Hepatite C no Transplante Hepático: Quando tratar? XX Workshop de Hepatites Virais de Pernambuco Sexta-feira - 20/05/2016 12:30h as 12:45h 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
J Hepatol. 2015 Jul;63(1):199-236 Guideline EASL 2015
AASLD and IDSA Recommendationsfor Testing, Managing and Treating Hepatitis C (Updated: February 24, 2016) 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 Published on Recommendations for Testing, Managing, and Treating Hepatitis C (http://live-hcv-guidance-new.gotpantheon.com)
PCDT: Protocolo Clínico e Diretrizes Terapêuticas para Hepatite C e Coinfecções: Indicações de tratamento imediato Coinfecçãocom o HIV Manifestações extra-hepáticas: porfiria cutânea, líquen plano grave com envolvimento de mucosa. Crioglobulinemiacom manifestação em órgão-alvo (olhos, pulmão, sistema nervoso periférico e central), Glomerulonefrite, Vasculites e PoliarteriteNodosa. 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 TrombocitopênicaIdiopática (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, Aidse Hepatites Virais. Brasília : Ministério da Saúde, 2015. 101p. : il.
Ally-1 Study Design Open label, cirrhotic or post-transplant, naïve or experienced, any genotype Week 12 Post-treatment Week 12 Post-treatment Week 24 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 DCV 60 mg once daily; SOF 400 mg once daily, RBV up to 1000 mg in divided doses Poordad F et al. Hepatology. 2016 Jan 11. doi: 10.1002/hep.28446. [Epub ahead of print]
ALLY-1 -Hepatology Inclusion criteria 18 yearsofage orolder Treatment naïve or treatment experienced Previous treatment failure with direct-acting antivirals allowed, except with NS5A inhibitors Infection with any HCV genotype Poordad F et al. Hepatology. 2016 Jan 11. doi: 10.1002/hep.28446. [Epub ahead of print]
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 Poordad F et al. Hepatology. 2016 Jan 11. doi: 10.1002/hep.28446. [Epub ahead of print]
ALLY-1 -Hepatology 12-week treatment regimen for all patients Daclatasvir 60 mg once daily plus sofosbuvir 400 mg once daily plus ribavirin Initialribavirindose 600 mg/day, adjustedto 1000 mg/daybasedon hemoglobin levels and creatinine clearance Poordad F et al. Hepatology. 2016 Jan 11. doi: 10.1002/hep.28446. [Epub ahead of print]
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) Bodymassindex, 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) Poordad F et al. Hepatology. 2016 Jan 11. doi: 10.1002/hep.28446. [Epub ahead of print]
HCV genotype, n (%) Demographics and Baseline Disease Characteristics Post-transplant cohort N=53 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) Poordad F et al. Hepatology. 2016 Jan 11. doi: 10.1002/hep.28446. [Epub ahead of print]
Resposta virológicasustentada de acordo com o genótipo do HCV N=30/31 N=9/10 N=10/11 Poordad F et al. Hepatology. 2016 Jan 11. doi: 10.1002/hep.28446. [Epub ahead of print]
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 (%) Discontinuations of ribavirin due to adverse events, n (%) Adverse events (any grade) on treatment in 10% of patients 1 (2) 4 (8) Headache 19 (36) Fatigue 15 (28) Anemia 10 (19) Diarrhea 10 (19) Nausea 3 (6) Arthralgia 7 (13) Poordad F et al. Hepatology. 2016 Jan 11. doi: 10.1002/hep.28446. [Epub ahead of print]
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. Poordad F et al. Hepatology. 2016 Jan 11. doi: 10.1002/hep.28446. [Epub ahead of print]
Daclatasvir combined with sofosbuviror simeprevirin 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]
Daclatasvir combined with sofosbuviror simeprevirin liver transplant recipients with severe recurrent hepatitis C infection The mean MELD score was 13.0 ± 6.0 Proportion with CTP A/B/C was 51%/31%/12%, respectively. Mean HCV RNA at daclatasvirinitiation was 14.3 6 log 10 IU/mL 37% had severe cholestatichcv 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. Fontana RJ et al. Liver Transpl. 2016 Feb 17. doi: 10.1002/lt.24416. [Epub ahead of print]
EOT response andsvr (%) 100 80 60 40 91 92 89 87 91 72 3 virological breakthroughs and 2 relapses Patients treated with daclatasvir/simeprevir ±RBV 20 ALL DCV+SOF ±RBV DCV+SMV ±RBV ALL DCV+SOF ±RBV DCV+SMV ±RBV EOT SVR12 Fontana RJ et al. Liver Transpl. 2016 Feb 17. doi: 10.1002/lt.24416. [Epub ahead of print]
Daclatasvir combined with sofosbuviror simeprevirin liver transplant recipients with severe recurrent hepatitis C infection 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. Fontana RJ et al. Liver Transpl. 2016 Feb 17. doi: 10.1002/lt.24416. [Epub ahead of print]
Gastroenterology 2015;149:649 659
randomized
Ledipasvirand SofosbuvirPlus Ribavirinfor Treatment of HCV Infection in Patients With Advanced Liver Disease Immunosuppressive agents among the 229 patients: tacrolimusin 174 patients (76%); mycophenolatemofetil, mycophenolatesodium, or mycophenolicacid in 82 patients (36%); cyclosporine in 34 patients(15%) Charlton M et al. Gastroenterol 2015;149:649 659
SVR 12 according to liver function post-transplant 100 80 96-98% 85-88% 60-75% SVR 12 (%) 60 40 All 6 pts with FCH = SVR 20 0 No/compensated cirrhosis Moderate hepatic impairment Severe hepatic impairment Charlton M et al. Gastroenterol 2015;149:649 659 Gastroenterology 2015;149:649 659
RESULTS - ADVERSE EVENTS Response rates in the12-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. Charlton M et al. Gastroenterol 2015;149:649 659
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.
v v v
ALL: SVR ITT = 90%
HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C AASLD
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
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
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
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
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
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
EASL 2015
EASL-Post transplant Patients without cirrhosis or with compensated (ChildPugh A) cirrhosis posttransplant 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)
EASL-Post transplant Patients without cirrhosis or with compensated (ChildPugh A) cirrhosis posttransplant can be treated with the need for immunosuppressant drug dose adjustments (or avoidance of cyclosporine): sofosbuvirand simeprevirwith ribavirin for 12 weeks (genotypes 1 and 4),
EASL-Post transplant Patients with decompensated(child-pugh B or C) cirrhosis can be treated: Sofosbuvir and ribavirin for 12 weeks (genotype 2) Sofosbuvirand ledipasvirwith ribavirinfor 12 weeks (genotypes 1, 4, 5 or 6) Sofosbuvirand daclatasvirwith ribavirinfor 12 weeks (all genotypes).
Quando iniciar o tratamento? Possivelmente entre 3 e 6 meses após o transplante hepático.
Interação medicamentosa Presente: ciclosporinaoutacrolimus+ ombitasvir/paritaprevir/ritonavir/ dasabuvir/ ribavirina ciclosporina + simeprevir Ausente: ciclosporina ou tacrolimus + ledipasvir/sofosbuvir ou daclatasvir
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
Sumário Consensos (EUA e EU) recomendam: tratamento por 12 semanas para todos quando a ribavirinaé associada tratamento por 24 semanas para todos quando a ribavirinanão é utilizada (AASLD)