HEPATITIS C: NIEUWE MIDDELEN EN BEREIKTE RESULTATEN Robert J. de Knegt, MDL-arts Erasmus MC, afd. Maag-Darm-Lever ziekten Rotterdam
[email protected]
Disclosures Honoraria for consulting or speaking (last 5 years): AbbVie, BMS, Gilead, Janssen-Cilag, Medtronic, Merck/Schering-Plough, Norgine, Roche Research grants (last 5 years): BMS, Janssen Cilag, Medtronic, Roche
De behandeling van hepatitis C, een revolutie !
Sustained Virologic Response in G1 (SVR)
Revolutie in de behandeling van hepatitis Estimated C 95-100% 100 90
Estimated 65-70%
80 70
60
+
+/-
42-50%
50
35%
40
+/-
30
20
Protease Inhibitor
10%
10
ribavirin
+
+/-
+ PEG-IFN
NS5a inhibitors
Prot Inhibitor NS5b inhibitors
0
1st Stage 1989-1998
2nd Stage 1998-2001
3rd Stage 2001- present
4th Stage
5th Stage
2012-2015
2015-2018
Veranderingen in HCV behandeling
Dore. Med J Aust 2012; 196 (10): 629-632.
HCV op de voorpagina’s • In 2013-2015: 19 (!) klinische studies over HCV in NEJM • Verschillen met betrekking tot: • Klinische situatuaties, ernst leverziekte • Virale genotypes
Patient • Naïve • Failure • Cirrhosis • Co-HIV • Liver transplantation
Virus • Genotype 1 • Genotype 2,3 • Genotype 4
Drugs • Ledipasvir • Sofosbuvir • Daclatasvir • Ombitasvir • Dasabuvir • Paritaprevir • Miraversen
Het werkt in klinische studies; maar ook in de dagelijkse praktijk ?
COSMOS SIM + SOF
GT-1
from phase-2 direct to real-life data
Cosmos & HCV-Target
HCV-TARGET: GT1, SOF+SIM plus/minus RBV
Compassionate-use programme DCV + SOF in Germany, Austria, Sweden and Netherlands (Amsterdam) SVR according to genotype DCV + SOF 100
100
97
98
100
95
DCV + SOF + RBV 100 100
98
Overall 100
100 100 100 92
85
SVR12, %a,b
80 60 40 20
37 38
d
12 12
49 d 50
40 40
18 e 58e 59 19
0
GT 1a
GT 1b
0
2 2
GT 2
2 2
11 11
11 13
f
GT 3
22 f 24
4 4
5 5
9 9
GT 4
HCV genotype 5 additional patients with GT 1 had no subtype data available; all 5 achieved SVR12. a HCV RNA < LLOQ (TD or TND). b Observed cases. c 2 patients in the DCV + SOF + RBV arm had unknown GT; both achieved SVR12. d 1 relapse. e 1 HCV RNA > LLOQ but discontinuation before week 12. f 1 relapse, 1 HCV RNA > LLOQ but discontinuation before week 12. Descriptive analysis only, results cannot be directly compared across subgroups or by treatment group.
9 Welzel TM, et al. EASL 2015, Poster PO772.
AMBER-GT1: virologic response 100%
2
10 18% 80%
24 32%
108 8
60%
41
40%
94 62%
TND
123 98%
17
39 98%
77
2 IU/mL TD-102 4 IU/mL 2 102-104 6 IU/mL 4 104-106
31
20%
TD
6 8 IU/mL 106-108
27 20 4
0% d0 n=186
d1 n=55
6 d7 n=76
w4 n=152
11 EOT n=125
1 FU w12 n=40
Among 125 patients who completed therapy HCV RNA was detectable in 2 cirrhotics who discontinued medication (the only who discontinued PTV/OBV/r ±DSV): • 1st demonstrated detectable/unquantifiable viral load at the early discontinuation on week 10, due to scheduled OLTx, but finally achieved SVR; • 2nd relapsed after discontinuation at week 2 due to suspition of hepatotoxicity (grade 3 ALT/bilirubin elevation). 10
ION-3: SOF/LDV ± RBV in GT1 non-cirrhotic treatment-naive patients ‒ SVR12 rates in the ITT population (N=647) SOF/LDV ± RBV 8 or 12 weeks
100
94,0
ION-3 N=647 93,0
97,7
GT1 treatment-naive patients
93,1
92,4
95,5
95,4
94,8
97,7
SVR12 (%)
80 Overall
60 GT1a
40
GT1b
20 n N
0
202 215
159 171
42 43
SOF/LDV* 8 weeks * One patient achieved SVR12, but was not subgenotyped; Error bars: 95% CI.
201 216
159 172
42 44
SOF/LDV + RBV 8 weeks
206 216
163 172
43 44
SOF/LDV 12 weeks
Kowdley K, et al. N Engl J Med 2014; 370:1879–1888 [supplement].
An Integrated Safety and Efficacy Analysis of >500 Patients with Compensated Cirrhosis Treated with LDV/SOF with or without RBV Pooled Phase 2/3 analysis of 513 HCV GT1 naive or experienced patients with compensated cirrhosis treated with LDV/SOF ± RBV for 12/24 weeks 96
100
95
98
80
SVR12 (%)
60
LDV/SOF ± RBV
40 20
0
n N
493 513
305 322
188 191
Overall
12 weeks
24 weeks
20 patients failed to achieve SVR12: 18 relapsed, 1 LTFU, 1 died (presumed infection) Bourlière M, et al. AASLD 2014, Boston. #82
Sub-analyses in treatmentexperienced patients indicate a trend towards higher SVR12 rates with RBV or with extended treatment duration: LDV/SOF 12 weeks = 90% LDV/SOF 24 weeks = 98% LDV/SOF + RBV 12 weeks = 96% LDV/SOF + RBV 24 weeks = 100%
Use of RBV resulted in more frequent AEs and hemoglobin declines
NIAID ERADICATE: SOF/LDV For 12 Weeks In GT1 HCV Co-infected With HIV On or Off ART Baseline characteristics
ARV untreated n=13 10 (77) 9 (75)
African American, n (%) G1a, n (%) IL28B non-CC genotype, 11 (85) n (%) HAI stage 3 fibrosis, n (%) 5 (38) Median CD4 T-cell count 687 (range) (319–1287) ARVs, (%) TDF/FTC + EFV TDF/FTC + RAL TDF/FTC + RPV TDF/FTC + RPV/RAL TDF/FTC + EFV/RAL
ART-naive, n=13 ART-treated, n=37
ARV treated n=37 32 (86) 30 (81) 31 (84)
8 (22) 576 (113–1612) 15 (41) 10 (27) 8 (21) 3 (8) 1 (3)
SOF/LDV safely administered in combination with several ARV regimens • No significant CD4 or HIV RNA changes • No renal toxicity observed • Well tolerated with no discontinuations
13/ 13
37/ 37
13/ 13
37/ 37
13/ 13
36/ 37
13/ 13
36/ 37
13/ 36/ 13 37
• One relapse at SVR12 • Second late relapse at SVR36? Reinfection? Townsend KS, et al. AASLD 2014, Boston. #84
ION-2: SVR Rates in GT1, Treatment-Experienced, Cirrhotic Patients 95,4 (Subgroup Analysis) 98,9 100,0 98,9 100,0 100,0 81,8 86,4 100
No cirrhosis
80
SVR12 (%)
Cirrhosis 60 40 20 0
n N
83 87
19 22
SOF/LDV 12 wks
89 89
18 22
86 87
22 22
88 89
22 22
SOF/LDV + RBV 12 wks
SOF/LDV 24 wks
SOF/LDV + RBV 24 wks
1a, N (%)
86 (79)
88 (79)
85 (78)
88 (79)
1b, N (%)
23 (21)
23 (21)
24 (22)
23 (21)
Afdhal N, et al. New Engl J Med. 2014;370:1483–1493 [supplement].
HCV-TARGET: Crude SVR rates among patients with available outcomes
Hoe maak je een keuze? Actueel Nederlands Richtsnoer - Samenwerking van beroepsverenigingen - Elke 3 maanden een update - Online beschikbaar
www.hcvrichtsnoer.nl
http://hcvsvrpredictor.liverdoc.com/#/ www.liverdoc.nl
Huidige beschikbare opties Viekirax (ombitasvir/paritaprevir/ ritonavir)
NS3/ NS4A
Harvoni (sofosbuvir/ledipasv ir)
Exviera (dasabuvir)
NS5B
Olysio (simeprevir)
NS3/ NS4A
Daklinza (daclatasvir)
Sovaldi
NS5B
Sovaldi
(sofosbuvir)
(sofosbuvir)
NS5A
NS5B
NS5B/ NS5A
Beschikbare geneesmiddelen Nederland • Nederland nu: sofosbuvir, daclatasvir, simeprevir • Voorbehouden aan patienten met “highest priority”
• Nederland vanaf 1 oktober: ombutasvir+paritaprevir en
dasabuvir • Alle GT1 en GT4 patienten, ongeacht fibrose-stadium
• Nederland vanaf 1 november: sofosbuvir+ledipasvir • Alle patienten ongeacht fibrose-stadium
Behandeling van hepatitis C is zinvol
• HCV is een
progressieve ziekte • Er is een verhoogde lever-gerelateerde sterfte, maar ook een verhoogde niet-lever gerelateerde sterfte
Effecten van behandeling international cohort N=530 -IFN treatment 1990-2003 - FU 8,4 yrs (6,1-11,4) - 70% men - SVR in 192 (36%)
- all cause mortality rate/10 yrs : - 8,9% (SVR) (N=13) - 26% (no SVR) (N=100) - HCC (N=83) (7vs 76) - 7 SVR - 76 no SVR
vd Meer et al; JAMA. 2012;308(24):2584-2593
Wedemeyer H et al., Abstract P0808 Improvement in liver function and non-invasive estimates of liver fibrosis 48 weeks after treatment with 3D and ribavirin in GT1 patients with cirrhosis. After ombutasvir, dasabuvir, paritaprevir.
SOLAR-2: LDV/SOF + RBV in Decompensated and Post-Liver Transplant Patients
Liver Function Change from Baseline to Follow-Up Week 4 MELD Score Change
Change in CTP Class
Pre/Post-Transplant (CTP B and C, n=136*) (8)
Change in MELD Score
4
2
n=95
n=18
A (5–6)
0 n=22
-2 -4
Followup B (7–9) Week 4 CTP C (10–12)
-6
A (5–6) n=73
B (7–9) n=100
C (10–12) n=54
67 (96)
31 (35)
2 (5)
3 (4)
57 (65)
20 (48)
0
0
20 (48)
no assessment: CTP A, n=3; CTP B, n=12; CTP C, n=12
-8 -10
Baseline CTP
(-11) (-17)
*Missing FU-4: n=24
Majority of patients showed improvements in MELD and CTP scores Manns, EASL, 2015, GO2
Regressie van leverfibrose • Gepaarde lever biopsie van een patient met een HCVlevercirrose voor en enkele jaren na behalen SVR Pre-treatment
Metavir F4
Post-treatment
Metavir F3
D’Ambrosio Hepatology 2012
Conclusies • Uitkomsten “real world” net zo goed als in de trials • Ook bij cirrose en na LTx goed resultaten, met op korte
termijn verbetering van leverfunctie en MELD score • Unmet needs: • Gedecompenseerde cirrose, rol ribavirine, timing voor of na LTx • GT3 en cirrose • Welke behandeling na falen op DAA-regime
Wat kun je zelf doen om de lever gezond te houden ?
Wat kun je zelf doen om de lever gezond te houden ? Koffie
Turmeric
Cacao
Grieks dieet
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