 kg, 12 mg/day if 75 kg) Objective SVR 12 (HCV RNA < 15 IU/mL), by ITT RETREATMENT STUDY Gane EJ, Hepatology. 217 ; 66 :183-9
Retreatment study: SOF/VEL + RBV in prior NS5A failure - Phase II SOF/VEL + RBV N = 69 Age, years, mean 57 Female, % 23 White, % 88 HCV RNA, log 1 IU/mL, mean 6.4 IL28B CC, % 33 Cirrhosis, % 26 Genotype 1a / 1b / 2 / 3, % 46 / 7 / 2 / 26 Prior SOF/VEL + VOX, % 41 Prior VEL dose : 25 mg / 5 mg, % 41 / 59 Prior treatment duration, 4-6W / 8W /12W, % 36 / 39 / 25 Relapse of prior treatment, % 99 Mean time to retreatment, days 356 Discontinuation, N Baseline characteristics, disposition and outcome 3 (adverse event, incarceration, withdrew consent) SVR 12 * 63/69 (91% [95% CI : 82-97]) * 4 patients excluded from analysis (still in follow-up) RETREATMENT STUDY Gane EJ, Hepatology. 217 ; 66 :183-9
Retreatment study: SOF/VEL + RBV in prior NS5A failure - Phase II % 1 97 8 6 4 2 N= 37 Genotype 1 SVR 12 by genotype, and by baseline RASs 93 78 14 18 Genotype 2 Genotype 3 N SVR 12 N SVR 12 N SVR 12 No RASs 32 97% 5 1% 4 1% RASs 5 (14%) 1% 9 (64%) 89% 13 (76%) 77% SVR 12 in cirrhosis : 78% vs 96% if no cirrhosis Niepowodzenia Genotype 1: 1 on-treatment virological failure after discontinuation for AE Genotype 2: 1 post-treatment relapse after discontinuation at W8 (pre-treatment with SOF/VEL) Genotype 3: 1 non-response ((pretreatment with SOF/VEL), 2 relapses (pre-treatment with SOF/VEL in 1, SOF/VEL + RBV in 1), 1 withdrew consent RETREATMENT STUDY Gane EJ, Hepatology. 217 ; 66 :183-9
Pacjenci po nieskutecznym leczeniu DAA Zatem może SOF/VEL/VOX
SVR12, % SOF/VEL/VOX lub SOF/VEL przez 12 tyg. u pacjentów leczonych nieskutecznie Inhibitorami Non-NS5A HCV GT 1 4 SVR12 w zależności od genotypu POLARIS-4 SOF/VEL/VOX 12 weeks (n=182) SOF/VEL 12 weeks (n=151) 1 98 96 95 1 97 96 1 89 85 8 6 1 relapse 1 death 2 LTFU 4 2 53 54 1 breakthrough 5 relapses 1 relapse 8 relapses 39 44 23 24 21 22 31 31 GT1a GT1b GT2 GT3 GT4 GT 1a GT 1b GT 2 GT 3 GT 4 32 33 52 54 44 52 19 19 X x x x Bourliere M, et al. N Engl J Med 217;376:2134-46 25
SVR12, % Połączona analiza POLARIS-1 i -4 Analiza oporności dla SOF/VEL/VOX podawanego przez 12 tygodni u pacjentów leczonych wcześniej DAA SVR12 in DAA-Experienced Patients With and Without RASs By HCV GT 1 98 99 1 1 97 1 1 1 1 1 99 1 1 94 94 97 97 8 6 4 2 41 42 173 175 45 45 59 59 69 71 8 8 23 23 3 3 23 23 3 3 GT 1 GT 2 GT 3 GT 4 6 69 7 5 53 47 5 2 2 9 9 36 37 31 32 No RASs Any RASs NS3 RASs NS5A RASs NS3 + NS5A RASs No impact of RAS on the SVR12 rate in DAA-experienced patients treated with SOF/VEL/VOX for 12 weeks Sarrazin, EASL 217, THU-248 26
Gdzie ci pacjenci..? Akcje przesiewowe: Populacja ogólna/wybrane grupy wiekoe versus screening w oparciu o czynniki ryzyka Zadanie na 218/219?
Wielokrotność koniecznego zwiększoenia wskaźnika rozpoznań A chalenge to increase a rate of new diagnosis to eliminate 9% of HCV in 23 Poland 6 5 Poland 4 Germany 3 England Spain 2 1 France Sweden,% 1,% 2,% 3,% 4,% 5,% 6,% 7,% 8,% 9,% Total Diagnosis Rate (%) at Baseline Curtuesy of Sarah Blech from Center of Disease Analysis 28
Gdzie ci pacjenci..? Dlaczego warto poszukiwać (oprócz choroby wątroby, manifestacji pozawątrobowych, itp.) RÓWNIEŻ
Cancer Free Survival Results: Risk of Other Major Cancers Prostate Cancer and Lung Cancer Prostate Cancer Lung Cancer Exposure N events Unadjusted rate /1 PY (95% CI) Adjusted HR (95% CI) N events Unadjusted rate /1 PY (95% CI) Adjusted HR (95% CI) DAA 86.35 (.28.43).71 (.52.97) 97.25 (.2.31).55 (.4.74) pre-daa IFN 8.31 (.25.39) 1. (ref) 97.24 (.19.29) 1. (ref) 1. 1..98.96.9.94.8.92.9.5 1. 1.5 2. 2.5 3. Years.7.5 1. 1.5 2. 2.5 3. Years DAA Pre-DAA IFN 19,862 15,285 1,528 778 4142 1756 67 8383 7792 6919 6187 5485 4854 489 31,355 24,121 16,461 11,74 6413 273 896 13,196 12,239 1,881 9762 8685 773 6514 Chokkalingam AP. EASL 218 oral 3
Cancer Free Survival Results: Risk of Other Major Cancers Leukemia and Bladder Cancer Leukemia Bladder Cancer Exposure N events Unadjusted rate /1 PY (95% CI) Adjusted HR (95% CI) N events Unadjusted rate /1 PY (95% CI) Adjusted HR (95% CI) DAA 35.9 (.6.13).38 (.24.6) 3.8 (.5.11).51 (.31.86) pre-daa IFN 63.16 (.12.2) 1. (ref) 38.9 (.7.13) 1. (ref) 1..98.96.94.92 1..98.96.94.92.9.9.5 1. 1.5 2. 2.5 3. Years.5 1. 1.5 2. 2.5 3. Years DAA Pre-DAA IFN 31,336 24,111 16,46 11,81 6,43 2688 89 13,172 12,215 1,856 9744 8678 7728 6513 31,382 24,149 16,488 11,11 6429 276 893 13,28 12,255 1,897 9783 877 7748 6531 Chokkalingam AP. EASL 218 oral 31
Results: Risk of Other Major Cancers Colorectal, Breast, Esophageal and Pancreas Cancer Exposure N events Unadjusted rate /1 PY (95% CI) Adjusted HR (95% CI) Colorectal Breast (female) Esophageal Esophageal DAA 69.18 (.14.23).95 (.65 1.39) Pre-DAA IFN 55.14 (.1.18) 1. (ref) DAA 58.44 (.34.57).95 (.64 1.43) Pre-DAA IFN 52.36 (.27.47) 1. (ref) DAA 14.4 (.2.6).62 (.28 1.43) Pre-DAA IFN 2.5 (.3.8) 1. (ref) DAA 17.4 (.3-.7).62 (.31-1.23) Pre-DAA IFN 22.5 (.3-.8) 1. (ref) Chokkalingam AP. EASL 218 oral 32
Podsumowanie Wzrost dostępności leków i leczenia (dla różnych grup pacjentów). 218 ostatni rok list oczekujących na leczenie? Skuteczna i bezpieczna terapia dla (prawie) wszystkich, także po wcześniejszych niepowodzeniach Zadanie: zidentyfikować niezdiagnozowanych. 33