Intra arterial treatment of hepatocellular carcinoma: Comparison of MELD score variations between radio-embolization and chemo-embolization.

PURPOSE: The purpose of this study was to assess liver function deterioration, as assessed using the model for end-stage liver disease (MELD) score variations, following transarterial chemo-embolization (TACE) versus selective internal radiation therapy (SIRT) in patients with unresectable unilobar hepatocellular carcinomas (HCC). PATIENTS AND METHODS: We retrospectively evaluated all patients who underwent a single conventional TACE or SIRT procedure in our department from May 2013 to May 2018 for unilobar unresectable HCC. A total of 86 patients (76 men, 20 women; mean age, 65.5 years) were included. There were 63 patients in the TACE group [56 men, 7 women; mean age, 65.1±9.6 (SD) years] and 23 patients in the SIRT group [20 men, 3 women; mean age, 70±9.2 (SD) years]. Delta MELD, defined as post treatment minus pre-treatment MELD score, was considered for liver function deterioration and compared between patients who underwent single lobar treatment of SIRT versus TACE. RESULTS: Patients in SIRT group had significant higher tumor burden, alpha-fetoprotein serum level, and rates of macroscopic vessel invasion. Mean pre-treatment MELD scores did not differ between TACE [mean, 8.41±1.71 (SD); range: 7.24-9.24] and SIRT groups [mean, 8.36±1.74 (SD); range: 7.07-9.21] (P=0.896) as well as Child-Pugh class and albumin-bilirubin (ALBI) grade distribution. However, following treatment, mean DeltaMELD was greater in TACE group (mean, 0.83±1.83 [SD]; range: -0.30--1.31) than in SIRT group (mean, -0.13±1.06 [SD]; range: -0.49-0.32) (P=0.021). At multivariate analysis, SIRT treatment was independently associated with a lower DeltaMELD score than TACE (R=-0.955 [-1.68; -0.406]; P=0.017;). CONCLUSION: Whereas performed in patients with higher tumor burden, SIRT resulted in lower degrees of liver function worsening as assessed using MELD score variations.

Safety of sofosbuvir-based regimens after liver transplantation: longitudinal assessment of renal function in the prospective ANRS CO23 CUPILT study.

BACKGROUND: In liver transplant recipients with hepatitis C virus recurrence, there is concern about renal safety of sofosbuvir-based regimens. Changes in serum creatinine or in the estimated glomerular filtration rate (eGFR) under treatment are used to look for possible renal toxicity. However, serum creatinine and eGFR are highly variable. AIM: To analyse renal function trajectory with numerous assays of serum creatinine over a long period of time. METHODS: In a multicentre cohort of 139 patients, the eGFR was obtained from serum creatinine using the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation. Slopes of eGFR were defined as a change in eGFR during a period divided by time. Pre-treatment, on-treatment and post-treatment periods were 9 months, 3-9 months and 4.5 months. Interactions between eGFR slopes and the pre-treatment eGFR, use of ribavirin or mycophenolate mofetil, and stage of fibrosis were addressed. On-treatment eGFR slopes were separated in tertiles. Pre- and post-treatment eGFR slopes were compared globally and according to tertiles. RESULTS: The post-treatment eGFR slope was significantly better than pre-treatment eGFR slope (+0.18 (IQR -0.76 to +1.32) vs -0.11 (IQR -1.01 to +0.73) mL/min/1.73 m2 /month, P = 0.03) independently of the pre-treatment eGFR (P = 0.99), ribavirin administration (P = 0.26), mycophenolate mofetil administration (P = 0.51) and stage of fibrosis (F3 and F4 vs lower stages, P = 0.18; F4 vs lower stages, P = 0.08; F4 Child-Pugh B and C vs lower stages, P = 0.38). Tertiles of on-treatment eGFR slopes were -1.71 (IQR -2.54 to -1.48), -0.78 (IQR -1.03 to -0.36) and +0.75 (IQR +0.28 to +1.47) mL/min/1.73 m2 /month. Pre- and post-treatment eGFR slopes were not significantly different according to tertiles (respectively, P = 0.34, 0.08, 0.73). CONCLUSION: The eGFR varies during treatment and gives a confusing picture of the renal safety of sofosbuvir-based regimens. In contrast, longitudinal assessment of the eGFR shows a rising trajectory over longer time, meaning that these therapies are safe for the kidneys in our cohort of liver transplant recipients.

Efficacy, safety and patient-reported outcomes of ledipasvir/sofosbuvir in NS3/4A protease inhibitor-experienced individuals with hepatitis C virus genotype 1 and HIV coinfection with and without cirrhosis (ANRS HC31 SOFTRIH study).

OBJECTIVES: Studies evaluating the efficacy and safety of the fixed-dose combination ledipasvir (LDV)/sofosbuvir (SOF) in patients coinfected with HIV-1 and hepatitis C virus (HCV) have mainly included treatment-naïve patients without cirrhosis. We aimed to evaluate the efficacy and safety of this combination in treatment-experienced patients with and without cirrhosis. METHODS: We conducted a multicentre, open-label, double-arm, nonrandomized study in patients coinfected with HIV-1 and HCV genotype 1 with and without cirrhosis, who had good viral suppression on their antiretroviral regimens. All patients were pretreated with a first-generation NS3/4A protease inhibitor (PI) plus pegylated interferon/ribavirin. Patients received a fixed-dose combination of LDV/SOF for 12 weeks, or for 24 weeks if cirrhosis was present. The primary endpoint was a sustained virological response (SVR) 12 weeks after the end of therapy. Secondary endpoints included safety, pharmacokinetics and patient-reported outcomes. RESULTS: Of the 68 patients enrolled, 39.7% had cirrhosis. Sixty-five patients [95.6%; 95% confidence interval (CI): 87.6-99.1%; P < 0.0001] achieved an SVR, with similar rates of SVR in those with and without cirrhosis. Tolerance was satisfactory, with mainly grade 1 or 2 adverse events. Among patient-reported outcomes, only fatigue significantly decreased at the end of treatment compared with baseline [odds ratio (OR): 0.36; 95% CI: 0.14-0.96; P = 0.04]. Mean tenofovir area under the plasma concentration-time curve (AUC) at week 4 was high, with mean ± SD AUC variation between baseline and week 4 higher in cirrhotic than in noncirrhotic patients (3261.57 ± 1920.47 ng/mL vs. 1576.15 ± 911.97 ng/mL, respectively; P = 0.03). Mild proteinuria (54.4%), hypophosphataemia (50.0%), blood bicarbonate decrease (29.4%) and hypokalaemia (13.2%) were reported. The serum creatinine level was not modified. CONCLUSIONS: LDV/SOF provided a high SVR rate in PI-experienced subjects coinfected with HCV genotype 1 and HIV-1, including patients with cirrhosis.

The negative impact of HBV/HCV coinfection on cirrhosis and its consequences.

BACKGROUND: Hepatitis B virus (HBV)/hepatitis C virus (HCV) confection has been rarely studied in nonasian series. AIM: To compare the characteristics of HBV/HCV coinfected patients to those of HBV- or HCV-monoinfected patients in the ANRS CO22 HEPATHER cohort study. PATIENTS AND METHODS: Of the 20 936 included patients, 95 had HBV/HCV coinfection (hepatitis B surface antigen, anti-HCV antibody and HCV RNA positive) and were matched with 375 HBV- and 380 HCV-monoinfected patients on age, gender and time since HBV or HCV diagnosis. RESULTS: F3-F4 fibrosis was more frequent in coinfected patients (58%) than in HBV- (32%, P < .0001), but similar in HCV-monoinfected patients (52%, P = .3142). Decompensated cirrhosis was more frequent in coinfected patients (11%) than in HBV- (2%, P = .0002) or HCV- (4%, P = .0275) monoinfected patients. Past excessive alcohol use was more frequent in coinfected patients (26%) than in HBV (12%, P = .0011), but similar in HCV monoinfected patients (32%, P = .2868). Coinfected patients had a higher proportion with arterial hypertension (42%) than HBV- (26%) or HCV-monoinfected patients (25%) (P < .003). Multivariable analysis confirmed the association between F3-F4 fibrosis and HCV infection in HBV-infected patients (OR = 3.84, 95% CI 1.99-7.43) and the association between decompensated cirrhosis and coinfection in HBV infected (OR = 5.58, 95% CI 1.42-22.0) or HCV infected patients (OR = 3.02, 95% CI 1.22-7.44). CONCLUSIONS: HCV coinfection harmfully affects liver fibrosis in HBV patients, while decompensated cirrhosis is increased in coinfected patients compared with HBV- or HCV-monoinfected patients. HCV treatment is as safe and effective in coinfected as monoinfected patients and should be considered following the same rules as HCV monoinfected patients.

Safety of Anti-TNF Treatment in Liver Transplant Recipients: A Systematic Review and Meta-analysis.

BACKGROUND AND AIM: Little is known about the risk of serious infection when combining anti-tumour necrosis factor [TNF] therapy for refractory inflammatory bowel disease [IBD] with immunosuppression after liver transplantation [LT]. Our aim was to investigate the infection risk in this patient group by systematic review and meta-analysis of the available data. METHODS: A search was conducted for full papers and conference proceedings through September 2015, regarding liver transplant recipients and anti-TNF therapy. All studies were appraised using the adapted Newcastle-Ottawa Scale [NOS]. Two reviewers independently extracted patient data [age, duration of follow-up, number of all infections, number of serious infections, time since transplant]. As an additional control population, primary sclerosing cholangitis [PSC]-IBD patients from the Leiden University Medical Center [LUMC] LT cohort were used. Poisson regression was used to compare serious infections (according to International Conference on Harmonisation [ICH] definition) per patien-year follow-up between the anti-TNF and control groups. RESULTS: In all 465 articles and abstracts were identified, of which eight were included. These contained 53 post-LT patients on anti-TNF therapy and 23 post-LT patients not exposed to anti-TNF therapy. From the LUMC LT-cohort, 41 PSC patients with PSC-IBD not exposed to anti-TNF therapy were included as control population. The infection rate for TNF-exposed patients was 0.168 serious infections per patient year, compared with 0.149 in the control patients (rate ratio 1.12 [95% confidence interval: 0.233-5.404, P = 0.886]. When correcting for time since transplant, the infection rate was 0.194 in the TNF-exposed vs 0.115 in the non-exposed [p = 0.219]. CONCLUSIONS: No significant increase in the rate of serious infection was observed in LT recipients with PSC-IBD during exposure to anti-TNF therapy.

Efficacy and Safety of Everolimus and Mycophenolic Acid With Early Tacrolimus Withdrawal After Liver Transplantation: A Multicenter Randomized Trial.

SIMCER was a 6-mo, multicenter, open-label trial. Selected de novo liver transplant recipients were randomized (week 4) to everolimus with low-exposure tacrolimus discontinued by month 4 (n = 93) or to tacrolimus-based therapy (n = 95), both with basiliximab induction and enteric-coated mycophenolate sodium with or without steroids. The primary end point, change in estimated GFR (eGFR; MDRD formula) from randomization to week 24 after transplant, was superior with everolimus (mean eGFR change +1.1 vs. -13.3 mL/min per 1.73 m2 for everolimus vs. tacrolimus, respectively; difference 14.3 [95% confidence interval 7.3-21.3]; p < 0.001). Mean eGFR at week 24 was 95.8 versus 76.0 mL/min per 1.73 m2 for everolimus versus tacrolimus (p < 0.001). Treatment failure (treated biopsy-proven acute rejection [BPAR; rejection activity index score >3], graft loss, or death) from randomization to week 24 was similar (everolimus 10.0%, tacrolimus 4.3%; p = 0.134). BPAR was more frequent between randomization and month 6 with everolimus (10.0% vs. 2.2%; p = 0.026); the rate of treated BPAR was 8.9% versus 2.2% (p = 0.055). Sixteen everolimus-treated patients (17.8%) and three tacrolimus-treated patients (3.2%) discontinued the study drug because of adverse events. In conclusion, early introduction of everolimus at an adequate exposure level with gradual calcineurin inhibitor (CNI) withdrawal after liver transplantation, supported by induction therapy and mycophenolic acid, is associated with a significant renal benefit versus CNI-based immunosuppression but more frequent BPAR.

Tacrolimus and the risk of solid cancers after liver transplant: a dose effect relationship.

Although increased rates of solid organ cancers have been reported following liver transplantation (LT), the impact of quantitative exposure to calcineurin inhibitors (CNI) remains unclear. We have therefore probed the relationship between the development of solid organ cancers following LT and the level of CNI exposure. This prospective single-center study was conducted between 1995 and 2008 and is based on 247 tacrolimus-treated liver transplant recipients who survived at least 1 year following surgery. The incidence of cancer was recorded, and the mean blood concentration of tacrolimus (TC) was determined at 1 and 3 years following LT. The study results indicate that 43 (17.4%) patients developed de novo solid cancers. Mean TC during the first year after LT was significantly higher in patients who developed solid organ tumors (10.3 ± 2.1 vs. 7.9 ± 1.9 ng/mL, p < 0.0001). Independent risks factors in multivariate analysis were tobacco consumption before LT (OR = 5.42; 95% CI [1.93-15.2], p = 0.0014) and mean annual TC during the first year after LT (p < 0.0001; OR = 2.01; 95% CI [1.57-2.59], p < 0.0001). Similar effects were observed in 216 patients who received tacrolimus continuously for ≥3 years. It appears therefore that CNI should be used with caution after LT, and that new immunosuppressive therapies could deliver significant clinical benefits in this regard.

Long-term hepatitis B virus surface antigen decay in HIV-1/hepatitis B virus-coinfected adults initiating a tenofovir-containing regimen.

Hepatitis B virus (HBV) surface antigen (HBsAg) decay was explored in HIV-1- and HBV-coinfected patients beginning antiretroviral (ARV) therapy containing tenofovir disoproxil fumarate (TDF). The mean HBsAg decay was 0.38 log(10) IU/ml/year (95% confidence interval [CI], 0.71 to 0.05) in 18 patients with sustained plasma HIV-1 RNA suppression and 0.15 log(10) IU/ml/year (0.21 to 0.09) in 12 patients experiencing HIV-1 virologic failure due to suboptimal adherence to ARV (P = 0.17). We estimated that six of these 18 patients will attain HBsAg values below 10 IU/ml after 10 years of treatment.

[Causes of early mortality after liver transplantation: a twenty-years single centre experience]. / Mortalité trois mois après transplantation hépatique : étude monocentrique sur une période de vingt ans.

OBJECTIVE: To define the causes of mortality of patients who died within the first three months after a liver transplantation. TYPE OF STUDY: Retrospective, observational, and single centre study. PATIENTS AND METHODS: Between March 1989 and July 2010, all patients who died within three months after a liver transplantation were included. Demographic characteristics, preoperative and peroperative data, donor characteristics, postoperative complications and causes of mortality were collected. RESULTS: Among the 788 performed liver transplantations, 76 patients died in intensive care unit (11%). The main indications of liver transplantation were alcoholic cirrhosis (30%), hepatitis C (28%), hepatocarcinoma (15%), primitive or secondary biliary cirrhosis (10%). Fifty percent of the patients were categorized as Child C. The main causes of death were non-function or dysfunction with retransplantation contra-indication graft (18%), sepsis (18%), neurological complications (12%), hemorrhagic shock (13%), (9%), multiorgan failures (5%), cardiac complications (6%). CONCLUSION: In this study, the main causes of mortality were infectious, neurological and hemorrhagic. These results emphasize the necessity for better control of sepsis, haemorrhage and immunosupressors.

Regression of new-onset diabetes mellitus after conversion from tacrolimus to cyclosporine in liver transplant patients: results of a pilot study.

INTRODUCTION: New-onset diabetes mellitus (NODM) has important implications for long-term outcome following liver transplantation. AIM: To evaluate the impact of conversion from tacrolimus to cyclosporine in liver transplant patients presenting NODM. METHOD: In a 12-month pilot study, 39 liver transplant patients with NODM were converted from tacrolimus to cyclosporine. Most patients (59%) were receiving antidiabetic therapy (18% insulin, 41% oral) and all patients had received dietary advice prior to the study. RESULTS: At month 12, NODM had significantly resolved (FBG<7 mmol/L without treatment) in 36% of patients (95% CI 20.8-51.0%). In the 16 patients not receiving antidiabetic drugs at baseline, mean FBG decreased from 8.1 mmol/L to 6.6 mmol/L (P=0.008) and mean HbA(1c) decreased from 6.4 to 6.0% (P=0.05). Steroids were stopped rapidly in the nine patients receiving steroids at inclusion but NODM resolution was observed in only one of these nine patients. No significant factors were identified that could have affected NODM resolution. There were three episodes of biopsy-proven acute rejection (7.7%), no graft losses and one death. Overall, cyclosporine tolerance was good with no significant change in creatinine clearance at month 12. Total cholesterol increased from 4.6 mmol/L to 5.1 mmol/L (P<0.001). CONCLUSIONS: These results suggest that liver transplant patients with NODM may benefit from conversion to cyclosporine from tacrolimus through improved glucose metabolism. Confirmation in a prospective, randomized comparative study is required.

Reduced-dose tacrolimus with mycophenolate mofetil vs. standard-dose tacrolimus in liver transplantation: a randomized study.

We conducted a multicenter randomized study in liver transplantation to compare standard-dose tacrolimus to reduced-dose tacrolimus with mycophenolate mofetil to reduce the occurrence of tacrolimus side effects. Two primary outcomes (censored criteria) were monitored during 48 weeks post-transplantation: occurrence of renal dysfunction or arterial hypertension or diabetes (evaluating benefit) and occurrence of acute graft rejection (evaluating risk). Interim analyses were performed every 40 patients to stop the study in the case of increased risk of graft rejection. One hundred and ninety-five patients (control: 100; experimental: 95) had been included when the study was stopped. Acute graft rejection occurred in 46 (46%) and 28 (30%) patients in control and experimental groups, respectively (HR = 0.59; 95% CI: [0.37-0.94]; p = 0.024). Renal dysfunction or arterial hypertension or diabetes occurred in 80 (80%) and 61 (64%) patients in control and experimental groups, respectively (HR = 0.68; 95% CI: [0.49-0.95]; p = 0.021). Renal dysfunction occurred in 42 (42%) and 23 (24%) patients in control and experimental groups, respectively (HR = 0.49; 95% CI: [0.29-0.81]; p = 0.004). Leucopoenia (p = 0.001), thrombocytopenia (p = 0.017) and diarrhea (p = 0.002) occurred more frequently in the experimental group. Reduced-dose tacrolimus with mycophenolate mofetil reduces the occurrence of renal dysfunction and the risk of graft rejection. This immunosuppressive regimen could replace full-dose tacrolimus in adult liver transplantation.

[Liver transplantation in a patient with alcoholic cirrhosis: discussion about nonabstinence]. / Discussion d'une transplantation hépatique chez un patient cirrhotique alcoolique incomplètement sevré.

Liver transplantation is the recognized treatment for serious cases of alcoholic cirrhosis. However, due to their poor image within society, patients with alcoholic cirrhosis are often less referred to transplant centres. This is even more surprising since in terms of patient' and graft's survival, the results of transplantation are comparable, if not better, than in other indications. Transplantation is the treatment for the liver disease, not a treatment for alcoholism. In the case of severe alcoholic disease, a relapse is neither surprising nor unacceptable or insignificant if severe. In this case, it has an impact on the long-term survival, notably due to mortality by cancer. All the medical teams carrying out transplants agree that abstinence is necessary when a patient is being evaluated for liver transplantation. However, it is not proven that a set period of 6 months' abstinence prior to the transplantation can modify the results. The problem of alcoholism must be treated specifically in terms of addiction both before and after transplantation.

Calcineurin Inhibitor Determination in Whole Blood With the RXL Dimension Analyzer: A Useful Tool for Immunosuppressive Drug Monitoring.

Routine monitoring of cyclosporine and tacrolimus levels is necessary to minimize adverse side effects and to ensure effective immunosuppression. The RXL Dimension apparatus conceived for ACMIA technologies is proposed to determine C0 and C2 cyclosporine levels and also tacrolimus levels in whole blood without any dilution or pretreatment using specific calibrators and Flex reagent cartridges (reagent stability: 72 hours for Neoral C0 and C2; 48 hours for tacrolimus). The assay ranges were between 25 to 500 ng/mL for C0; 350 to 2000 ng/mL for C2; and 1.2 to 30 ng/mL for tacrolimus. Within-run and between-day imprecision were <10% for cyclosporine. The coefficient of linearity was r(2) = .998 for C0, C2, and tacrolimus. Moreover, for cyclosporine and tacrolimus assays, the time for the first result was 20 minutes. Cyclosporine (C0, n = 152; C2, n = 54) and tacrolimus (n = 70) ACMIA assays were compared with enzyme-multiplied immunoassay technique (EMIT) cyclosporine and tacrolimus assays (V-Twin, Siemens ex-Dade Behring Laboratories) among 276 transplant patients: 119 kidney, 67 liver, 28 heart, and 62 bone marrow transplantations. Values obtained with the ACMIA assay were highly correlated with the EMIT assay for CsA C0 levels (ACMIA = 1.04 EMIT - 9.32; r(2) = .97); CsA C2 levels (ACMIA = 1.15 EMIT - 53.7; r(2) = .94); and tacrolimus levels (ACMIA = 0.93 EMIT - 0.16; r(2) = .93). In conclusion, the RXL Dimension analyzer is a useful tool for routine monitoring with a single method for C0 and C2 cyclosporine and tacrolimus level determinations in whole blood without any dilution or preanalytic treatment.

[Value of MRCP for diagnosis of biliary complications after liver transplantation]. / Evaluation de la cholangiographie par résonance magnétique dans le diagnostic des complications biliaires après transplantation hépatique.

PURPOSE: To assess the value of MRCP in the detection of biliary complications after orthotopic liver transplantation. MATERIALS AND METHODS: 27 transplanted patients with suspected biliary complication underwent a total of 34 MR and direct cholangiography procedures. MRCP were reviewed by 2 independent reviewers blinded to clinical and laboratory findings. The biliary tract was divided into 7 segments, and all lesions were evaluated using this segmental anatomy. Each segment was evaluated for the presence of dilatation, stenosis and intra-ductal debris. MRCP results were compared to results frpm direct cholangiography. RESULTS: 216 (98%) of 221 biliary segments could be evaluated on MRCP, with good to excellent visualization in 179 (80%) cases. Segmental analysis showed sensitivity, specificity and accuracy values of 85%, 81% and 83% for the detection of biliary stenosis, 82%, 81% and 81% for the detection of biliary dilatation, and 60%, 88% and 80% for the detection of inyraductal debris. CONCLUSION: MRCP is accurate for the detection of biliary stenosis and dilatation in patients after liver transplantation and provides an alternative to direct cholangiography.

Anaplastic lymphoma kinase (ALK) protein expressing lymphoma after liver transplantation: case report and literature review.

Most post transplantation lymphoproliferative disorders (PTLDs) are Epstein-Barr virus (EBV) associated B cell proliferations. We report a case of aggressive anaplastic large cell lymphoma expressing the anaplastic lymphoma kinase (ALK) protein in a 58 year old man who had previously undergone liver transplantation. A definite diagnosis was not possible on histopathological examination. Immunostaining clearly showed a predominant population of small irregular lymphocytes, admixed with large cells strongly positive for CD30, epithelial membrane antigen, and the ALK protein. Neoplastic cells were of the T/cytotoxic phenotype. In situ hybridisation with EBV encoded early RNA probes showed only a few scattered positive non-neoplastic small lymphocytes. Polymerase chain reaction analysis of immunoglobulin and T cell receptor rearrangements was negative. The NPM-ALK fusion transcript associated with the t(2;5) translocation was detected by reverse transcription polymerase chain reaction. A review of the literature revealed 76 cases of T cell PTLD, showing a broad spectrum of morphological features and clinical behaviour. Most of these cases were EBV negative (61 of 76) and occurred after renal transplantation (48 of 76). To our knowledge, this is the first case of ALK positive lymphoma occurring in the setting of organ transplantation. This observation stresses the need for accurate immunostaining for diagnosing this rare, apparently aggressive, lymphoma in immunosuppressed patients.