Hepatite C no Transplante Hepático: Quando tratar?

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Hepatite C no Transplante Hepático:

Quando tratar?

André Castro Lyra

# Prof. Associado e Livre Docente do Dept^o de Medicina – Universidade Federal da Bahia

# Chefe do Serviço de Gastro-Hepatologia do Hospital Universitário Prof. Edgard Santos - UFBA

# Coordenador do Serviço de Gastro-Hepatologia do Hospital São Rafael

XX Workshop de Hepatites Virais de Pernambuco

Sexta-feira - 20/05/2016 – 12:30h as 12:45h

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J Hepatol. 2015 Jul;63(1):199-236

Guideline EASL 2015

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AASLD and IDSA Recommendations for Testing,

Managing and Treating Hepatitis C

(Updated: February 24, 2016)

Published on Recommendations for Testing, Managing, and Treating Hepatitis C (http://live-hcv-guidance-new.gotpantheon.com)

Recommendations for When and in Whom to Initiate Treatment:

Treatment is recommended for all patients with chronic HCV infection, except those with short life expectancies that cannot be remediated by treating HCV, by transplantation, or by other directed therapy. Patients with short life expectancies owing to liver disease should be managed in consultation with an expert.

UNIQUE PATIENT POPULATIONS: PATIENTS WHO DEVELOP RECURRENT HCV INFECTION POST–LIVER TRANSPLANTATION

Rating: Class I, Level A

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PCDT: Protocolo Clínico e Diretrizes Terapêuticas para Hepatite C e Coinfecções: Indicações de tratamento imediato

• Coinfecção com o HIV

• Manifestações extra-hepáticas: porfiria cutânea, líquen plano grave com envolvimento de mucosa.

• Crioglobulinemia com manifestação em órgão-alvo (olhos, pulmão, sistema nervoso periférico e central), Glomerulonefrite, Vasculites e Poliarterite Nodosa.

• Sinais clínicos ou evidências ecográficas sugestivas de cirrose hepática (varizes de esôfago, ascite)

• Insuficiência hepática e ausência de carcinoma hepatocelular, independente da necessidade de transplante hepático

• Insuficiência renal crônica

• Púrpura Trombocitopênica Idiopática (PTI)

• Pós-transplante de fígado

• Fibrose hepática avançada (METAVIR F3 ou F4)

• Biópsia com resultado METAVIR F2 há mais de 3 anos Protocolo Clínico e Diretrizes Terapêuticas para Hepatite C e Coinfecções/ Ministério da Saúde, Secretaria de Vigilância em Saúde, Departamento de DST, Aids e Hepatites Virais. – Brasília : Ministério da Saúde, 2015. 101p. : il.

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Ally-1 Study Design

Cirrhotic N=60 Up to 20% nonGT1 Up to 20% Child C

DCV/SOF/RBV SVR12

Post-transplant N=53 Up to 20% nonGT1

DCV/SOF/RBV SVR12

Week 12 Post-treatment

Week 24 Post-treatment

Week 12

DCV 60 mg once daily; SOF 400 mg once daily, RBV up to 1000 mg in divided doses

Open label, cirrhotic or post-transplant, naïve or experienced, any genotype

Poordad F et al. Hepatology. 2016 Jan 11. doi: 10.1002/hep.28446. [Epub ahead of print]

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ALLY-1 - Hepatology

• Inclusion criteria

– 18 years of age or older

– Treatment naïve or treatment experienced

• Previous treatment failure with direct-acting antivirals allowed, except with NS5A inhibitors

– Infection with any HCV genotype

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ALLY-1 - Hepatology

• Enrolled patients with advanced cirrhosis or HCV recurrent post–liver transplantation

– Advanced cirrhosis cohort

• Child-Turcotte-Pugh (CTP) score A, B, C

• Model for End-Stage Liver Disease (MELD) scores 8-40

• Hepatocellular carcinoma allowed

– Post–liver transplantation HCV recurrence cohort

• ≥ 3 months posttransplantation

• No evidence of rejection at enrollment

• Use of any immunosuppressive regimen

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ALLY-1 - Hepatology

• 12-week treatment regimen for all patients

– Daclatasvir 60 mg once daily plus sofosbuvir 400 mg once daily plus ribavirin

• Initial ribavirin dose 600 mg/day, adjusted to 1000 mg/day based on hemoglobin levels and creatinine clearance

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Demographics and Baseline Disease Characteristics Post-transplant cohort N=53

Age, median (range) years 59 (22–82)

Male, n (%) 38 (72)

Race, n (%)

White 51 (96)

Black/African-American 1 (2)

Asian 1 (2)

Ethnicity, n (%)

Hispanic/Latino 13 (25)

Non-Hispanic/Latino 40 (75)

Body mass index, n (%)

<25 kg/m2 10 (19)

25 to <30 kg/m2 27 (51)

≥30 kg/m2 16 (30)

Hemoglobin, median (range) g/dL 13.40 (7.9–16.6)

Creatinine, median (range) mg/dL 1.18 (0.63–2.23)

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Demographics and Baseline Disease Characteristics Post-transplant cohort N=53

HCV genotype, n (%)

1 41 (77)

1a 31 (58)

1b 10 (19)

2 0

3 11 (21)

HCV RNA 38 (72)

Mean (SD), log10 IU/mL 6.61 (0.71)

≥ 8 × 105 IU/mL, n (%) 47 (89)

Estimated METAVIR fibrosis score, n(%)a 1 (2)

F0 6 (11)

F1 10 (19)

F2 7 (13)

F3 13 (25)

F4 16 (30)

Not reported 1 (2)

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Resposta virológica sustentada de acordo com o genótipo do HCV

N=10/11 N=9/10

N=30/31

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On-treatment Safety Event

Post-transplant cohort N=53

Deaths, n 0

Serious adverse events, n (%) 5 (9)

Grade 3-4 adverse events, n (%) 4 (8)

Discontinuations of all study medication due to adverse events, n (%)

1 (2) Discontinuations of ribavirin due to

adverse events, n (%)

4 (8) Adverse events (any grade) on treatment in ≥10% of

patients

Headache 19 (36)

Fatigue 15 (28)

Anemia 10 (19)

Diarrhea 10 (19)

Nausea 3 (6)

Arthralgia 7 (13)

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Number

Cirrhotic N =60

Post-transplant N = 53

Transplant & treatment extension 3 N/A

Completed intended 12 weeks treatment 56 52

Discontinued 1 1

Other 1^a 0

Adverse Event 0 1^b

Lack of efficacy 0 0

a. Subject discontinued due to liver transplant at week 3 but did not enter treatment extension or follow up.

b. Subject discontinued all treatment at week 4 due to headache.

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Daclatasvir combined with sofosbuvir or simeprevir in liver transplant recipients with severe recurrent hepatitis C infection

• Efficacy and safety data for daclatasvir-based all-oral antiviral therapy in liver transplant (LT) recipients with severe recurrent HCV.

• Daclatasvir 60 mg/day was administered for up to 24 weeks as part of a compassionate use protocol.

• The study included 97 LT recipients with a mean age of 59.3 ± 8.2 years;

• 93% had genotype 1 HCV

• 31% had biopsy-proven cirrhosis

Fontana RJ et al. Liver Transpl. 2016 Feb 17. doi: 10.1002/lt.24416. [Epub ahead of print]

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• The mean MELD score was 13.0 ± 6.0

• Proportion with CTP A/B/C was 51%/31%/12%, respectively.

• Mean HCV RNA at daclatasvir initiation was 14.3 ×6 log₁₀IU/mL

• 37% had severe cholestatic HCV infection.

• Antiviral regimens were selected by the local investigator:

– daclatasvir/sofosbuvir (n = 77), – daclatasvir/simeprevir (n = 18),

– daclatasvir/simeprevir/sofosbuvir (n = 2)

• 35% overall received ribavirin.

Daclatasvir combined with sofosbuvir or simeprevir in liver transplant recipients with severe recurrent hepatitis C infection

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EOT response and SVR

(%)

91 89

100 80 60 40 20

EOT SVR12

• 3 virological

breakthroughs and

• 2 relapses

• Patients treated with daclatasvir/simeprevir

± RBV

92

ALL _DCV+SOF

±RBV

DCV+SMV

±RBV

87

72 91

ALL DCV+SOF

±RBV

DCV+SMV

±RBV

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• CTP and MELD scores significantly improved between daclatasvir-based treatment initiation and last contact.

• None of the 8 patient deaths (6 during and 2 after therapy) were attributed to therapy.

Daclatasvir combined with sofosbuvir or simeprevir in liver transplant recipients with severe recurrent hepatitis C infection

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Gastroenterology 2015;149:649–659

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randomized

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Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease

• Immunosuppressive agents among the 229 patients:

– tacrolimus in 174 patients (76%);

– mycophenolate mofetil, mycophenolate sodium, or mycophenolic acid in 82 patients (36%);

– cyclosporine in 34 patients (15%)

Charlton M et al. Gastroenterol 2015;149:649–659

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SVR 12 according to liver function post-transplant

SVR 12 (%)

96-98%

100 80 60 40 20

0 No/compensated cirrhosis

Moderate hepatic impairment

Severe hepatic impairment 85-88%

60-75%

Gastroenterology 2015;149:649–659 All 6 pts with FCH = SVR

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RESULTS - ADVERSE EVENTS

• Response rates in the 12- and 24-week groups were similar.

• Thirteen patients (4%) discontinued the ledipasvir and sofosbuvir combination prematurely because of adverse events;

• 10 paYents died →complicaYons related to hepaYc decompensaYon.

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HEPATOLOGY, Vol. 61, No. 6, 2015

• The treatment regimen consisted of SMV and SOF with or without RBV for 12 weeks

• At the discretion of the treating physicians, weight-based RBV was used in selected patients.

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v

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ALL:

SVR ITT = 90%

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HCV Guidance: Recommendations for

Testing, Managing, and Treating Hepatitis C

AASLD

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Treatment-naive and -experienced patients with HCV genotype 1 or 4 infection in the allograft, including those with compensated cirrhosis

• Daily daclatasvir (60 mg), sofosbuvir (400 mg), and low initial dose of RBV (600 mg, increased as tolerated) for 12 weeks

• Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) with weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks

Alternative:

• Daily sofosbuvir (400 mg) plus simeprevir (150 mg) with or without weight-based RBV for 12 weeks

(29)

Treatment-naive and -experienced patients with HCV genotype 1 or 4 infection in the allograft, including those with compensated cirrhosis,

who cannot tolerate RBV

• Daily daclatasvir (60 mg), sofosbuvir (400 mg) for 24 weeks

• Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 24 weeks

(30)

Treatment-naive and -experienced liver transplant recipients

with decompensated cirrhosis(Child Turcotte Pugh [CTP] class B or C) who have HCV genotype 1 or 4 infection in the allograft

• Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) with low dose RBV (600 mg, increased as tolerated) for 12 weeks

(31)

Treatment-naive and -experienced patients with HCV genotype 3 infection in the allograft, including those with compensated cirrhosis

• Daily daclatasvir (60 mg), sofosbuvir (400 mg), and low initial dose of RBV (600 mg, increased as tolerated) for 12 weeks

• Daily sofosbuvir (400 mg) and weight-based RBV for 24 weeks

(32)

Treatment-naive and -experienced patients with HCV genotype 3 infection in the allograft, including those with compensated cirrhosis,

who cannot tolerate RBV

• Daily daclatasvir (60 mg), sofosbuvir (400 mg) for 24 weeks

(33)

Treatment-naive and -experienced liver transplant recipients with decompensated cirrhosis (Child Turcotte Pugh [CTP] class B or C)

who have HCV genotype 3 infection in the allograft.

• Daily sofosbuvir (400 mg) and low initial dose of RBV (600 mg, increased as tolerated) for 24 weeks

(34)

EASL

2015

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EASL- Post transplant

• Patients without cirrhosis or with compensated (ChildPugh A) cirrhosis post- transplant can be treated without the need for immunosuppressant drug dose adjustments:

– Sofosbuvir and ribavirin for 12 weeks (genotype 2)

– Sofosbuvir and ledipasvir with ribavirin for 12 weeks (genotypes 1, 4, 5 or 6) – Sofosbuvir and daclatasvir with ribavirin for 12 weeks (all genotypes)

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EASL- Post transplant

• Patients without cirrhosis or with compensated (ChildPugh A) cirrhosis post- transplant can be treated with the need for immunosuppressant drug dose adjustments (or avoidance of cyclosporine):

– sofosbuvir and simeprevir with ribavirin for 12 weeks (genotypes 1 and 4),

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• Patients with decompensated (Child-Pugh B or C) cirrhosis can be treated:

– Sofosbuvir and ribavirin for 12 weeks (genotype 2)

– Sofosbuvir and ledipasvir with ribavirin for 12 weeks (genotypes 1, 4, 5 or 6)

– Sofosbuvir and daclatasvir with ribavirin for 12 weeks (all genotypes).

EASL- Post transplant

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Quando iniciar o tratamento?

• Possivelmente entre 3 e 6 meses após o transplante hepático .

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Interação medicamentosa

• Presente:

– ciclosporina ou tacrolimus + ombitasvir/paritaprevir/ritonavir/

dasabuvir/ ribavirina

– ciclosporina + simeprevir

• Ausente:

– ciclosporina ou tacrolimus + ledipasvir/sofosbuvir ou daclatasvir

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Sumário

• O tratamento da hepatite C na recidiva do pós transplante é altamente eficaz e bem tolerado

• A maioria dos autores parece optar por iniciar a terapia entre 3 e 6 meses depois do transplante

• Não há necessidade de ajuste dos imunossupressores com o uso do daclatasvir e/ou sofosbuvir

• Pode haver interação do simeprevir com ciclosporina

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Sumário

• Consensos (EUA e EU) recomendam:

– tratamento por 12 semanas para todos quando a ribavirina é associada

– tratamento por 24 semanas para todos quando a ribavirina NÃO é utilizada (AASLD)