Tractament antiviral del VHC en pacients amb cirrosi avançada

(1)

José A. Carrión

Hepatologia. Servei de Digestiu Hospital del Mar. Parc de Salut Mar

Barcelona

Tractament antiviral del VHC en pacients amb cirrosi avançada

Curs de formació de la SCD Dijous 14 de Maig de 2015

(2)

Historia Natural de la Cirrosi

Mortalitat anual Estadi 1à1,5%

Estadi 2à 2%

Estadi 3à10%

Estadi 4à21%

Estadi 5à27%

From D’Amico G. Chapter 2. Natural History and Stages of Cirrhosis. 2014. DOI 10.1007/978-1-4939-0002-2_2

(3)

Opcions Terapèutiques

Beneficis del Tractament

(4)

Bourlière M, et al. AASLD 2014. Abstract 82

Pooled Analysis of LDV/SOF ± RBV in Pts With Compensated Cirrhosis

100 80 60 40 20 0

Total Treatment Naive 92 96 98 100

SVR12 (%)

118 204 133 58

96 98 97

47 45 33 36

100

Treatment Experienced 90

96 98

71 159 100 22 100 12 wks of LDV/SOF

12 wks of LDV/SOF + RBV

24 wks of LDV/SOF

24 wks of LDV/SOF + RBV

n =

GT1 HCV-infected pts who participated in phase II/III trials of LDV/SOF (N = 513)

SVR12 rates lower in patients with a platelet count < 75,000 cells/mm³(84%)

(5)

Contraindicació d’ Interferó en Cirrosi Avançada

59 (24-67) 34 (67)

22 (43) 22 (43) 7 (14) Edat (anys)

Sexe (home, %) Child-Pugh (n, %):

- A (5,6) - B (7-9) - C (10-12)

59 (36-66) 34 (67)

23 (45) 22 (43) 6 (12) IFN-Peg alfa 2a + RBV

n=51, (%)

Control

n=51, (%) p Ns

ns

ns ns ns n=102

Trombopènia (<40.000) Neutropènia (< 750) Anèmia (Hb < 10 g/L)

Interrupció del tractament (n, %) Pacients/ Infeccions bacterianes Descompensació clínica (n,%) Èxitus (n, %)

20 (39) 23 (45) 34 (67) 22 (43) 12 (25)/ 19

16 (31) 8 (16)

9 (18) 2 (4) 2 (4)

- 3 (6)/ 3 14 (27) 7 (14)

0.02

<0.01

<0.01 ns ns

Carrión et al. J Hepatol 2009

(6)

SOLAR-1: Phase II Trial of LDV/SOF + RBV in Decompensated Cirrhosis

Flamm SL, et al. AASLD 2014. Abstract O239.

LDV/SOF + RBV*

(n = 55) LDV/SOF + RBV*

(n = 53)

Wk 24 GT 1 or 4

decompensated liver disease

(N = 108)

Wk 12

Stratified by CPT class B or C (≤ 12 p) SOLAR-1 in Decompensated Cirrhosis^[1]

Baseline Characteristic ^{CPT B} ^{CPT C}

12 Wks (n = 30)

24 Wks (n = 29)

12 Wks (n = 23)

24 Wks (n = 26) MELD score, n (%)

§ < 10 6 (20) 8 (28) 0 0

§ 10-15 21 (70) 16 (55) 16 (70) 13 (50)

§ 16-20 3 (10) 5 (17) 7 (30) 12 (46)

§ 21-25 0 0 0 1 (4)

Median bilirubin, mg/dL (range) 2.0 (0.6-5.5) 1.4 (0.8-4.5) 2.9 (1.2-14.5) 3.8 (1.1-5.7) Median albumin, g/L (range) 2.9 (2.1-3.7) 3.0 (2.2-3.4) 2.6 (1.6-3.5) 2.6 (2.0-3.3)

Median INR (range) 1.3 (1.0-1.5) 1.3 (1.0-2.6) 1.4 (1.2-1.9) 1.4 (1.1-2.2)

Median platelets, x 10³µL (range) 88 (36-212) 73 (30-154) 81 (39-177) 71 (32-179)

Ascites, n (%) 17 (57) 17 (59) 22 (96) 25 (96)

Encephalopathy, n (%) 20 (67) 16 (55) 21 (91) 23 (88)

(7)

Pts, n (%) CPT B CPT C

12 Wks (n = 30)

24 Wks (n = 29)

12 Wks (n = 23)

24 Wks (n = 26)

AE 29 (97) 27 (93) 23 (100) 26 (100)

SAE 3 (10) 10 (34) 6 (26) 11 (42)

Treatment-emergent, -related SAEs 2 (7) 0 0 2 (8)

Treatment discontinuation due to AE 0 1 (3) 0 2 (8)

RVS 12

26/

30

26/

29

20/

23

23/

26

(8)

CPT B/C (7-12) Pre-Transplant

Post-Transplant

Fibrosis (F0-F3)

CPT B/C (7-12) CPT A (5-6)

SVR12

SVR12 LDV/SOF + RBV

LDV/SOF + RBV

Wk 0 Wk 12 Wk 24 Wk 36

Manns M et al, EASL 2015, General Session O02 FCH

Post-Transplant

• GT 1 or 4 treatment-naïve or -experienced patients

• Main exclusion criteria: CPT >12

• RBV dosing in CPT B and C cirrhosis: 600 mg/day; subsequent dose escalation

• Combine pre- and post-transplant CPT B and CPT C patients (n=160)

(9)

Pre/Post-Transplant CPT B + CPT C (n=160)

Patients, n (%)

12 Weeks n=78

24 Weeks n=82

Median age, y (range) 58 (27-76) 58 (23-79)

MELD >15, n (%) 22 (28) 19 (23)

Ascites, n (%) 51 (65) 64 (78)

Encephalopathy, n (%) 37 (47) 45 (55)

Median total bilirubin, mg/dL (range) 2.3 (0.3-8.9) 2.3 (0.3-11.2) Median albumin, g/dL (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) Median hemoglobin, g/dL (range) 13 (10-16) 12 (9-17) Median CL_Cr, mL/min (range) 79 (30-190) 80 (34-224)

Manns M et al, EASL 2015, General Session O02

85 88

0 20 40 60 80 100

CPT B & C Pre and Post

64/

78

72/

82

(10)

Seguretat de LDV/SOF + RBV en Cirrosi Decompensada. SOLAR-1+SOLAR-2

Samuel D et al. EASL2015_P0774

(11)

ALLY-1: SOF + DCV + RBV in Cirrhotic or Posttransplant HCV-Infected Pts

• Multicenter, open-label phase III trial in advanced cirrhosis (n = 60) or post–liver transplant (n = 53) pts with genotypes 1-6

• Treatment: 12 wks of daclatasvir 60 mg QD + sofosbuvir 400 mg QD + RBV

– Initial RBV dose 600 mg/day, adjusted to 1000 mg/day based on hemoglobin levels and creatinine – Pts with advanced cirrhosis who interrupted treatment due to liver transplantation could receive 12

additional wks of therapy immediately after transplantation

Poordad F, et al. EASL 2015. Abstract LO8.

100

80

60

40

20

0

SVR12 (%)

All Pts

Advanced Cirrhosis

Post- transplant

50/60 50/53

83 94

n/N =

Child-Pugh Class

Advanced Cirrhosis Cohort

11/12 92

A B C

30/32 94

9/16 56

Child-Pugh class C (n= 16) or albumin < 2.8 g/dL (n= 18) had SVR12 rates of 56%

(12)

SOF + NS5A Inhibitors ± RBV in Pts With GT1/3 HCV and Decompensated Cirrhosis

• Observational cohort study of National Health Service of England (N = 467)

• At physician’s discretion, pts received 12 wks SOF + LDV or DCV ± RBV

Baseline Characteristic All Pts (N = 467)

Genotype 1 (n = 235)

Genotype 3 (n = 189)

Other Genotypes (n = 43)

CTP B, % 66.2 68.5 64.0 62.8

CTP C, % 9.9 8.1 12.7 7.0

Mean MELD score (range) 11.9 (6-36) 11.3 (6-24) 12.6 (6-36) 11.9 (6-22)

SOF + LDV + RBV 54.0 35.1 13.1 5.8

SOF + DCV + RBV 36.8 9.6 24.4 2.8

RBV-free regimen 9.2 5.6 3.0 0.6

Foster GR, et al. EASL 2015. Abstract O002.

(13)

SVR12 among pts with other HCV GTs: 89% (n = 27) with SOF + LDV + RBV; 85%

(n = 13) with SOF + DCV + RBV; 100% (n = 3) SOF + DCV

12-wk SOF + LDV + RBV 12-wk SOF + LDV 12-wk SOF + DCV + RBV 12-wk SOF + DCV

N =

100

80

60

40

20

0

All

SVR12, % (ITT)

252 28 172 15 80

71 74 73

GT1 GT3

P < .05

59

43

70 71

164 21 45 5 61 7 114 7

86 81 82

60

SOF + NS5A Inhibitors ± RBV in Pts With GT1/3 HCV and Decompensated Cirrhosis

Foster GR, et al. EASL 2015. Abstract O002.

(14)

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.

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

MELD 10-15 MELD 16-21 MELD > 21

37/

67 67/

92

19/

28 55 73 68

5/

8

7/

10 2/

3 63 70 67

0/

1

6/

6 1/

1 100 100

GT1 GT2 GT3

100 80 60 40 20 0

SVR12 (%)

11/

21

79/

107 19/

29

21/

26

10/

26 66

81

39 74

52

n/N =

(15)

Predictors of response (multivariate analysis):

• Positive predictor of response: higher albumin (P = .026)

• Negative predictors of response:

– elevated total bilirubin (P = .002) – 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 (11.4) 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)

*Defined as HE, variceal bleeding, hepatic failure, hepatic hydrothorax, bacterial peritonitis.

HCV TARGET: Real-World Sofosbuvir Use in Pts With MELD > 10

(16)

Tractament del VHC en Cirrosi Avançada

Sofosbuvir + Simeprevir:

12 setmanes

24 setmanes + RBV en difícils de curar Sofosbuvir +

Daclatasvir:

Cirrosi: 12 setmanes + RBV

Cirrosi descompensada: 24 setmanes + RBV Sofosbuvir +

Ledipasvir:

Cirrosi: 12 semanas + RBV

Cirrosi descompensada: 12-24 sem + RBV Paritraprevir/r +

Ombitasvir + Dasabuvir:

GT 1b : 12 setmanes sense RBV (+RBV en cirrosi)(child A)

GT 1a amb Cirrosi: 24 setmanes + RBV

Pacients en llista d’espera de trasplantament hepàtic:

OBV/PTV/rtv + DSV + RBV SOF + DCV ± RBV

SOF/LDV ± RBV SOF + SMV ± RBV

La durada del tractament serà de 12-24 setmanes. La càrrega viral ha de ser no detectable almenys 30 dies abans del trasplantament.

(17)

Opcions Terapèutiques

Beneficis del Tractament

(18)

Benefici del Tractament en Cirrosi Compensada

F3-F4 (N=449)

Morgan T et al. Hepatology 2010, 52: 833-44

(19)

Normal range (0.2-

0 1.2)

1 2 3 4

Baseline FU Week 4

(13.7)

p <0.001

F0-F3 + CPT A

Normal range (0.2-

0 1.2)

1 2 3 4

Baseline FU Week 4

p <0.001

(11.2) (19.1)

CPT B + CPT C

Normal range (3.3- 4.9)

1 2 3 4 5

p <0.001

0

Baseline FU Week 4

Median Total Bilirubin (mg/dL)Median Total Albumin (g/dL)

Normal range (3.3-4.9)

1 2 3 4 5

p <0.001

0

Baseline FU Week 4

Benefici del Tractament del VHC en Cirrosi Avançada

(20)

n=5 n=5 n=2 n=3

(-8) (+10)

CPT B CPT C

12 wk (n=30)* 24 wk (n=29)* 12 wk (n=23)* 24 wk (n=26)*

CANVI EN LA PUNTUACIÓ DE CHILD-PUGH

60% 68% 65% 79%

(21)

Pre/Post-Transplant (CPT B and C, n=136*)

-10 -8 -6 -4 -2 0 2 4

n=18

(-17)

Change in MELD Score

(-11)

(8)

70%

16%

CANVI EN LA PUNTUACIÓ DE MELD

(22)

CANVI HEMODINÀMIC DEL GPVH

Afdhal N et al. EASL2015_LP13

(5%) (24%)

(23)

CANVI HEMODINÀMIC EN PACIENTS AMB GPVH≥12 mmHg

• MELD <10 va ser la única variable que es va associar un descens del GPVH ≥20%

• La milloria de la funció hepàtica i del MELD va ser independent del canvi de GPVH

(24%)

(42%)

Afdhal N et al. EASL2015_LP13

(24)

59 ± 10 11 (45.8)

0 (0) 24 (100) 13.1 ± 1.9 Edat (anys)

Ascites

Child-Pugh (n, %):

- A (5,6) - B (7-9) MELD

62 ± 8 31 (60.8)

3 (5.8) 48 (94.1) 13.3 ± 2.8 RVS

N=24, (%) NR

n=51, (%) p ns ns

ns ns ns N=75

Pacients/ Event Clínic

Ascites/ 1000 pacients-mes

Encefalopatia/ 1000 pacients-mes Sagnat per VE/ 1000 pacients-mes

Infeccions bacterianes/ 1000 pacients-mes CHH/ 1000 pacients-mes

Èxitus/ 1000 pacients-mes Supervivència (mes)

49 (95.1)/ 137 20.8

14.3 7.8 7.8 4.5 9.4 53

<0.01

<0.01 ns

<0.01

Iacobellis A et al. Clinical Gastroenterology and Hepatology 2011;9:249-253

8 (33.3)/ 10 2.2

0 1.5

0 3.7 1.5 73

(25)

Curry MO, et al. Gastroenterology 2015 Jan;148(1):100-107

• N= 61 en llista per a TF

• Tractament: SOF + RBV fins el TH o 48 setmanes

• Exclusió: Child-Pugh >7 i/o MELD >21

• Genotip: 1, 2, 3, 4

• N= 43 van arribar al TF (43, 93% amb CV ILD)

• RVS12 postTF: 30/43 (70%)

• RVS12 Global: 30/61 (49%) per recaigudes (9) i NR-BK (5)

< 30 dies amb CV ILD: 9/13 (69%)

> 30 dies amb CV ILD: 1/27 (4%)

(26)

Conclusions

• Els tractaments amb interferó estan contraindicats en pacients amb cirrosi descompensada (Child-Pugh B o C)

• Els tractaments de major eficàcia incorporen al menys dos antiviral d’acció directe (AAD) amb ribavirina. En cas de

contraindicació o intolerància a la ribavirina esta indicat allargar el tractament 24 setmanes

• La seguretat dels AAD en pacients amb cirrosi avançada es excel·lent

• El tractament antiviral millora la funció hepàtica (Child-Pugh, MELD) en més de la meitat dels pacients però el seu efecte

hemodinàmic (GPVH) precoç és limitat i per tant pot persistir el risc de descompensació i la necessitat de transplantament.

• Les dades d'eficàcia i seguretat en pacients amb Child-Pugh>12 i/o MELD >20 son molt limitades