Laurence Lavayssière

Influence of immunosuppressive therapy on the natural history of genotype 3 hepatitis-E virus infection after organ transplantation.

Background. Hepatitis-E virus (HEV) infection can be responsible for chronic hepatitis in solid-organ transplant patients. Methods. We identified 33 cases of autochthonous acute HEV infection in solid-organ transplant patients. Results. Among 27 HEV-positive patients, who had a follow-up of more than 6 months, 16 (59.25%) evolved to chronic HEV infection, defined by persisting elevated liver-enzyme levels and positive serum HEV RNA 6 months after diagnosis. Serial liver biopsies showed progression in liver activity and liver fibrosis. Three patients developed liver cirrhosis. The proportion of patients receiving tacrolimus compared with cyclosporine A was significantly higher in patients who evolved to chronic disease. Immunosuppressive therapy was reduced in patients with chronic hepatitis; however, those who had a dramatic decrease in tacrolimus trough levels were more likely to clear the virus. Four chronic liver transplant patients were cleared off the virus at 14, 16, 22, and 23 months after diagnosis. At last follow-up, their tacrolimus trough levels and daily steroid doses were significantly lower than those who remained viremic. These four patients had lower liver-enzyme levels and lower activity scores on liver biopsies, and their peripheral blood CD3- and CD4-positive cell counts were also significantly higher. Conclusions. The rate of chronic HEV-related hepatitis is approximately 60% in solid-organ transplant patients. When possible, the reduction of immunosuppressive drugs targeting T cells should be considered as a first-line therapeutic option.

Incidence and Predictive Factors for Infectious Disease after Rituximab Therapy in Kidney-Transplant Patients

Rituximab off‐label use includes organ transplantation. We review the occurrence of infectious disease and its outcome after rituximab therapy. Between April 2004 and August 2008, 77 kidney‐transplant patients received rituximab therapy [2–8 courses (median 4) of 375 mg/m2 each] for various reasons. Their results were compared with a control group (n = 902) who had received no rituximab. After a median follow‐up of 16.5 (1–55) months for rituximab patients and 60.9 (1.25–142.7) months for control patients, the incidence of infectious disease was 45.45% and 53.9% (ns), respectively. The incidence of bacterial infection was similar between the two groups, whereas the viral‐infection rate was significantly lower, and the rate of fungal infection was significantly higher in the rituximab group. Nine out of 77 patients (11.68%) died after rituximab therapy, of which seven deaths (9.09%) were related to an infectious disease, compared to 1.55% in the controls (p = 0.0007). In the whole population, the independent predictive factors for infection‐induced death were the combined use of rituximab and antithymocyte‐globulin given for induction or anti‐rejection therapy, recipient age, and bacterial and fungal infections. After kidney transplantation, the use of rituximab is associated with a high risk of infectious disease and death related to infectious disease.

Efficacy and Safety of Sofosbuvir-Based Antiviral Therapy to Treat Hepatitis C Virus Infection After Kidney Transplantation.

There is no approved therapy for hepatitis C virus (HCV) infection after kidney transplantation, and no data regarding the use of new‐generation direct antiviral agents (DAAs) have been published so far. The aims of this pilot study were to assess the efficacy and safety of an interferon‐free sofosbuvir‐based regimen to treat chronic HCV infection in kidney transplant recipients. Twenty‐five kidney transplant recipients with chronic HCV infection were given, for 12 (n = 19) or 24 weeks (n = 6), sofosbuvir plus ribavirin (n = 3); sofosbuvir plus daclatasvir (n = 4); sofosbuvir plus simeprevir, with (n = 1) or without ribavirin (n = 6); sofosbuvir plus ledipasvir, with (n = 1) or without ribavirin (n = 9); and sofosbuvir plus pegylated‐interferon plus ribavirin (n = 1). A rapid virological response, defined by undetectable viremia at week 4 after starting DAA therapy, was observed in 22 of the 25 patients (88%). At the end of therapy, HCV RNA was undetectable in all patients. At 4 and 12 weeks after completing DAA therapy, all had a sustained virological response. The tolerance to anti‐HCV therapy was excellent and no adverse event was observed. A significant decrease in calcineurin inhibitor levels was observed after HCV clearance. New‐generation oral DAAs are efficient and safe to treat HCV infection after kidney transplantation.

Rituximab therapy for de novo mixed cryoglobulinemia in renal transplant patients.

Background. Type II or III cryoglobulins are fairly prevalent in renal-transplant (RT) patients, and are often related to chronic hepatitis C virus (HCV) infection. However, they rarely result in graft dysfunction. They are sustained by proliferation of oligoclonal B-cells. Systemic B-cell depletion and clinical remission of the systemic effects of cryoglobulins have been achieved in HCV-positive immunocompetent patients with a human/mouse chimeric monoclonal antibody that specifically reacts with the CD20 antigen (i.e., rituximab). Thus, this provides the rationale to use rituximab for cryoglobulin-related graft dysfunction in RT patients. Methods. Three RT patients, of whom one was HCV-positive, developed renal-function impairment long after transplantation, as well as de novo nephrotic syndrome (n=2) and severe hypertension (n=2). This latter case was related to type III cryoglobulinemia and was associated with membranoproliferative glomerulonephritis. In addition to their baseline standard immunosuppression, the patients were given weekly rituximab infusions of 375 mg/m2 (two infusions in patient and four infusions for the other two cases). Results. This treatment resulted in a dramatic improvement in renal parameters, particularly in a sustained remittence of nephrotic syndrome, a sustained clearance of cryoglobulins in two cases, but also in severe infectious complications in two cases. Conclusion. We conclude that rituximab therapy is highly effective in cryoglobulin-related renal dysfunction in RT patients; however, due to chronic immunosuppression, this is at the expense of infectious complications.

Prevalence, incidence and risk factors for donor-specific anti-HLA antibodies in maintenance liver transplant patients.

Although large retrospective studies have identified the presence of donor‐specific antibodies (DSAs) to be a risk factor for rejection and impaired survival after liver transplantation, the long‐term predicted pathogenic potential of individual DSAs after liver transplantation remains unclear. We investigated the incidence, prevalence and consequences of DSAs in maintenance liver transplant (LT) recipients. Two hundred sixty‐seven LT recipients, who had undergone transplantation at least 6 months previously and had been screened for DSAs at least twice using single‐antigen bead technology, were included and tested annually for the presence of DSAs. At a median of 51 months (min–max: 6–220) after an LT, 13% of patients had DSAs. At a median of 36.5 months (min–max: 2–45) after the first screening, 9% of patients have developed de novo DSAs. The sole predictive factor for the emergence of de novo DSAs was retransplantation (OR 3.75; 95% CI 1.28–11.05, p = 0.025). Five out of 21 patients with de novo DSAs (23.8%) developed an antibody‐mediated rejection. Fibrosis score was higher among patients with DSAs. In conclusion, monitoring for the development of DSAs in maintenance LT patients is useful in case of graft dysfunction and to identify patients with a high risk of developing liver fibrosis.

Entecavir Therapy for Adefovir-Resistant Hepatitis B Virus Infection in Kidney and Liver Allograft Recipients

The aim of our study was to assess the efficacy and safety of entecavir in kidney- and liver-transplant recipients with chronic hepatitis B virus (HBV) infection. Ten male transplant patients with chronic HBV infection (eight kidney- and two liver-transplant patients), who have become adefovir (n=9) or lamivudine-resistant (n=1) were given entecavir at 0.5 to 1 mg/d. All patients were HBs Ag positive: six were HBe Ag(−)/HBe Ab(+), and four were HBe Ag(+)/HBe Ab(−). After a median follow-up of 16.5 months, entecavir therapy was associated with a significant decrease in HBV DNA viral load, that is, 3.86 (2.71–6.46) log10 copies/mL at baseline down to 2.94 (2.15–4) log10 copies/mL at last follow-up (P=0.004). Rate of HBV DNA clearance was 50% in both HBeAg(+) and HBeAg(−) patients. There were no significant changes in renal function or hematological parameters. This study demonstrates that entecavir therapy is safe and efficient in HBV(+) organ-transplant patients.

Donor-Specific Antibodies after Ceasing Immunosuppressive Therapy, with or without an Allograft Nephrectomy

BACKGROUND AND OBJECTIVES Within the last few years, anti-human leukocyte antigen detection assays have significantly improved. This study asked, using the Luminex single-antigen assay, whether an allograft nephrectomy allowed donor-specific alloantibodies to appear that were not previously detected in the serum when the failed kidney was still in place. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS After losing the kidney allograft and stopping immunosuppressive therapy, the proportions of donor-specific alloantibodies and nondonor-specific alloantibodies were compared in patients who had (n=48; group I) and had not (n=21; group II) undergone an allograft nephrectomy. Allograft nephrectomies were performed at 150 days after kidney allograft loss, and the time between allograft nephrectomy and last follow-up was 538 ± 347 days. RESULTS At kidney allograft loss, donor-specific alloantibodies were detected in three group II patients (14.2%) and six group I patients (12.5%). At last follow-up, donor-specific alloantibodies were detected in 11 patients (52.4%) without and 39 patients (81%) with an allograft nephrectomy (P=0.02). Anti-human leukocyte antigen class I donor-specific alloantibodies were positive in 23.8% of group II and 77% of group I patients (P<0.001); anti-human leukocyte antigen class II donor-specific alloantibodies were positive in 42.8% of group II and 62.5% of group I patients. Independent predictive factors for developing donor-specific alloantibodies after losing kidney allograft and stopping immunosuppressants were number of anti-human leukocyte antigen A/B mismatches at transplantation (zero versus one or more) and allograft nephrectomy. CONCLUSIONS The development of donor-specific alloantibodies was significantly greater in patients with a failed kidney who had undergone an allograft nephrectomy compared with those patients who had not undergone allograft nephrectomy.

Blood salvage autotransfusion during transplantation for hepatocarcinoma : does it increase the risk of neoplastic recurrence?

Impact of intraoperative blood salvage autotransfusion (IBSA) on neoplastic recurrence. during liver transplantations for hepatocellular carcinoma (LT‐HCC). Between January 1989 and February 2003, 16 patients received a LT‐HCC without IBSA. This group was compared with 31 patients who received the same surgical procedure during the same period, but with IBSA. Data were prospectively collected. All patients had at least a 1‐year postoperative follow up. Pairing was made according to the size of the largest nodule. The percentage of recurrence observed in the two groups was similar: 6.4% in the IBSA group vs. 6.3% in the group without IBSA. The median amount of transfused salvage blood was 1558 ml. The differences observed between the two groups concerned the Child score which was A in 58% patients of the IBSA group vs. 80% in the other group; the percentage of severe portal hypertension was 55% in the IBSA group vs. 31%; the median number of packed red blood cell units transfused intraoperatively was 7 in the IBSA group vs. 0, and the median number of frozen fresh plasma units transfused intraoperatively was 11 in the IBSA group vs. 4.5. It appears that IBSA, essentially used during the most haemorrhagic transplantations, could be used in the case of HCC because it does not modify the risk of neoplastic recurrence.

Hepatitis E virus-induced severe myositis

Fig. 1. Outcome of biochemical and virological parameters. To the Editor: Genotype 3 hepatitis E virus (HEV3) infection is responsible for self-limiting acute hepatitis, chronic HEV3 infection leading to cirrhosis in immunosuppressed patients, and several extra-hepatic manifestations, i.e., neurological symptoms, kidney injury, and severe thrombocytopenia [1–5]. Ribavirin therapy has been shown to be an efficient therapy for chronic HEV infection [6,7]. Herein, we report on a first case of Guillain–Barré syndrome associated with severe necrotizing myositis that occurred in a liver-transplant patient in acute HEV-infection phase, who then recovered after ribavirin therapy. A 65-year-old liver-transplant male presented, 7 years after transplantation for alcoholic liver disease, with an autochthonous acute HEV infection (Fig. 1): jaundice, increased liverenzyme levels, positive serum HEV RNA (126,000 copies/ml, genotype 3f), and positive anti-HEV IgG and IgM (Wantai Biologic Pharmacy Enterprise, Beijing, People’s Republic of China). All other causes of hepatitis were ruled out. The source of HEV infection has not been clearly identified. However, the patient had eaten undercooked pork meat. He was receiving cyclosporine A (C2 level at 600 ng/ml), mycophenolatemofetil, and steroids. Cyclosporine A doses were dramatically decreased (C2 level at 300 ng/ml). Ten days later, he was unable to stand upright. Neurological examination showed severe quadriparesis, with proximal muscle weakness and abolition of biceps, patellar, and Achilles’ tendon reflexes, as well as a right lower facial palsy. Creatine kinase (CK) level was increased to 191,603 IU/ L (normal <170 IU/L). Electrophysiological studies showed signs of peripheral demyelinating polyradiculopathy with abolition or prolongation of F-wave responses and sensory conduction was altered more in upper limbs. At rest, needle electromyography showed diffuse abnormal spontaneous activity in all four limbs. Cerebrospinal-fluid (CSF) analysis showed elevated protein level (0.64 g/L), no leukocytes, and no HEV RNA, whereas serum HEV RNA was still positive (49,600 copies/ml). The CSF to serum-albumin ratio was 12.81. The CSF (IgG:albumin) to serum (IgG:albumin) ratio was 0.47. Cryoglobulinemia, serum anti-ganglioside (GM1, GM-2, GM-3, GM4, GD1A, GD1B, GD2, GD3, GT1A, GD1B, GQ1B) antibodies, anti-myelin-associated glycoprotein antibodies, as well as serum and CSF onconeuronal antibodies, were negative. A biopsy specimen of the left bicep brachial muscle showed myopathic changes, with a significant percentage of necrotic muscle fibers ( 10%) and some inflammatory elements. There was no capillary thickening. The day after admission, he developed acute respiratory failure that required mechanical ventilation. Because of suspected HEV-induced Guillain–Barré syndrome associated with severe myositis, mycophenolatemofetil was withdrawn and the patient was given intravenous immunoglobulins (1 g/kg/d for 2 days) and ribavirin therapy [400 mg/d adapted to his glo-

Predictive factors for posttransplant diabetes mellitus within one-year of liver transplantation.

Introduction. The aims of our single-center study were to identify whether pretransplant diabetes had an impact on patient survival and, secondly, the predictive factors for development of new-onset diabetes mellitus (NODM) (as defined by American Diabetes Association/World Health Organization). Patients and Methods. One hundred seventy-nine consecutive adult orthotopic liver-transplant patients were included in this study. Immunosuppression was based on calcineurin inhibitors with steroids, with or without mycophenolate mofetil, and with or without induction therapy. To evaluate the predictive factors for NODM, donor and recipient pre- and posttransplant data were included. Results. At transplantation, 38 patients had diabetes (group I), and the 141 nondiabetic patients constituted group II. In group I, paternal history of diabetes was more frequent (P=0.03), as was length of exposure to smoking (P=0.03), higher pretransplant glycemia (P<0.001), and shorter cold-ischemia (P=0.027) compared with group II. Pretransplant diabetes in group I resulted in a mortality rate of 39.5% at 1 year compared with 19.1% in group II (P=0.009). In group II, in multivariate analysis, independent predictive factors for NODM at M12 were pretransplant glycemia (P=0.037), alcohol-induced end-stage liver disease (P=0.04), and cumulative steroid dose within 1-year posttransplant (P=0.05). Conclusion. Of the independent predictive risk factors for NODM, only steroid dose is modifiable, emphasizing the need for individualized immunosuppression.