RESUMO
The development of multiple highly effective and safe direct-acting antivirals to treat hepatitis C virus (HCV) has resulted in greater ease and confidence in managing HCV infection in transplant recipients that in turn has impacted the solid organ transplant community as well. In the United States, the opioid epidemic has increased the number of overdose deaths with a concomitant increase in younger HCV viremic donors after brain death being identified. At the same time, a decrease in HCV viremic transplant candidates has led to a growing interest in exploring the use of HCV viremic liver and kidney donor allografts in HCV-negative recipients. To date, experience with the use of HCV viremic liver and kidney allografts in HCV-negative recipients is limited to a few small prospective research trials, case series, and case reports. There are also limited data on recipient and donor selection for HCV viremic liver and kidney allografts. In response to this rapidly changing landscape in the United States, experts in the field of viral hepatitis and liver and kidney transplantation convened a meeting to review current data on liver and kidney recipient selection and developed consensus opinions related specifically to recipient and donor selection of HCV viremic liver and kidney allografts.
Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/transmissão , Transplante de Rim/efeitos adversos , Transplante de Fígado/efeitos adversos , Seleção de Pacientes , Complicações Pós-Operatórias/prevenção & controle , Aloenxertos/patologia , Aloenxertos/virologia , Antibioticoprofilaxia/normas , Biópsia , Consenso , Conferências de Consenso como Assunto , Seleção do Doador/normas , Hepacivirus/isolamento & purificação , Hepatite C Crônica/virologia , Humanos , Rim/virologia , Transplante de Rim/normas , Fígado/patologia , Fígado/virologia , Transplante de Fígado/normas , Complicações Pós-Operatórias/virologia , Transplantados , Estados Unidos , Viremia/transmissão , Viremia/virologiaRESUMO
RATIONALE & OBJECTIVE: Hepatitis C virus (HCV) infection is common among maintenance dialysis patients. Few studies have examined both dialysis survival and transplantation outcomes for HCV-seropositive patients because registry data sets lack information for HCV serostatus. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Adult long-term dialysis patients treated by a US national dialysis provider between January 1, 2004, and December 31, 2014. EXPOSURE: HCV antibody serostatus obtained as part of clinical data from a national dialysis provider. OUTCOMES: Mortality on dialysis therapy, entry onto the kidney transplant waiting list, kidney transplantation, and estimated survival benefit from kidney transplantation versus remaining on the waitlist. ANALYTICAL APPROACH: After linking clinical data with data from the Organ Procurement and Transplantation Network, Cox and cause-specific hazards regression were implemented to estimate the associations between HCV seropositivity and mortality, as well as entry onto the kidney transplant waitlist. Cox regression was also used to estimate the survival benefit from transplantation versus dialysis among HCV-seropositive individuals. RESULTS: Among 442,171 dialysis patients, 31,624 (7.2%) were HCV seropositive. HCV seropositivity was associated with a small elevation in the rate of death (adjusted HR [aHR], 1.09; 95% CI, 1.07-1.11) and a substantially lower rate of entry onto the kidney transplant waitlist (subdistribution HR [sHR], 0.67; 95% CI, 0.61-0.74). Once wait-listed, the kidney transplantation rate was not different for HCV-seropositive (sHR 1.10; 95% CI, 0.96-1.27) versus HCV-seronegative patients. HCV-seropositive patients lived longer with transplantation (aHR at 3 years, 0.42; 95% CI, 0.27-0.63). Receiving an HCV-seropositive donor kidney provided a survival advantage at the 2-year posttransplantation time point compared to remaining on dialysis therapy waiting for an HCV-negative kidney. LIMITATIONS: No data for HCV viral load or liver biopsy. CONCLUSIONS: HCV-seropositive patients experience reduced access to the kidney transplantation waitlist despite deriving a substantial survival benefit from transplantation. HCV-seropositive patients should consider foregoing HCV treatment while accepting kidneys from HCV-infected donors to facilitate transplantation and prolong survival.
Assuntos
Causas de Morte , Hepatite C/epidemiologia , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/terapia , Transplante de Rim/mortalidade , Listas de Espera , Adulto , Estudos de Coortes , Feminino , Rejeição de Enxerto , Sobrevivência de Enxerto , Hepacivirus/isolamento & purificação , Hepatite C/sangue , Humanos , Falência Renal Crônica/diagnóstico , Transplante de Rim/métodos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Diálise Renal/métodos , Diálise Renal/mortalidade , Estudos Retrospectivos , Medição de Risco , Testes Sorológicos/métodos , Estatísticas não Paramétricas , Análise de Sobrevida , Estados UnidosAssuntos
Vírus da Hepatite E/patogenicidade , Hepatite E/epidemiologia , Transplante de Rim , Infecções Oportunistas/epidemiologia , Anticorpos Anti-Hepatite/sangue , Hepatite E/diagnóstico , Hepatite E/imunologia , Hepatite E/virologia , Vírus da Hepatite E/genética , Vírus da Hepatite E/imunologia , Interações Hospedeiro-Patógeno , Humanos , Hospedeiro Imunocomprometido , Imunossupressores/efeitos adversos , Transplante de Rim/efeitos adversos , Infecções Oportunistas/diagnóstico , Infecções Oportunistas/imunologia , Infecções Oportunistas/virologia , Prevalência , Estudos Prospectivos , RNA Viral/genética , Estudos Soroepidemiológicos , Resultado do Tratamento , Estados Unidos/epidemiologia , Carga ViralRESUMO
BACKGROUND: Differences in tacrolimus dosing across ancestries is partly attributable to polymorphisms in CYP3A5 genes that encode tacrolimus-metabolizing cytochrome P450 3A5 enzymes. The CYP3A5*1 allele, preponderant in African Americans, is associated with rapid metabolism, subtherapeutic concentrations, and higher dose requirements for tacrolimus, all contributing to worse outcomes. Little is known about the relationship between CYP3A5 genotype and the tacrolimus pharmacokinetic area under the curve (AUC) profile in African Americans or whether pharmacogenetic differences exist between conventional twice-daily, rapidly absorbed, immediate-release tacrolimus (IR-Tac) and once-daily extended-release tacrolimus (LifeCycle Pharma Tac [LCPT]) with a delayed absorption profile. STUDY DESIGN: Randomized prospective crossover study. SETTING & PARTICIPANTS: 50 African American maintenance kidney recipients on stable IR-Tac dosing. INTERVENTION: Recipients were randomly assigned to continue IR-Tac on days 1 to 7 and then switch to LCPT on day 8 or receive LCPT on days 1 to 7 and then switch to IR-Tac on day 8. The LCPT dose was 85% of the IR-Tac total daily dose. OUTCOMES: Tacrolimus 24-hour AUC (AUC0-24), peak and trough concentrations (Cmax and Cmin), time to peak concentration, and bioavailability of LCPT versus IR-Tac, according to CYP3A5 genotype. MEASUREMENTS: CYP3A5 genotype, 24-hour tacrolimus pharmacokinetic profiles. RESULTS: â¼80% of participants carried the CYP3A5*1 allele (CYP3A5 expressers). There were no significant differences in AUC0-24 or Cmin between CYP3A5 expressers and nonexpressers during administration of either IR-Tac or LCPT. With IR-Tac, tacrolimus Cmax was 33% higher in CYP3A5 expressers compared with nonexpressers (P=0.04): With LCPT, this difference was 11% (P=0.4). LIMITATIONS: This was primarily a pharmacogenetic study rather than an efficacy study; the follow-up period was too short to capture clinical outcomes. CONCLUSIONS: Achieving therapeutic tacrolimus trough concentrations with IR-Tac in most African Americans results in significantly higher peak concentrations, potentially magnifying the risk for toxicity and adverse outcomes. This pharmacogenetic effect is attenuated by delayed tacrolimus absorption with LCPT. TRIAL REGISTRATION: Registered at ClinicalTrials.gov, with study number NCT01962922.
Assuntos
Citocromo P-450 CYP3A/genética , Preparações de Ação Retardada/uso terapêutico , Transplante de Rim/efeitos adversos , Tacrolimo/farmacocinética , Tacrolimo/uso terapêutico , Adulto , Negro ou Afro-Americano/genética , Área Sob a Curva , Estudos Cross-Over , Citocromo P-450 CYP3A/efeitos dos fármacos , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Rejeição de Enxerto , Sobrevivência de Enxerto , Humanos , Imunossupressores/farmacocinética , Imunossupressores/uso terapêutico , Transplante de Rim/métodos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Farmacogenética , Cuidados Pós-Operatórios/métodos , Prognóstico , Estudos Prospectivos , Medição de Risco , Resultado do TratamentoRESUMO
With a worldwide prevalence of 6% to 40% among patients with end-stage renal disease, hepatitis C virus (HCV) infection is a significant cause of comorbidity in kidney transplant candidates and recipients alike. Hepatitis C infection negatively impacts patient and allograft outcomes, predisposes to progressive liver disease and increases the risks of glomerular disease as well as new onset diabetes after transplantation. Treatment options until now have revolved around interferon, limited in efficacy, restricted to pretransplant administration because of concerns related to allograft dysfunction and immune stimulation, and fraught with high rates of intolerance. Direct-acting antivirals therapies are now emerging, providing the opportunity to effectively cure chronic HCV infection and to reduce the burden of hepatic and extrahepatic complications of HCV that are observed in kidney recipients, thereby offering hope of improved patient outcomes. Against a description of the major outcomes and risks that HCV+ kidney candidates and recipients encounter, and a summary of the pertinent studies of interferon-based therapies in this population, this review discusses the potential role for emerging direct-acting antivirals, proposing treatment algorithms that should be considered in the management of these complex patients. Conundrums relating to the new treatment, including the potential impact on the utilization of kidneys from HCV-infected donors, are presented.