Laure Esposito

Hepatitis E Virus and Chronic Hepatitis in Organ-Transplant Recipients

Hepatitis E virus (HEV) is considered an agent responsible for acute hepatitis that does not progress to chronic hepatitis. We identified 14 cases of acute HEV infection in three patients receiving liver transplants, nine receiving kidney transplants, and two receiving kidney and pancreas transplants. All patients were positive for serum HEV RNA. Chronic hepatitis developed in eight patients, as confirmed by persistently elevated aminotransferase levels, serum HEV RNA, and histologic features of chronic hepatitis. The time from transplantation to diagnosis was significantly shorter and the total counts of lymphocytes and of CD2, CD3, and CD4 T cells were significantly lower in patients in whom chronic disease developed.

Ribavirin Therapy Inhibits Viral Replication on Patients With Chronic Hepatitis E Virus Infection

BACKGROUND & AIMS Hepatitis E virus (HEV) infection can evolve to chronic hepatitis in immunocompromised patients. Pegylated α-interferon can effectively treat chronic HEV infection after liver transplantation but is contraindicated for kidney transplantation. We assessed the antiviral effect of ribavirin monotherapy in patients with chronic HEV infection following kidney transplantation. METHODS In a pilot study performed at Toulouse University Hospital, 6 patients that received kidney transplants who were positive for HEV RNA (infected with HEV for 36.5 months; [range, 11-46 months]) were given ribavirin monotherapy for 3 months. Ribavirin was given at 600-800 mg/day in 2 separate doses, based on the patients ability to clear creatinine. RESULTS Median serum concentration of HEV RNA at baseline was 5.77 log copies/mL (range, 4.35-7.35 log copies/mL). Three months after ribavirin therapy commenced, HEV RNA was undetectable in serum samples from all patients. A sustained virologic response was observed in 4 patients; the other 2 patients relapsed at 1 and 2 months after ribavirin therapy ended. At the end of the study, all patients had normal levels of alanine and aspartate aminotransferase. Anemia was the main side effect caused by ribavirin therapy. CONCLUSIONS Ribavirin monotherapy inhibits the replication of HEV in vivo and might induce a sustained virological response in patients with chronic HEV infections. Further studies are required to determine the optimal duration of ribavirin therapy.

Hepatitis E Virus‐Related Cirrhosis in Kidney‐and Kidney–Pancreas‐Transplant Recipients

Hepatitis E virus (HEV) infection was thought to be responsible for acute hepatitis that did not become chronic. However, we have recently reported that HEV infection can evolve to chronic hepatitis, at least in solid‐organ transplant patients. We report on two cases of rapidly progressive of HEV‐related cirrhosis that occurred in two organ‐transplant patients. Case 1: A kidney–pancreas‐transplant patient developed acute HEV hepatitis 60 months after transplantation, which evolved to chronicity as defined by persisting elevated liver‐enzyme levels and positive serum HEV RNA. At 22 months after the acute phase, she presented with cirrhosis and portal hypertension, that is ascites and esophagus varices. Case 2: A kidney‐transplant patient developed acute hepatitis 36 months after transplantation, which persisted and remained unexplained for 38 months. Then, HEV RNA was searched for in their serum and stools, and was found to be positive in both. Retrospective analysis of available stored serum, mainly the serum obtained at the acute phase, confirmed the diagnosis of chronic hepatitis E. In both cases, a liver biopsy showed cirrhosis. We conclude that HEV infection cannot only evolve to chronic hepatitis, but can also be responsible for rapidly progressing cirrhosis in organ‐transplant patients.

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.

Pegylated Interferon-α for Treating Chronic Hepatitis E Virus Infection after Liver Transplantation

This study assessed the effect of a 3-month course of pegylated interferon-alpha-2a (Peg-IFN-alpha-2a) in 3 liver transplant patients with chronic active hepatitis E. A virological response was sustained for 6 and 5 months in 2 patients after Peg-IFN-alpha-2a therapy was completed. A relapse was observed in the third patient.

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.

Hepatitis E virus and the kidney in solid-organ transplant patients.

Background. Hepatitis E virus (HEV) infection is an emerging disease in industrialized countries. Few data regarding genotype 3 HEV extrahepatic manifestations exist. Methods. We assessed kidney function and histology in solid-organ transplant patients during HEV infection. In all, 51 cases of genotype 3 HEV infections were diagnosed (34 kidney, 14 liver, and 3 kidney-pancreas transplant patients). Of these, 43.2% were cleared of the virus spontaneously within 6 months of infection, whereas 56.8% evolved to chronic hepatitis. Twelve of these patients completed a 3-month antiviral therapy and were followed up for 6 months posttreatment. Kidney function (estimated glomerular filtration rate [eGFR] obtained by the Modification of Diet in Renal Disease equation) and proteinuria were assessed before infection, during HEV infection and during follow-up. Kidney biopsies were obtained from patients with high proteinuria and decreased eGFR levels. Results. During HEV infection, there was a significant decrease in eGFR in both kidney- and liver-transplant patients. Glomerular diseases were observed in kidney biopsies obtained during the acute and chronic phases. This included membranoproliferative glomerulonephritis and relapses in IgA nephropathy. The majority of patients had cryoglobulinemia that became negative after HEV clearance. Kidney function improved and proteinuria decreased after HEV clearance. Conclusion. HEV-associated glomerulonephritis seems to be an HEV-related extrahepatic manifestation. Further studies are required to confirm these observations.

Leflunomide treatment for polyomavirus BK-associated nephropathy after kidney transplantation.

Polyomavirus‐associated nephropathy (PVAN) affects 1–10% of kidney‐transplant (KT) patients, with graft failure/loss in approximately 90% of cases. Reducing immunosuppression is the key treatment option, but addition of leflunomide may improve BK Virus (BKV) clearance and graft survival. In a prospective open‐labeled study, 12 KT patients with biopsy‐proven PVAN were treated with reduced immunosuppression and leflunomide. BKV viremia and graft function were followed. PVAN was diagnosed at 6 months (3–192) post‐transplant; median serum creatinine concentration (sCC) was 189 μmol/l (92–265). After 16 months (8–30) of follow‐up, the sCC was 150 μmol/l (90–378, NS). Renal function improved in six cases (50%), remained stable in two (16.6%) and deteriorated in four (33.4%), with graft loss in two (17%). Clearance of BKV viremia was observed in five (42%) cases. Side effects included anemia in six cases leading to leflunomide withdrawal in two patients, and mild thrombocytopenia. In KT patients diagnosed with PVAN, leflunomide plus reduced immunosuppression improved graft function in 66.6%, cleared BKV viremia in 42%, and resulted in side effects in 17%. This limited efficacy contrasts with other reports and falls short of expectation. We conclude that active screening, earlier diagnosis and intervention remain the cornerstones of treatment.

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.