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

Hepatitis web study

• Erradicar la infección por el virus de la hepatitis C. +++

• Mejorar la función hepátic +/-

• Aumentar la Supervivencia ???

• Prevenir la recurrencia de la infección por VHC Post TX +++

Resumen