G.-P. Pageaux

Impact of pretransplantation transarterial chemoembolization on survival and recurrence after liver transplantation for hepatocellular carcinoma.

The actual impact of transarterial chemoembolization before liver transplantation (LT) for hepatocellular carcinoma (HCC) on patient survival and HCC recurrence is not known. Between 1985 and 1998, 479 patients with HCC in 14 French centers were evaluated for LT. Among these 479 patients, this case‐control study included 100 patients who received transarterial chemoembolization before LT (TACE group) and 100 control patients who did not receive chemoembolization (no‐TACE group). Patients and controls were matched for the pre‐LT tumor characteristics, the period of transplantation, the time spent on the waiting list, and pre‐ and posttransplantation treatments. Kaplan‐Meier estimates were calculated 5 years after LT and were compared with the log‐rank test. The mean waiting time before LT was 4.2 ± 3.2 months in the TACE group and 4.3 ± 4.4 months in the no‐TACE group. The median number of TACE procedures was 1 (range: 1‐12). Demographic data, median alpha‐fetoprotein level (21.6 ng/mL and 22.0 ng/mL, respectively), and pre‐ and post‐LT morphologic characteristics of the tumors did not differ in the TACE and no‐TACE groups. Overall 5‐year survival was 59.4% with TACE and 59.3% without TACE (ns). Survival rates did not differ significantly between the two groups with respect to the time on the waiting list, the tumor diameter, or the type of TACE (selective or nonselective). In the TACE group, 30 patients had tumor necrosis ≥80% on the liver explant with a 5‐year survival rate of 63.2%, compared with 54.2% among their matched controls (P = 0.9). In conclusion, with a mean waiting period of 4.2 months and 1 TACE procedure, pre‐LT TACE does not influence post‐LT overall survival and disease‐free survival. (Liver Transpl 2005;11:767–775.)

In vitro infection of adult normal human hepatocytes in primary culture by hepatitis C virus

In vitro infection of adult normal human hepatocytes in primary culture has been performed for investigating the replication cycle of hepatitis C virus (HCV) in differentiated cells. Hepatocytes were prepared from liver tissue resected from donors who tested negative for HCV, and inoculation was performed 3 days after plating with 33 HCV serum samples of different virus load and genotype. The presence of intracellular HCV RNA, detected by a strand-specific rTth RT-PCR assay, was used as evidence of infection. A kinetics analysis of HCV replication revealed that intracellular negative-strand RNA appeared at day 1 post-infection with a maximum level at days 3 and 5, followed by a decrease until day 14. At day 5, we estimated that the copy level of viral RNA was amplified at least 15-fold in infected cells. The level of intracellular HCV RNA in response to different serum samples was reproducible from one hepatocyte culture to another, suggesting that there is no inter-individual variability in the susceptibility of hepatocytes to HCV infection. These findings indicate that adult human hepatocytes in primary culture retain their susceptibility to in vitro HCV infection and support HCV RNA replication. This model should represent a valuable tool for the study of initial steps of the HCV replication cycle and for the evaluation of antiviral molecules.

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.

Genetic predisposition to drug-induced hepatotoxicity

Drug-induced hepatitis is uncommon and generally unpredictable. Hepatotoxicity may be related to the drug itself, or to chemically reactive metabolites which can bind covalently to hepatic macromolecules and may lead to either idiosyncratic, toxic hepatitis or to immunoallergic hepatitis. There is now evidence indicating that genetic variations in systems of biotransformation or detoxication may modulate either the toxic or sensitizing effects of some drugs. Thus, the genetic deficiency in a particular hepatic cytochrome P 450 isozyme (CYP 2D6) is involved in per-hexiline liver injury. The deficiency in CYP 2C19 might also contribute to Atrium hepatotoxicity. Slow acetylation related to N-acetyltransferase 2 deficiency contributes to sulfonamide hepatitis. The genetic deficiency in glutathione synthetase may increase the susceptibility to several drugs including acetaminophen. A constitutional deficiency in another cell defense mechanism, still not characterized, seems to increase significantly the risk of hepatotoxicity with halothane, phenytoin, carbamazepine, phenobarbital, sulfamides and amineptine.

Model for end-stage liver disease exceptions in the context of the french model for end-stage liver disease score–based liver allocation system†

Model for End‐Stage Liver Disease (MELD) score–based allocation systems have been adopted by most countries in Europe and North America. Indeed, the MELD score is a robust marker of early mortality for patients with cirrhosis. Except for extreme values, high pretransplant MELD scores do not significantly affect posttransplant survival. The MELD score can be used to optimize the allocation of allografts according to a sickest first policy. Most often, patients with small hepatocellular carcinomas (HCCs) and low MELD scores receive extra points, which allow them appropriate access to transplantation comparable to the access of patients with advanced cirrhosis and high MELD scores. In addition to patients with advanced cirrhosis and HCC, patients with a number of relatively uncommon conditions have low MELD scores and a poor prognosis in the short term without transplantation but derive excellent benefits from transplantation. These conditions, which correspond to the so‐called MELD score exceptions, justify the allocation of a specific score for appropriate access to transplantation. Here we report the conclusions of the French consensus meeting. The goals of this meeting were (1) to identify which conditions merit MELD score exceptions, (2) to list the criteria needed for defining each of these conditions, and (3) to define a reasonable time interval for organ allocation for each MELD exception in the general context of organ shortages. MELD exceptions were discussed in an attempt to reconcile the concepts of transparency, equity, justice, and utility. Liver Transpl 17:1137–1151, 2011.

Education by a nurse increases response of patients with chronic hepatitis C to therapy with peginterferon-α2a and ribavirin.

BACKGROUND & AIMS Education of patients with chronic hepatitis C has been proposed to increase response to therapy with peginterferon and ribavirin. We performed a prospective study to determine the effects of systematic consultation by a nurse on patient adherence and the efficacy of therapy. METHODS We analyzed data from 244 patients who received either systematic consultation after each medical visit from a nurse who used a standard evaluation grid and provided information about the disease and treatment (group A [GrA], n = 123) or the conventional clinical follow-up procedure (group B [GrB], n = 121). Treatment lasted 24 to 48 weeks. RESULTS Characteristics of each group were similar at baseline, including prior treatment (42.6% in GrA and 36.0% in GrB). Overall, GrA had significantly better adherence to treatment than GrB (74.0% vs 62.8%), especially among patients who received 48 weeks of treatment (69.7% vs 53.2%; P < .03). Significantly more patients in GrA had a sustained virologic response, compared with GrB overall (38.2% vs 24.8%; P < .02), as well as treatment-naive patients (47.1% vs 30.3%; P < .05), and those with genotypes 1, 4, or 5 infections (31.6% vs 13.3%; P < .007). There were no differences between GrA and GrB in response of patients with genotypes 2 or 3 infections or advanced fibrosis. Prognostic factors for a sustained virologic response (based on bivariate and multivariate analyses) were virologic response at week 12 (odds ratio [OR], 1.9; P < .0001), genotypes 2 or 3 (OR, 2.9; P < .0001), therapeutic education (OR, 2.5; P < .02), and lack of previous treatment (OR, 2.3; P < .005). CONCLUSIONS Therapeutic education by a specialized nurse increases the response of patients with hepatitis C to therapy, particularly in difficult-to-treat patients.

Treatment of recurrent HCV infection following liver transplantation: results of a multicenter, randomized, versus placebo, trial of ribavirin alone as maintenance therapy after one year of PegIFNα-2a plus ribavirin.

BACKGROUND & AIMS We aimed at determining the effect of maintenance therapy with ribavirin alone, after a year of combined peginterferon-alfa 2a (PegIFNα-2a) and ribavirin therapy, on viral response and liver histology after liver transplantation (LT). METHODS Hundred and one patients with recurrent HCV and a minimum of stage 1 fibrosis (METAVIR scoring), 1-5years after LT, were enrolled. PegIFNα-2a and ribavirin were initiated at 90 μg/wk and 600 mg/d, respectively, then increased or adjusted as a function of tolerance. At 12 months, combination therapy was discontinued and patients were randomized to ribavirin or placebo for a further 12 months. Growth factor use was permitted. RESULTS At 18 months, a sustained virological response (SVR) was obtained in 47.9% of patients in Per Protocol (PP) analysis, and was higher in patients with genotype 2 or 3 than in patients with genotype 1 or 4, in patients with genotypes 1+4 receiving ciclosporine than in those receiving tacrolimus, in patients with worse renal function, in those having received EPO, in patients with lower weight, and in those with lower viral load at 3 months. Using logistic regression, only the early viral response, recipient weight and renal function were independently associated with better SVR. SVR, viral load, activity, and fibrosis scores were similar, at M18 and M30, in patients randomized to ribavirin, or to placebo. CONCLUSIONS A PP SVR was achieved in 47.9% of patients with established recurrent hepatitis C after LT. Maintenance therapy with ribavirin alone does not improve the virological response or the histological parameters.

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.

Impact of tumour differentiation to select patients before liver transplantation for hepatocellular carcinoma.

Aim: To generate a new score with improved accuracy compared with Milan criteria to select patients.

EASL and AASLD recommendations for the diagnosis of HCC to the test of daily practice

To evaluate the diagnostic performance of CT, MRI and CEUS alone and in combination, for the diagnosis of HCC between 10 and 30 mm, in a large population of cirrhotic patients.