tratamiento de la cirrosis descompensada buti.pdf · interferón en pacientes con cirrosis...
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Tratamiento de la hepatitis C con cirrosis descompensada en
2015
Maria Buti Hospital Valle de Hebron
Barcelona
Cirrosis Hepática
Estadío 1
•Compensada •No VE
Estadío 2
•Compensada •Con VE
Estadío 3
•No compensada
•Ascitis
Estadío 4
• No compensada
•HDA
Estadío 5
•No compensada
• Infecciones • Insuf. renal
1% 3-4% 20% 57% 67%
Tsochatzis, Bosch & Burroughs, Lancet 2014
Mortalidad
• Erradicar la infección por el virus de la hepatitis C.
• Mejorar la función hepática.
• Aumentar la Supervivencia
• Prevenir la recurrencia de la infección por VHC Post TX
Objetivos del Tratamiento
www.hcvguidelines.org access Feb 19, 2015
Tratamiento de la Hepatitis C No recomendados en pacientes con cirrosis descompensada (CP B o C).
Any IFN-based therapy Rating: Class III, Level A Monotherapy with PEG-IFN, RBV, or a direct-acting antiviral Rating: Class III, Level A Telaprevir-, boceprevir-, or simeprevir-based regimens Rating: Class III, Level A
Carrion et al, J Hepatol 2009
Interferón en pacientes con cirrosis descompensada se asocia con mayor riesgo de infecciones y empeoramiento de la función hepática.
Afdhal et al. EASL 2014.
HC
V R
NA
< LL
OQ
(%)
Clinical Events, n Ascites Hepatic Encephalopathy
SOF + RBV (n = 25)
Observation (n = 25)
SOF + RBV (n = 25)
Observation (n = 25)
Baseline 6 9 5 2
Wk 12 5 8 3 3
Wk 24 0 7 0 4
100
80
60
40
20
0 Wk 2 Wk 4 Wk 8 Wk 12
56
100 94
Wk 24
CTP A CTP B
44
75
100 100 100 94 93
Treatment before LT SOF+RBV for 48 wks
Decompensated cirrhosis ( CTP A and B )
-6
-4
-2
0
2
4
6
-6
-4
-2
0
2
4
6
Child-Pugh A (n=20) Child-Pugh B (n=29)
Cam
bio
de M
ELD
desd
e ba
sal
SOF + RBV Observation 24 weeks
n=2 n=5 n=1 n=3
Efecto en la Función Hepática
Afdhal et al, EASL 2014
70% 50%
93
64
0
20
40
60
80
100
Transplant pTVR 12
41/44* 25/39*†
Vira
l Res
pons
e Ra
te (%
)
*3 subjects were >LLOQ at transplant. †1 subject has not reached pTVR12, 1 subject LTFU at Week 8 post transplant.
No Recurrence (n=28)
Recurrence (n=10)
>30 days TND
- Compensated cirrhosis (CTP ≤7, MELD<22) - + HCC - Any genotype (72% G1) - 44 underwent LT
Treatment until LT (max 48 weeks)
Treatment before LT with SOF+RBV 24 wks
Curry et al, Gastroenterology 2015
Tratamiento con Antivirales Directos
METABOLISMO CIRROSIS
CTP-A CTP-B CTP-C
Sofosbuvir Renal Si Si
Si
Simeprevir Hepático Si Si No
Paritaprevir/r Hepático Si Si No
Ledipasvir Hepático Si Si Si
Ombitasvir Hepático Si Si Si
Daclatasvir Hepático Si Si Si
Dasabuvir Hepático Si Si Si
Bifano M, et al. AASLD 2011. Abstract 1362. Garimella K, et al. Clinical Pharm 2014. Abstract P43. Sofosbuvir [package insert]. Simeprevir [package insert]. Khatri A, et al. AASLD 2012. Abstract 758. German, et al. AASLD 2013. Abstract 467. Kirby R, et al.
Clinical Pharm 2013 Abstract PO20
Eficacia y Seguridad: SOF/LDV+RBV
Flamm et al, AASLD 2014
W 0 W 12 W 24 W 48 W 72
SOF/LDV+ RBV (dosis inicial 600mg/d)
SOF/LDV + RBV (dosis inicial 600mg/d)
n=53
n=55 RVS12
RVS12
Estudio aleatorizado 1:1, genotipo 1 o 4, naïve o pre-tratados. Cirrosis descompensada Child B (7-9) ó C (10-12)
Eficacia y Seguridad: SOF/LDV+RBV
Flamm et al,AASLD2014
Característica Child-Pugh B Child-Pugh C
12 semanas n=30
24 semanas n=29
12 semanas n=23
24 semanas n=26
Sexo masculino n (%) 22 (73) 18 (62) 14 (61) 18 (69)
Edad (años) 60 (28-69) 58 (35-69) 58 (41-71) 59 (48-68)
Genotipo 1a/4 n (%) 19 (63) / 1 (3) 22 (76) / 0 15 (65) / 2 (9) 18 (69) / 0
Tratamiento previo n (%) 22 (73) 19 (66) 11 (48) 18 (69)
MELD <10 10-15 16-20 21-25
6 (20)
21 (70) 3 (10)
0
8 (28)
16 (55) 5 (17)
0
0
13 (50) 12 (46)
1 (4)
0
13 (50) 12 (46)
1 (4)
Ascitis / EH n (%) 17 (57) / 20 (67) 17 (59) / 16 (55) 22 (96) / 21 (91) 25 (96) / 23 (88)
Bilrrubina 2 (0,6-5,5) 1,4 (0,8-4,5) 2,9 (1,2-14,5) 3,8 (1,1-5,7)
INR 1,3 (1-1,59) 1,3 (1-2,6) 1,4 (1,2-1,9) 1,4 (1,1-2,2)
Albumina 2,9 (2,1-3,7) 3 (2,2-3,4) 2,6 (1,6-3,5) 2,6 (2-3,3)
Plaquetas 88 (36-212) 73 (30-154) 81 (39-177) 71 (32-179)
Eficacia y Seguridad: SOF/LDV+RBV
Flamm et al ,AASLD2014
87 87 86 89 89 90
0
20
40
60
80
100
Total Child B Child C
12 semanas
24 semanas
18/20 19/22 24/27 26/30 42/47 45/52
* Se trasplantaron 6 pacientes durante el estudio y están excluidos del análisis de eficacia.
2 relapsers 1 muerte
1 relapsers 2 muerte
1 relapsers 1 muerte
1 LTFU
1 relapsers 1 muerte
Eficacia y Seguridad: SOF/LDV+RBV
Flamm et al, AASLD 2014
Característica Child B Child C
12 semanas 24 semanas 12 semanas 24 semanas
EAs 29 (97) 27 (93) 23 (100) 26 (100)
EAs grado 3/4 2 (7) 8 (28) 6 (26) 11 (42)
EAGs 3 (10) 10 (24) 6 (26) 11 (42)
Discontinuación por EAs 0 1 (3) 0 2 (8)
EAGs relacionados con tto 2 (7) 0 0 2 (8)
Muerte 1 (3) 2 (7) 2 (9) 1 (4)
EAGs relacionados: anemia, EH, hemoperitoneo DC: sepsis, EH, hemoperitoneo Muertes: shock séptico, FMO, insuficiencia renal, parada cardíaca.
Efecto en la Función Hepática: SOF+LDV+RBV
-10
-8
-6
-4
-2
0
2
4
Child-Pugh C (n=49)
12 semanas 24 semanas
n=2 n=3
Flamm et al, AASLD 2014
65% 79%
Ascitis Encefalopatía Hepática
Pacientes, n SOF + RBV
n=25 Observación
n=25 SOF + RBV
n=25 Observación
n=25
Basal 6 9 5 2
Semana 12 5 8 3 3
Semana 24 0 7 0 4
Efecto en la Función Hepática
Afdhal et al, EASL 2014
SOLAR-2 Interim Results: LDV/SOF + RBV in Decompensated Cirrhosis or Transplant
LDV/SOF + RBV* (n = 164)
LDV/SOF + RBV* (n = 164)
Wk 24 GT1 or 4 HCV with
decompensated cirrhosis or recurrent HCV after liver transplantation
(N = 328)
Wk 12
Manns M, et al. EASL 2015. Abstract G02.
*RBV dose: weight-based (1000 mg/day if < 75 kg; 1200 mg/day if ≥ 75 kg) for METAVIR F0-F3 and CTP A cirrhosis; 600 mg/day with subsequent dose escalation for CTP B/C cirrhosis. LDV/SOF 90/400 mg QD.
Baseline Characteristic Pre- transplantation CTP B or C
12 Wks (n = 78) 24 Wks (n = 82)
MELD score > 15, n (%) 22 (28) 19 (23)
Median T bilirubin, mg/dL (range) 2.3 (0.3-8.9) 2.3 (0.3-11.2)
Median albumin, g/L (range) 2.8 (1.9-4.2) 2.9 (1.9-3.8)
Median INR (range) 1.3 (1.0-2.1) 1.3 (1.0-2.2)
Median platelets, x 103/µL (range) 77 (27-237) 80 (28-211)
Ascites, n (%) 51 (65) 64 (78)
Encephalopathy, n (%) 37 (47) 45 (55)
SOLAR-2: SVR12 and Safety in GT1 or 4 HCV by Liver Disease Subgroup
Outcome PreTransplant CTP B or C
LDV/SOF + RBV for 12 Wks
(n = 78)
LDV/SOF + RBV for 24 Wks
(n = 82)
SVR12, % (n/N)
Genotype 1 88 (57/65) 89 (54/61) Genotype 4 57 (4/7) 86 (6/7)
Safety, n (%) SAE 22 (28) 23 (28)
Trt-related SAE 2 (3) 4 (5)
Trt discont. for AE 1 (1) 4 (5)
Deaths 3 (4) 4 (5)
Manns M, et al. EASL 2015. Abstract G02.
LDV/SOF + RBV 12 Weeks 24 Weeks
87 85 96
72
0102030405060708090
100
CPT B CPT C
SVR
12 (%
)
Manns M., EASL Vienna 2015
18
SVR12. GT1 PreTransplant CPT B and C SOLAR-2
ALLY-1: DCV, SOF + RBV combination for HCV patients with advanced cirrhosis or post-transplant recurrence
Poordad F, et al. EASL 2015, Vienna. #LO8
SVR12 by Child-Pugh class: Advanced cirrhosis cohort, all genotypes
90,9 83,7 89,2
96,8
75,0 [VALOR]
.0
55,6
100
72,7
92,0 94,0
56,0
0
20
40
60
80
100
A B C
Child-Pugh class
91,3
95,7 78,
4 75,7
No Yes No Yes >3.5 2.8–3.5
<2.8
SVR
12
(%)
<1.7 1.7─2.3
>2.3 <2.0 2.0─3.0
>3.0
Ascites HE Albumin g/dL
INR Total bilirubin mg/dL
11/ 12
30/ 32
9/ 16
21/ 23
29/ 37
22/ 23
28/ 37
10/ 11
30/ 31
10/ 18
41/ 49
6/ 8
3/ 18
33/ 37
9/ 12
8/ 11
SOF+DCV+RBV for 12 weeks
HCV TARGET: Real-World Sofosbuvir Use in Pts With MELD > 10
• 39 academic centers and 13 community centers in US, Germany, Israel, Canada
Reddy RK, et al. EASL 2015. Abstract O007. Reproduced with permission.
Baseline Characteristic
All Pts (N = 253)
SOF + RBV (n = 102)
SOF + SMV (n = 117)
SOF + SMV + RBV (n = 34)
Mean age, yrs (range) 59 (38-80) 59 (40-80) 60 (41-74) 60 (38-72)
Previous treatment, % 59 56 60 68
Hx of decompensation, % 73 75 73 71
Liver cancer, % 17 23 10 21
100
80
60
40
20
0
SVR
12 (%
)
GT1 Naive GT2 Exp’d GT3 Exp’d
3/7
31/40
6/10
21/26
10/26
MELD 10-15 MELD 16-21 MELD > 21
37/67
67/92
19/28
55 73 68 60 81
39
78 43
5/8
7/10
2/3
63 70 67
0/1
6/6
1/1
100 100
n/N =
HCV TARGET: Safety of Sofosbuvir Regimens in Pts With MELD > 10
• Observed AEs in line with known SOF-associated AEs
• Multivariate analysis: higher albumin positive predictor of response (P = .026)
• Negative predictors of response included elevated total bilirubin (P = .002) and genotype 1a HCV (P = .069)
Reddy RK, et al. EASL 2015. Abstract O007.
Outcome All Pts (N = 234)
SOF + RBV (n = 88)
SOF + SMV (n = 114)
SOF + SMV + RBV (n = 32)
Any serious AE, n (%) 44 (17.4) 27 (26.5) 8 (6.8) 9 (26.5)
Hepatic decompensation* 16 (6.3) 10 (19.6) 2 (1.7) 4 (11.8)
Infections 10 (4.0) 7 (7.1) 2 (1.7) 1 (2.9)
Death, n (%) 3 (1.2) 0 2 (1.7) 1 (2.9)
Liver transplantation performed on treatment, n (%)
12 (5.1) 4 (4.6) 3 (2.6) 5 (15.6)
*Defined as HE, variceal bleeding, hepatic failure, hepatic hydrothorax, bacterial peritonitis.
Hepatitis web study
UK EAP for Decompensated HCV: SVR12 By Genotype and Regime
0102030405060708090
100
All G1 G3 Others
SOF/LDV/RBV SOF/LDV SOF/DCV/RBV SOF/DCV
252 28 172 15 164 21 45 5 61 7 114 7 27 13 3
SVR
12 ra
te %
, ITT
SVR12 defined as HCV RNA at 12 weeks post treatment < 30 IU/ml Foster GR et al, EASL Vienna 2015
22
Hepatitis web study
UK EAP for Decompensated HCV: Serious Adverse Events. Follow-up at Week 4
Number of events (% of total SAEs)
Number of patients (% of total population)
Total SAEs 175 119 (25.5%)
Likely related to liver disease and/or HCV therapy 138 (78.9%) 100 (21.4%)
Likely unrelated to liver disease and/or HCV therapy 37 (21.1%) 37 (7.9%)
Ascites 55 (31.4%) 38 (8.1%)
Hepatic encelopathy 28 (16%) 23 (4.9%)
Variceal bleed 6 (3.4%) 6 (1.3%)
Infection 26 (14.9%) 23 (4.9%)
Liver transplantation 16 (3.4%)
New HCC 7 (1.5%)
Discontinuation of DAAs 42 (9%)
Deaths 14 (3.0%)
Foster GR et al, EASL Vienna 2015
23
Hepatitis web study
UK EAP for Decompensated HCV: Change in MELD Baseline-Follow Up Week 4
Change in MELD
N (%)
Mean age
Mean MELD
Mean platelets (109/L)
Mean albumin
(g/L) Ascites N
(%) HE
N (%) Bleeds N (%)
Improve by > 2 92 (41.8) 55.2 13.6* 78 32* 33
(35.9) 18 (19.6) 28 (30.4)
Worse by > 2 23 (10.5) 57.5 10.7* 91 29* 10
(43.5) 2
(8.7) 6
(26.1)
*No significant MELD score change in 105 (47.7%) of patients Foster GR et al, EASL Vienna 2015
24