Etude rétrospective de l'influence des polymorphismes génétiques de CYP3A4, CYP3A5 et ABCB1 des donneurs et des receveurs sur les effets des immunosuppresseurs en transplantation hépatique

Liver transplantation is now a well mastered surgery with standardized procedures, but the long-term clinical outcomes of the graft and the patient remain uncertain. The pharmacogenetic study of the calcineurin inhibitors (CNI) cyclosporine and tacrolimus should help to understand the variability of their pharmacokinetics and therapeutic or side effects. In the first part of this work, we reviewed the main pharmacogenetic studies of CNI in liver transplantation, focusing on the three polymorphisms mostly involved in CNI pharmacokinetics (CYP3A4*22, CYP3A5*3 et ABCB1 exons 12, 21, 26) and their possible associations with clinical outcomes. To date, the only pharmacogenetic test consensually recommended in organ transplantation is the CYP3A5*3 variant for a better selection of the initial tacrolimus dose in kidney transplantation. The second part of this work was a retrospective cohort study in liver transplantation to investigate the influence of the above mentioned donor’s and recipient’s genotypes, involved in the metabolism (CYP3A4*22, CYP3A5*3) and the membrane transport (ABCB1 exons 12, 21 and 26) of cyclosporine and tacrolimus. 170 patients were enrolled in this study with a mean follow-up of more than ten years. Our main results are that: the recipient CYP3A5*1 allele was associated with a higher risk of graft loss than the CYP3A5*3 allele; the recipient ABCB1 exon 12 TT genotype was associated with a lower risk of chronic rejection than the CC genotype; overexposure to CNI, initial renal function and recipient age were associated with a higher risk of post-transplantation renal dysfunction. No genetic factor was associated with patient survival, acute rejection, liver function tests, recurrence of viral or other initial liver disease, or nephrotoxicity. Prospective characterization of both recipient and donor CYP3A4, CYP3A5 and ABCB1 polymorphisms could help to optimize immunosuppressive therapy for each candidate to liver transplantation. Further studies (pharmacogenetics of calcineurin pathway, early biomarkers of graft dysfunction, ...), should help to define a personalized profile for each transplant patient in order to best adapt the immunosuppressive strategy on the long term.La transplantation hépatique est une technique chirurgicale maîtrisée, mais le devenir à long terme du greffon et de l’hôte doit encore être amélioré. L’étude pharmacogénétique des inhibiteurs de la calcineurine (CNI) devrait permettre de comprendre la variabilité de leurs effets thérapeutiques et toxiques. Dans un premier temps, nous avons réalisé une revue de la littérature concernant la pharmacogénétique des CNI en greffe d’organe et surtout hépatique en particulier les trois polymorphismes les plus impliqués dans la pharmacocinétique des CNI (CYP3A4*22, CYP3A5*3 et ABCB1 exons 12, 21, 26) et leurs éventuelles associations avec le devenir clinique du patient. L’état actuel des connaissances valide l’intérêt du génotype CYP3A5*3 pour adapter au mieux la posologie précoce de tacrolimus seulement en greffe rénale. Dans un second temps, nous avons mené une étude de cohorte rétrospective visant à étudier la pertinence et l’intérêt des génotypes du donneur et du receveur d’organe mentionnés précédemment, intervenant dans le métabolisme (CYP3A4*22, CYP3A5*3) et le transport membranaire (ABCB1 exons 12, 21 et 26) de la cyclosporine et du tacrolimus en transplantation hépatique. 170 patients avec un suivi de plus de 10 ans en moyenne ont été inclus. Les principaux résultats montrent que : l’allèle CYP3A5 *1 du receveur était associé significativement à un risque plus élevé de perte de greffon à long terme comparé à l’allèle CYP3A5 *3 ; l’allèle TT de l’exon 12 d’ABCB1 du receveur était associé à un risque moins élevé de rejet chronique ; et l’exposition à des doses élevées de CNI, la valeur initiale de la fonction rénale et l’âge du receveur étaient également indépendamment associés au risque d’altération de la fonction rénale. La caractérisation de ces marqueurs pharmacogénétiques en transplantation hépatique pourrait permettre d’adapter les traitements immunosuppresseurs pour chaque patient transplanté. D’autres voies de recherche (pharmacogénétique de la voie calcineurine, biomarqueurs précoces des lésions du greffon, ...) seront nécessaires pour identifier un profil personnalisé pour chaque greffé afin d’adapter au mieux la stratégie thérapeutique à long terme

Retrospective study on influence of donor and recipient CYP3A4, CYP3A5 and ABCB1 genotypes on anticalcineurin therapy effect in liver transplantation

La transplantation hépatique est une technique chirurgicale maîtrisée, mais le devenir à long terme du greffon et de l’hôte doit encore être amélioré. L’étude pharmacogénétique des inhibiteurs de la calcineurine (CNI) devrait permettre de comprendre la variabilité de leurs effets thérapeutiques et toxiques. Dans un premier temps, nous avons réalisé une revue de la littérature concernant la pharmacogénétique des CNI en greffe d’organe et surtout hépatique en particulier les trois polymorphismes les plus impliqués dans la pharmacocinétique des CNI (CYP3A4*22, CYP3A5*3 et ABCB1 exons 12, 21, 26) et leurs éventuelles associations avec le devenir clinique du patient. L’état actuel des connaissances valide l’intérêt du génotype CYP3A5*3 pour adapter au mieux la posologie précoce de tacrolimus seulement en greffe rénale. Dans un second temps, nous avons mené une étude de cohorte rétrospective visant à étudier la pertinence et l’intérêt des génotypes du donneur et du receveur d’organe mentionnés précédemment, intervenant dans le métabolisme (CYP3A4*22, CYP3A5*3) et le transport membranaire (ABCB1 exons 12, 21 et 26) de la cyclosporine et du tacrolimus en transplantation hépatique. 170 patients avec un suivi de plus de 10 ans en moyenne ont été inclus. Les principaux résultats montrent que : l’allèle CYP3A5 *1 du receveur était associé significativement à un risque plus élevé de perte de greffon à long terme comparé à l’allèle CYP3A5 *3 ; l’allèle TT de l’exon 12 d’ABCB1 du receveur était associé à un risque moins élevé de rejet chronique ; et l’exposition à des doses élevées de CNI, la valeur initiale de la fonction rénale et l’âge du receveur étaient également indépendamment associés au risque d’altération de la fonction rénale. La caractérisation de ces marqueurs pharmacogénétiques en transplantation hépatique pourrait permettre d’adapter les traitements immunosuppresseurs pour chaque patient transplanté. D’autres voies de recherche (pharmacogénétique de la voie calcineurine, biomarqueurs précoces des lésions du greffon, ...) seront nécessaires pour identifier un profil personnalisé pour chaque greffé afin d’adapter au mieux la stratégie thérapeutique à long terme.Liver transplantation is now a well mastered surgery with standardized procedures, but the long-term clinical outcomes of the graft and the patient remain uncertain. The pharmacogenetic study of the calcineurin inhibitors (CNI) cyclosporine and tacrolimus should help to understand the variability of their pharmacokinetics and therapeutic or side effects. In the first part of this work, we reviewed the main pharmacogenetic studies of CNI in liver transplantation, focusing on the three polymorphisms mostly involved in CNI pharmacokinetics (CYP3A4*22, CYP3A5*3 et ABCB1 exons 12, 21, 26) and their possible associations with clinical outcomes. To date, the only pharmacogenetic test consensually recommended in organ transplantation is the CYP3A5*3 variant for a better selection of the initial tacrolimus dose in kidney transplantation. The second part of this work was a retrospective cohort study in liver transplantation to investigate the influence of the above mentioned donor’s and recipient’s genotypes, involved in the metabolism (CYP3A4*22, CYP3A5*3) and the membrane transport (ABCB1 exons 12, 21 and 26) of cyclosporine and tacrolimus. 170 patients were enrolled in this study with a mean follow-up of more than ten years. Our main results are that: the recipient CYP3A5*1 allele was associated with a higher risk of graft loss than the CYP3A5*3 allele; the recipient ABCB1 exon 12 TT genotype was associated with a lower risk of chronic rejection than the CC genotype; overexposure to CNI, initial renal function and recipient age were associated with a higher risk of post-transplantation renal dysfunction. No genetic factor was associated with patient survival, acute rejection, liver function tests, recurrence of viral or other initial liver disease, or nephrotoxicity. Prospective characterization of both recipient and donor CYP3A4, CYP3A5 and ABCB1 polymorphisms could help to optimize immunosuppressive therapy for each candidate to liver transplantation. Further studies (pharmacogenetics of calcineurin pathway, early biomarkers of graft dysfunction, ...), should help to define a personalized profile for each transplant patient in order to best adapt the immunosuppressive strategy on the long term

Effet de l'activité physique adaptée sur l'aptitude aérobie et la force musculaire chez les patients en attente de greffe hépatique (étude pilote)

LIMOGES-BU Médecine pharmacie (870852108) / SudocSudocFranceF

Traitement du carcinome hépatocellulaire par chimioembolisation lipiodolée (revue de la littérature et étude de 57 cas)

LIMOGES-BU Médecine pharmacie (870852108) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Rooibos, a fake friend

International audienc

Liver elastometry and alcohol withdrawal: Median-term follow-up in a psychiatric unit

International audienceThe measurement of liver stiffness (LS) shows promise as a follow-up tool after alcohol withdrawal, but it has mainly been studied in the early phase or in patients with severe liver disease. A 6-month ancillary study of a specific psychiatric cohort of alcoholic patients without known liver disease followed after withdrawal was conducted (Clinical Trial NCT01491347). Clinical and biological data and LS values were collected every 2 months. A total of 129 patients were included in the study; 93 had an LS assessment within the first 7 days, and 37 had all four LS measurements. Only seven (7.5%) patients had an initial LS > 12.1 kPa, the threshold used to define severe fibrosis. Abstinence was not associated with changes inLS at the various median-term follow-up periods. However, LS of abstinent subjects decreased significantly relative to that of non-abstinent subjects between M0 and M2. CAP™ values were not associated with abstinence. The systematic median-term follow-up of withdrawn patients does not appear to be contributory. However, LS could help to detect relapse in the first 2 months after withdrawal for subjects treated in a psychiatric hospital for dependence. It thus could serve as a motivation tool. Prospective studies with various and higher baseline LS values are warranted for simultaneous longitudinal assessment, including for very short- and long-term LS after withdrawal

Evaluation of Longitudinal Exposure to Tacrolimus as a Risk Factor of Chronic Kidney Disease Occurrence Within the First-year Post-Liver Transplantation

International audienceBackground. Renal failure is predictive of mortality in the early postliver-transplantation period and calcineurin inhibitors toxicity is a main challenge. Our aim is to assess the impact of longitudinal tacrolimus exposure (TLE) and other variables on chronic kidney disease (CKD)-free 1-year-survival. Methods. Retrospective data of consecutive patients transplanted between 2011 and 2016 and treated with tacrolimus were collected. TLE and all relevant pre- and post-liver transplantation (LT) predictive factors of CKD were tested and included in a time-to-event model. CKD was defined by repeated estimated glomerular filtration rate (eGFR) values below 60 mL/min/1.73m 2 at least for the last 3 months before M12 post-LT. Results. Data from 180 patients were analyzed. CKD-free survival was 74.5% and was not associated with TLE. Pre-LT acute kidney injury (AKI) and eGFR at 1-month post-LT (eGFR M1 ) <60 mL/min/1.73m 2 were significant predictors of CKD. By distinguishing 2 situations within AKI (ie, with or without hepatorenal syndrome [HRS]), only HRS-AKI remained associated to CKD. HRS-AKI and eGFR M1 <60 mL/min/1.73m 2 increased the risk of CKD (hazard ratio, 2.5; 95% confidence interval, 1.2-4.9; hazard ratio, 4.8; 95% confidence interval, 2.6-8.8, respectively). Conclusions. In our study, TLE, unlike HRS-AKI and eGFR M1 , was not predictive of CKD-free survival at 1-year post-LT. Our results once again question the reversibility of HRS-AKI

Tacrolimus Exposure Before and After a Switch From Twice-Daily Immediate-Release to Once-Daily Prolonged Release Tacrolimus: The ENVARSWITCH Study

International audienceLCP-tacrolimus displays enhanced oral bioavailability compared to immediate-release (IR-) tacrolimus. The ENVARSWITCH study aimed to compare tacrolimus AUC 0–24 h in stable kidney (KTR) and liver transplant recipients (LTR) on IR-tacrolimus converted to LCP-tacrolimus, in order to re-evaluate the 1:0.7 dose ratio recommended in the context of a switch and the efficiency of the subsequent dose adjustment. Tacrolimus AUC 0–24 h was obtained by Bayesian estimation based on three concentrations measured in dried blood spots before (V2), after the switch (V3), and after LCP-tacrolimus dose adjustment intended to reach the pre-switch AUC 0–24 h (V4). AUC 0–24 h estimates and distributions were compared using the bioequivalence rule for narrow therapeutic range drugs (Westlake 90% CI within 0.90–1.11). Fifty-three KTR and 48 LTR completed the study with no major deviation. AUC 0–24 h bioequivalence was met in the entire population and in KTR between V2 and V4 and between V2 and V3. In LTR, the Westlake 90% CI was close to the acceptance limits between V2 and V4 (90% CI = [0.96–1.14]) and between V2 and V3 (90% CI = [0.96–1.15]). The 1:0.7 dose ratio is convenient for KTR but may be adjusted individually for LTR. The combination of DBS and Bayesian estimation for tacrolimus dose adjustment may help with reaching appropriate exposure to tacrolimus rapidly after a switch

Patients Treated for HCV Infection and Listed for Liver Transplantation in a French Multicenter Study: What Happens at Five Years?

International audienceBackground: Direct-acting antiviral (DAA) agents for the treatment of hepatitis C virus (HCV) infection have been proven safe and effective in cirrhotic patients awaiting liver transplantation (LT). However, in the long term, data remain minimal regarding the clinical impact of viral eradication on patients listed for decompensated cirrhosis or hepatocellular carcinoma (HCC). We aimed to elucidate the clinical outcomes of patients regarding delisting and the evolution of HCC during the long-term follow-up. Methods: An observational, multicenter, retrospective analysis was carried out on prospectively collected data from HCV-positive patients treated with an interferon-free regimen while awaiting LT in 18 French hospitals. Results: A total of 179 patients were included in the study. The indication for LT was HCC in 104 (58.1%) patients and cirrhosis in 75 (41.9%) patients. The sustained virological response was 84.4% and the treatment was well tolerated. At five years, among 75 patients with cirrhosis treated for HCV, 19 (25.3%) were delisted following improvement after treatment. Predictive factors for delisting highlighted an absence of ascites, MELD score ≤ 15, and Child–Pugh score ≤ 7. No patients with refractory ascites were delisted. Among patients with HCC, 82 (78.9%) were transplanted. The drop-out rate was low (6.7%) and few recurrences of HCC after LT were observed. Conclusions: DAAs are safe and effective in patients awaiting LT for cirrhosis or HCC. A quarter of patients with cirrhosis can be delisted because of clinical improvement. Predictive factors for delisting, as a result of improvement, may assist prescribers, before initiating HCV infection therapy in the long-term perspective