RESUMO
Fibrosing cholestatic hepatitis (FCH) is a less common but well-recognized severe complication of recurrent hepatitis C virus (HCV) infection post-liver transplant. This condition is fatal without successful treatment and to date; post-transplant antiviral interferon-based antiviral therapy has been associated with guarded success. The new era of protease inhibitors in the treatment of chronic HCV infection may alter the dismal outcome of this condition. To date, however, the experience with protease inhibitors in this condition is unreported. We report a post-liver transplant recipient with HCV associated FCH treated successfully with boceprevir, peginteferon and ribavirin for severe FCH. The patient was young woman who was a null responder pre-transplant to peginterferon and ribavirin. The peak serum bilirubin 391 µmol/L normalized to 15 µmol/L by week 8 of therapy. The pre-treatment HCV viral load of > 78 million IU/mL, decreased to 78 IU/mL at week 8 of therapy and was undetectable by week 12 and at the end of 48 week of treatment. 12 weeks post treatment, the HCV viral load remains undetectable. Significant anemia and neutropenia were encountered. Tacrolimus dosage titrated to trough levels, required marked reduction to 0.5 mg three times weekly. Despite the suboptimal peginterferon and ribavirin dosing, limited by adverse effects, full boceprevir dosing was maintained, with resolution of liver dysfunction. Boceprevir was obtained on compassionate grounds from the manufacturer before its licensure in Canada and this was the first use of boceprevir in the world for post-transplant FCH.
Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Transplante de Fígado , Polietilenoglicóis/uso terapêutico , Prolina/análogos & derivados , Ribavirina/uso terapêutico , Carga Viral/efeitos dos fármacos , Adulto , Quimioterapia Combinada , Feminino , Hepacivirus , Humanos , Imunossupressores/uso terapêutico , Interferon alfa-2 , Prolina/uso terapêutico , RNA Viral/sangue , Proteínas Recombinantes/uso terapêutico , Tacrolimo/uso terapêutico , Resultado do TratamentoRESUMO
PURPOSE: Chronic hepatitis C virus (HCV) is a major problem affecting up to 170 million people worldwide. Two protease inhibitors have recently been approved that will revolutionize treatment. Our objective was to summarize and evaluate the literature pertaining to the pharmacokinetics of boceprevir and telaprevir, in order to provide clinicians with insight into the management of actual and potential drug interactions. SUMMARY: A standardized search using MEDLINE (1948-November 2011), EMBASE (1980-November 2011), IPA (1970-November 2011), Google, and Google Scholar that combined the search terms boceprevir, telaprevir, pharmacokinetics, drug interaction, and drug metabolism was performed. Manual reference searches of chosen articles were completed. Monographs and articles, conference proceedings, and abstracts were evaluated. Boceprevir and telaprevir are both substrates and inhibitors of cytochrome P450 3A4 and telaprevir is a substrate of p-glycoprotein. Levels of boceprevir are decreased in patients taking efavirenz but effects with other antiretrovirals are minimal or unknown. Coadministration with efavirenz may compromise telaprevir levels and should be avoided. Telaprevir may increase levels of cyclosporine, tacrolimus, atorvastatin, and amlodipine, which may expose patients to increased adverse effects. Conclusions. Significant drug-drug interactions occur with both boceprevir and telaprevir. Until studies are reported and experience is gained with these agents, clinicians will need to be careful when administering in high-risk populations and those receiving chronic therapy with interacting agents. Studies are urgently needed in HIV patients taking antiretrovirals and patients taking chronic immunosuppression as these populations are at increased risk of experiencing clinically significant interactions.
Assuntos
Fármacos Anti-HIV/farmacocinética , Hepatite C Crônica/tratamento farmacológico , Imunossupressores/farmacocinética , Oligopeptídeos/farmacocinética , Prolina/análogos & derivados , Inibidores de Proteases/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/efeitos dos fármacos , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Interações Medicamentosas , Infecções por HIV/metabolismo , Humanos , Hospedeiro Imunocomprometido/fisiologia , Prolina/farmacocinética , Transplante/fisiologiaRESUMO
INTRODUCTION: Hepatitis B virus (HBV) related liver transplant (LT) recipients face a high risk of HBV reinfection in the absence of continuous post-operative HBV prophylaxis. Combination HBV prophylaxis with hepatitis B immune globulin (HBIg) and nucleos(t)ide anti-viral agents prevents HBV recurrence in 90 to 100% of patients who undergo transplantation for hepatitis B and is considered the standard of care in Canada. Post liver transplant HBV prophylaxis protocols vary with regard to the dosing, duration and routes of HBIg administration. All Canadian transplant centres managing liver transplant patients were surveyed as to their HBV transplant protocols. RESULTS: Results of the survey showed that the majority of the Canadian transplant centres use an oral antiviral in combination with long term or indefinite HBIg for prevention of HBV recurrence post liver transplantation. Studies were done to test new protocols using lower HBIg doses given intramuscularly or subcutaneously alone or in combination with antiviral agents.
Conclusion. Long term HBIg administration post transplantation in combination with antiviral agents is an integral part of Canadian HBV related liver transplant protocol.
Assuntos
Antivirais/administração & dosagem , Hepatite B/tratamento farmacológico , Hepatite B/cirurgia , Imunoglobulinas/administração & dosagem , Transplante de Fígado/normas , Padrão de Cuidado , Administração Oral , Canadá , Esquema de Medicação , Quimioterapia Combinada , Pesquisas sobre Atenção à Saúde , Humanos , Prevenção Secundária , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Patients who receive liver transplantation for chronic hepatitis B infection require long-term combination therapy with hepatitis B immunoglobulin (HBIG) and oral antiviral medication to prophylax against graft re-infection. This study examines the efficacy and patient preference of subcutaneous (SC) administration of HBIG in maintaining anti HBs titres > 100 IU/L. MATERIALS AND METHODS: 12 patients who were stable while receiving our standard IM HBIG protocol received an alternate formulation by SC injection, consisting of 10 mL (3120 IU) HBIG as 4 x 2.5 mL SC injections. SC injection were repeated as soon as titres reached 100-150 IU/mL during the 3 month study period. A questionnaire was administered upon study entry and exit to subjectively assess patient preference. RESULTS: Anti- HBs Cmax after first injection was 441.6 IU/L +/- 81.5, and Tmax was 7.1 +/- 3.2 days. SC injections were required every 56 days, which compared well to the frequency of required IM injections prior to study enrollment of 45 days. The patients mean ratings of pain on a 0-10 scale were 5 for the IM route and 1.6 for the SC route. All patients preferred the SC injections to the IM. CONCLUSION: SC administration of HBIG can effectively maintain anti HBs levels above the requisite 100 IU/L while substantially decreasing patient discomfort and improving patient satisfaction, and therefore becomes a very attractive alternative to IM HBIG injections. Further studies and wider use of SC HBIG based on this study may alter the standard practice of transplantation centers
Assuntos
Vacinas contra Hepatite B/administração & dosagem , Hepatite B Crônica/prevenção & controle , Hepatite B Crônica/cirurgia , Imunoglobulinas/administração & dosagem , Transplante de Fígado , Adulto , Idoso , Antivirais/uso terapêutico , Colúmbia Britânica , Esquema de Medicação , Quimioterapia Combinada , Feminino , Anticorpos Anti-Hepatite B/sangue , Hepatite B Crônica/complicações , Humanos , Injeções Intramusculares , Injeções Subcutâneas , Transplante de Fígado/efeitos adversos , Masculino , Pessoa de Meia-Idade , Preferência do Paciente , Projetos Piloto , Estudos Prospectivos , Prevenção Secundária , Inquéritos e Questionários , Fatores de Tempo , Resultado do TratamentoRESUMO
Recurrent hepatitis C virus (HCV) infection after liver transplantation is a significant cause of morbidity, mortality and graft loss. Spontaneous clearance of recurrent HCV after liver transplant is a rarely reported phenomenon. We report a case of a 66-year-old woman who underwent liver transplantation for HCV cirrhosis (treatment- naive genotype 2) under immunosuppression with tacrolimus, mycophenolate mofetil (MMF), and short-term corticosteroids. The patient developed histologically proved severe cholestatic recurrence of HCV hepatitis. Immunosuppression was reduced to tacrolimus monotherapy because of cytopenia. She subsequently became RNA negative at week 44 post- transplant while on tacrolimus and MMF despite no antiviral therapy. A spontaneous sustained virologic clearance was confirmed with subsequent HCV nucleotide testing. Only a few similar cases have been reported in the literature with uninterrupted immunosuppression and subsequent spontaneous clearance. Our experience, and the few other published cases in the literature, suggests that spontaneous clearance of HCV after liver transplantation is a rare but real phenomenon. Better understanding of this phenomenon may help to manage recurrent HCV disease after transplantation.
Assuntos
Hepatite C/cirurgia , Cirrose Hepática/cirurgia , Transplante de Fígado/efeitos adversos , Idoso , Biópsia , Quimioterapia Combinada , Feminino , Hepacivirus/genética , Hepatite C/complicações , Hepatite C/diagnóstico , Humanos , Imunossupressores/uso terapêutico , Cirrose Hepática/virologia , RNA Viral/sangue , Recidiva , Remissão Espontânea , Fatores de Tempo , Resultado do Tratamento , Carga ViralRESUMO
Portopulmonary hypertension (PPH) is an infrequent, but well-recognized complication of liver cirrhosis. PPH in those with end-stage liver disease has a significant impact on per-operative and intra-operative mortality, with liver transplantation being contraindicated in those individuals with mean pulmonary artery pressure exceeding 50 mmHg. Vasodilatory therapy is the mainstay of pharmacotherapy for PPH, although the evidence of benefit is largely extrapolated from the pulmonary hypertension literature. We report the use of the phosphodiesterase inhibitor, sildenafil, in a patient with end stage liver disease and PPH, with a pulmonary artery pressure before transplantation of 75 mmHg, to reduce pulmonary artery pressure prior to a successful liver transplant.