The optimal timing of hepatitis C therapy in liver transplant-eligible patients: Cost-effectiveness analysis of new opportunities.

Different strategies of DAAs treatment are currently possible both pre- and postliver transplantation (LT). Clinical and economic consequences of these strategies still need to be adequately investigated; this study aims at assessing their cost-effectiveness. A decision analytical model was created to simulate the progression of HCV-infected patients listed for decompensated cirrhosis (DCC) or for hepatocellular carcinoma (HCC). Three DAAs treatment strategies were compared: (i) a 12-week course of DAAs prior to transplantation (PRE-LT), (ii) a 4-week course of DAAs starting at the time of transplantation (PERI-LT) and (iii) a 12-week course of DAAs administered at disease recurrence (POST-LT). The population was substratified according to HCC presence and, in those without HCC, according to the MELD score at listing. Data on DAAs effectiveness were estimated using a cohort of patients still followed by 11 transplant centres of the European Liver and Intestine Transplant Association and by data available in the literature. In this study, PRE-LT treatment strategy was dominant for DCC patients with MELD<16 and cost-effective for those with MELD16-20, while POST-LT strategy emerged as cost-effective for DCC patients with MELD>20 and for those with HCC. Sensitivity analyses confirmed PRE-LT as the cost-effective strategy for patients with MELD≤20. In conclusion, PRE-LT treatment is cost-effective for patients with MELD≤20 without HCC, while treatments after LT are cost-effective in cirrhotic patients with MELD>20 and in those with HCC. It is worth reminding, though, that the final choice of a specific regimen at the patient level will have to be personalized based on clinical, social and transplant-related factors.

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.

Renal function at two years in liver transplant patients receiving everolimus: results of a randomized, multicenter study.

In a 24-month prospective, randomized, multicenter, open-label study, de novo liver transplant patients were randomized at 30 days to everolimus (EVR) + Reduced tacrolimus (TAC; n = 245), TAC Control (n = 243) or TAC Elimination (n = 231). Randomization to TAC Elimination was stopped prematurely due to a significantly higher rate of treated biopsy-proven acute rejection (tBPAR). The incidence of the primary efficacy endpoint, composite efficacy failure rate of tBPAR, graft loss or death postrandomization was similar with EVR + Reduced TAC (10.3%) or TAC Control (12.5%) at month 24 (difference -2.2%, 97.5% confidence interval [CI] -8.8%, 4.4%). BPAR was less frequent in the EVR + Reduced TAC group (6.1% vs. 13.3% in TAC Control, p = 0.010). Adjusted change in estimated glomerular filtration rate (eGFR) from randomization to month 24 was superior with EVR + Reduced TAC versus TAC Control: difference 6.7 mL/min/1.73 m(2) (97.5% CI 1.9, 11.4 mL/min/1.73 m(2), p = 0.002). Among patients who remained on treatment, mean (SD) eGFR at month 24 was 77.6 (26.5) mL/min/1.73 m(2) in the EVR + Reduced TAC group and 66.1 (19.3) mL/min/1.73 m(2) in the TAC Control group (p < 0.001). Study medication was discontinued due to adverse events in 28.6% of EVR + Reduced TAC and 18.2% of TAC Control patients. Early introduction of everolimus with reduced-exposure tacrolimus at 1 month after liver transplantation provided a significant and clinically relevant benefit for renal function at 2 years posttransplant.

Everolimus with reduced tacrolimus improves renal function in de novo liver transplant recipients: a randomized controlled trial.

In a prospective, multicenter, open-label study, de novo liver transplant patients were randomized at day 30±5 to (i) everolimus initiation with tacrolimus elimination (TAC Elimination) (ii) everolimus initiation with reduced-exposure tacrolimus (EVR+Reduced TAC) or (iii) standard-exposure tacrolimus (TAC Control). Randomization to TAC Elimination was terminated prematurely due to a higher rate of treated biopsy-proven acute rejection (tBPAR). EVR+Reduced TAC was noninferior to TAC Control for the primary efficacy endpoint (tBPAR, graft loss or death at 12 months posttransplantation): 6.7% versus 9.7% (-3.0%; 95% CI -8.7, 2.6%; p<0.001 for noninferiority [12% margin]). tBPAR occurred in 2.9% of EVR+Reduced TAC patients versus 7.0% of TAC Controls (p = 0.035). The change in adjusted estimated GFR from randomization to month 12 was superior with EVR+Reduced TAC versus TAC Control (difference 8.50 mL/min/1.73 m(2) , 97.5% CI 3.74, 13.27 mL/min/1.73 m(2) , p<0.001 for superiority). Drug discontinuation for adverse events occurred in 25.7% of EVR+Reduced TAC and 14.1% of TAC Controls (relative risk 1.82, 95% CI 1.25, 2.66). Relative risk of serious infections between the EVR+Reduced TAC group versus TAC Controls was 1.76 (95% CI 1.03, 3.00). Everolimus facilitates early tacrolimus minimization with comparable efficacy and superior renal function, compared to a standard tacrolimus exposure regimen 12 months after liver transplantation.

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 for hepatocellular carcinoma and potential application of PSI]. / Carcinome hépatocellulaire et transplantation hépatique : rôle futur des inhibiteurs de la mTOR.

Liver transplantation is considered the best treatment of hepatocellular carcinoma but its efficacy depends on the risk of tumour recurrence. The risk of recurrence depends on tumour characteristics but is also influenced by immunosuppressive regimens. Immunosuppressants of the mTOR inhibitors family share anti-tumour properties which are already taken into account in the treatment of renal carcinoma and advanced hepatocellular carcinoma. These features make interesting their use in liver transplantation for hepatocellular carcinoma, with the following goals: to reduce the risk of post-transplant tumour recurrence, to expand the indications of liver transplantation for hepatocellular carcinoma and eventually to slow down tumour growth during the waiting period. However, to date, the potential role of mTOR inhibitors after liver transplantation for hepatocellular carcinoma is only based on small encouraging proof of concept studies. Large randomized studies are therefore required to further define the specific indications of these compounds. The demonstration of a beneficial impact of mTOR inhibitors in the setting of liver transplantation for hepatocellular carcinoma would be a major therapeutical advance.

[Hepatic transplantation]. / La transplantation hépatique.

The first liver transplantation (LT) was conducted in 1963. After a two-decade development phase with the improvement of surgical and anesthesia-resuscitation techniques, and a better control of allograft rejection, LT has become the benchmark treatment for the majority of end-stage liver diseases. Since the 1980s, indications of LT have gradually expanded and the current main indications in adults are hepatocellular carcinoma at an early stage (15 to 30% of indications), C cirrhosis (15 to 40% of indications) and alcoholic cirrhosis (20 to 25% of indications). Five thousand LTs are performed yearly in Europe, including 1000 LTs in France, with, over the 2000-2006 period, survival rates of 86, 75 and 68% at one, five and 10 years, respectively. Several advances have accompanied the increasing number of indications and these excellent results: (a) the development of more specific immunosuppressive drugs to prevent rejection, the incidence of which is currently less than 20%: tacrolimus, mycophenolic acid, anti-IL2 receptor antibodies, mTOR inhibitors, (b) a policy of active recruitment of organs together with surgical innovations (split liver, domino LT, living donor transplantation) contributing to the expansion of the pool of organs, (c) standardization of organ allocation policies, based on the sickest first policy. The applicability of LT, however, remains limited by the shortage of organs and the occurrence of long-term complications of immunosuppression. Due to the lack of effective alternative perspectives to LT for the treatment of end-stage liver diseases, the two major challenges for the liver transplant community should be the optimization of organ recruitment and the development of innovative immunosuppressive regimens able to overcome the side effects of current immunosuppressive drugs. The development of non heart beating donation and appropriate use of intrafamilial donation could partly compensate for the organ shortage in the midterm. The identification of molecular signatures in tolerant patients in whom immunosuppression could be stopped, and induction of tolerance, trough lymphocyte depletion or T lymphocyte costimulation blockade, are the most advanced research ways to reduce complications of immunosuppression.

Natural history and therapeutic management of recurrent hepatocellular carcinoma after liver transplantation.

While the natural history and appropriate diagnostic and management practices are relatively well defined for hepatocellular carcinoma (HCC), data are scarce concerning the characteristic features and treatment modalities for recurrent HCC after liver transplantation. The time of recurrence appears to impact survival more significantly than localization, but to date, guidelines for therapeutic management of recurrent HCC have not been established. Data in the literature shows that late and unifocal recurrence has a better prognosis when treated by surgery or radiofrequency. In the event of early recurrence, surgery cannot be recommended due to the lack of evidence and the high risk of advanced disease. Systemic therapy can be discussed in a situation of multifocal recurrence. Proliferative signal inhibitors exhibit both immunosuppressive and antiproliferative properties and liver transplantation teams tend to introduce such treatment despite the lack of extensive data.

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.

Reuse of a liver graft five days after initial transplantation.

Brain death is a possible complication of orthotopic liver transplantation (OLT). In these cases, if the liver graft continues to function normally it could be resued for another recipient. To our knowledge this is the second reported case of liver graft reuse after brain death of the first recipient.

Orthotopic liver transplantation with preservation of the caval and portal flows. Technique and results in 62 cases.

Sixty-two OLTs in 61 patients were performed using a technical modification reported recently, including total hepatectomy with preservation of the inferior vena cava, partial clamping of the native vena cava, and side-to-side cavacaval anastomosis. We further modified the technique by adding the early construction of a temporary end-to-side portacaval shunt, and, more recently, by using an end-to-side caval reconstruction. With this technique, the caval and portal flows were maintained throughout the procedure. Hemodynamic parameters were analyzed prospectively during the operative period and remained stable at all stages of the procedure. Venous bypass was avoided in all cases without need for increased fluid infusion. Operative time and transfusion requirements were 6.8 +/- 1.6 hr and 9.8 +/- 4.3 U of packed RBC, respectively. There were no specific complications or deaths due to the technique used and hospital mortality was 10% (6/61). The technique used in this study is a safe adjunct to the technical armamentarium of clinical liver transplantation. Its main advantage seems to be hemodynamic stability throughout the procedure, obviating the need for venous bypass or fluid overload.

Improved clinical outcomes for liver transplant recipients using cyclosporine monitoring based on 2-hr post-dose levels (C2).

BACKGROUND: A prospective, open-label, study was conducted at 29 centers in 9 countries, involving 307 de novo liver transplant patients to compare the clinical usefulness of monitoring 2-hr post-dose cyclosporine (CsA) levels (C2) with conventional trough cyclosporine blood levels (pre-dose) (C0). METHODS: Neoral oral therapy was initiated at 15 mg/kg/day and dose adjusted according to predetermined C2 or C0 target level ranges. The primary efficacy variable was treatment failure at 3 months, where evaluation was based on a composite endpoint of biopsy-proven rejection, treatment for rejection, graft loss, death, or premature withdrawal/discontinuation from the study. RESULTS: Baseline characteristics were similar between groups. Graft loss at 12 weeks (retransplantation or death) occurred in 6.8% C2 and in 7.0% C0 patients. Overall incidence of treated acute rejection was lower for C2 (23.6%) than C0 patients (31.6%) (P=0.144, Cochran-Mantel-Haenszel [CMH] test). In hepatitis C virus (HCV)-negative patients, the incidence of rejection in the C2 group was significantly less than in the C0 group (21.2% vs. 33.0%; P<0.05), whereas in HCV-positive patients, the rejection rate was similar in both groups (26.7% for C2 group vs. 27.3% for C0 group: P=0.81). C2 patients (n=16) who reached minimum target CsA levels by day 3 had a notably low incidence of rejection (12.5%), whereas there was no difference in the incidence of rejection in C0 patients, irrespective of time to reach target level. For biopsy-proven acute rejections (21.6% for C2 vs. 30.4% for C0), the incidence of moderate and severe histological diagnosis was significantly lower in the C2 group than in the C0 group (47% vs. 73%; P=0.01). Safety profiles were similar between the two groups, with few patient withdrawals due to adverse events (9.5% for C2; 7.0% for C0). CONCLUSIONS: Using C2 monitoring, the overall incidence of acute cellular rejection was lower compared with the C0 group, and the histological severity of acute rejections was shown to be significantly milder for the C2 group, indicative of good long-term prognosis. These data demonstrate that the use of C2 monitoring is superior to C0 and results in a reduction in the incidence and severity of acute cellular rejection without detrimental effect on the drug safety profile.

Serial quantitative determination of hepatitis C virus RNA levels after liver transplantation. A useful test for diagnosis of hepatitis C virus reinfection.

After liver transplantation for hepatitis C virus (HCV)-related cirrhosis, recurrent viral infection is almost constant, resulting in acute graft dysfunction in 30-75% of cases. Acute graft dysfunction in the post-transplant period may also be the result of various causes (such as rejection, CMV infection, sepsis, or technical problems). Therefore, the role of HCV reinfection is often difficult to document. The aim of this study was to assess the diagnostic value of serial HCV RNA quantitation in this setting. Fourteen patients transplanted with follow-up greater than 6 months were studied. HCV RNA was quantitated before and serially after transplantation, using branched DNA technology. In cases of acute graft dysfunction, usual investigations and additional HCV RNA quantitation were conducted. There were 15 episodes of acute graft dysfunction in 12 patients. Six episodes had a hepatitic biochemical pattern, and 5 of them were associated with a concomitant HCV RNA peak. Nine episodes had a mixed, hepatitic, and cholestatic biochemical pattern, and 5 of them were associated with a concomitant peak of HCV RNA. Overall, 10 of 15 (66%) episodes of acute graft dysfunction were associated with HCV RNA peak, which strongly suggests that HCV was the etiologic factor. In 9 of these 10 episodes, no other cause of dysfunction was found, and one had associated CMV disease. In 5 cases, no peak of HCV RNA was observed and the causes of dysfunction were CMV (in 2 cases) and rejection, granulomatosis, and unknown (in 1 case each). Serial quantitations of HCV RNA levels after liver transplantation for cirrhosis C provide a useful tool in the diagnosis of HCV reinfection of the graft.

Increased incidence of oropharyngeal squamous cell carcinomas after liver transplantation for alcoholic cirrhosis.

BACKGROUND: THE aim of this study was to describe the features of posttransplantation tumors observed in a series of liver transplant recipients with special reference to patients receiving a transplant for alcoholic cirrhosis. METHODS: Among 171 consecutive liver transplant recipients, 90 patients who had received a first liver allograft for cirrhosis were studied. After liver transplantation, detection of de novo malignancies was prospectively undertaken and the characteristics of the patients in whom tumors occurred were compared with those in whom tumors did not develop. RESULTS: With a follow-up of 45.2+/-21.2 months, 11 tumors were observed in 90 patients (overall incidence of 12.2%). The incidence of tumors was higher in patients receiving a transplant for alcoholic cirrhosis than in patients receiving a transplant for nonalcoholic cirrhosis (26.7% vs. 5.0%, P<0.01). Squamous cell carcinoma (SCC) of the oropharynx or esophagus and posttransplant lymphoproliferative disorders were mainly observed. SCC (uvula in two cases, tongue in one case, esophagus in one case, pharynx in one case) occurred exclusively in patients transplanted for alcoholic cirrhosis (16.7% vs. 0%, P=0.001). The incidence of posttransplant lymphoproliferative disorders was similar in alcoholics and nonalcoholics (6.7% vs. 5%, NS). Survival was not influenced by the occurrence of SCC. CONCLUSION: The incidence of oropharyngeal SCC could be high in patients receiving a transplant for alcoholic cirrhosis. This could be due to an additional effect of posttransplantation immunosuppression in patients exposed to alcohol and tobacco before transplant. Careful posttransplantation screening of oropharyngeal SCC is warranted after liver transplantation for alcoholic cirrhosis.

Inhibitor against coagulation factor V after liver transplantation.

A new case of anti-factor V inhibitor is described in a 46-year-old man, who received a liver transplantation for hepatocellular carcinoma, without exposure to bovine thrombin or fibrin glue during the operative course. The inhibition occurred on the 14th postoperative day, while the patient was being treated with oxacillin, azathioprine, and a new immunosuppressive drug, FK506. The inhibition was of short duration (3 days), and no bleeding complication occurred despite a very low plasmatic level of factor V activity and antigen (<5%). Plasma samples drawn after cessation of FK506 disclosed a dose-dependent inhibitory activity when alcoholic solutions of FK506 were exogeneously added; this suggests a possible role of the FK506 drug in the occurrence of this anti-factor V inhibitor.

[Sheathing periostitis and Crohn's disease]. / Périostose engainante et maladie de Crohn.

Periostitis is an uncommon extradigestive lesion in Crohn's disease. We report two cases. The first patient was a young man presenting with moderate digestive symptoms, intense bone pain and high fever simulating osteomyelitis. The second case was more similar to those previously reported in the literature as the periostal new bone formation occurred in a woman already treated for Crohn's disease. These observations show the importance for clinicians to be aware of the association of periostitis and Crohn's disease, especially as corticotherapy is susceptible to improve bone pain as well as digestive symptoms.

[A rare cause of portal vein thrombosis: closed abdominal trauma]. / Une cause rare de thrombose portale: le traumatisme fermé de l'abdomen.

Abdominal trauma is a rare and poorly documented cause of portal vein thrombosis. We report here the case of a patient in whom portal vein thrombosis was diagnosed one month after an abdominal blunt trauma. Post-traumatic origin of thrombosis was confirmed by the negativity of an exhaustive aetiological investigation. Thrombosis involved portal bifurcation and right and left portal veins, but remained asymptomatic. A particularity of this case was that a total regression of the thrombosis was observed under anticoagulation therapy.

[Nodular regenerative hyperplasia of the liver associated with azathioprine therapy]. / Hyperplasie nodulaire régénérative du foie associée à la prise d'azathioprine.

Three cases of nodular regenerative hyperplasia of the liver associated with azathioprine therapy are reported. The indication of azathioprine differed in each of the 3 cases including kidney transplantation, graft-versus-host disease following bone marrow transplantation, and suspicion of bowel inflammatory disease, respectively. In all three patients, nodular regenerative hyperplasia was discovered after a prolonged administration of azathioprine (24 to 40 months), with a cumulative dose of 52 to 120 g. Under light microscopy, vascular lesions were associated with nodular regenerative hyperplasia in the 3 cases and consisted of sinusoidal dilatation (2 cases), perisinusoidal fibrosis (2 cases), and peliosis (1 case). In two patients, nodular regenerative hyperplasia was responsible for severe portal hypertension which was treated by portacaval shunt. These findings are strongly suggestive of a role of azathioprine in the occurrence of nodular regenerative hyperplasia. The mechanism of azathioprine-induced nodular regenerative hyperplasia could be related to sinusoidal lesions caused by azathioprine and responsible for liver hypoperfusion, with regenerative hyperplasia in the areas remaining normally perfused. Patients receiving long-term therapy with azathioprine should be followed-up regularly and liver biopsy should be performed when clinical or biochemical liver abnormalities are observed.