RATG, rabbit antithymocyte globulins; anti-IL2R, anti-interleukine-2 receptor blockers; C2, concentration 2 h after intake; mTOR, mammalian target of rapamycin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; γGT, gamma-glutamyltranspeptidase; WBCC, white blood-cell count; HEV, hepatitis E virus; NS, not significant.
Letter to the Editor
How Should Hepatitis E Virus Infection Be Defined in Organ-Transplant Recipients?
Article first published online: 9 MAY 2013
© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons
American Journal of Transplantation
Volume 13, Issue 7, pages 1935–1936, July 2013
How to Cite
Kamar, N., Rostaing, L., Legrand-Abravanel, F. and Izopet, J. (2013), How Should Hepatitis E Virus Infection Be Defined in Organ-Transplant Recipients?. American Journal of Transplantation, 13: 1935–1936. doi: 10.1111/ajt.12253
- Issue published online: 26 JUN 2013
- Article first published online: 9 MAY 2013
- Manuscript Accepted: 14 MAR 2013
- Manuscript Received: 28 JAN 2013
To the Editor:
Within the last few years, it has been shown that hepatitis-E virus (HEV)-infection can induce chronic hepatitis and rapid progression of liver fibrosis in solid-organ-transplant (SOT) patients [1, 2]. However, if immunosuppressive-drug doses are decreased or a short course of ribavirin therapy is given, then sustained HEV clearance can be achieved [3, 4]. Hence, these therapeutic strategies are recommended for patients who develop chronic HEV infection . However, there is no established definition for chronic HEV infection, although carrying HEV for more than 6 months has been suggested as a definition for chronic hepatitis E, by some authors . Herein, we report the natural history of HEV infection in SOT patients to determine the most adequate definition of chronic HEV infection.
At our institution, the routine follow-up protocols for SOT patients include that they attend as an out-patient every 3–4 months, during which blood samples are obtained. In addition, biological parameters are checked every 1–1.5 months in a private laboratory. Between 2004 and 2012, 77 cases of HEV infection were diagnosed among our SOT population. In all cases, the date of HEV infection was exactly determined, using stored frozen sera if necessary. Liver-enzyme levels were normal within the month before HEV infection in all patients. Serum HEV RNA (detected by a real-time polymerase chain reaction) was negative in all cases within the 2 months before HEV infection. After HEV infection was diagnosed, HEV RNA was assessed at months 1 and 3, and thereafter every 3 months until HEV clearance. Eight patients were excluded from this study because of insufficient follow-up (n = 4) or because anti-viral therapy was initiated before the 6th month postinfection (n = 4). Hence, data from 69 SOT patients were analyzed. The patients' characteristics are presented in Table 1. HEV strains belonged to genotype 3 in 57 patients; we failed to sequence the strains of the other 12 patients. Immunosuppressive therapies were not changed significantly between diagnosis and 6 months later.
|Resolving group1 (n = 21)||Chronic group1 (n = 48)||p-Value|
|Age (years)||51 ± 13||48 ± 13||NS|
|Calcineurin inhibitors: Y/N||20/8||35/6||NS|
|Cyclosporine A C2 level (ng/mL)||523 ± 164||352 ± 248||NS|
|Tacrolimus trough level (ng/mL)||7.6 ± 3.7||10.5 ± 5.7||0.08|
|Mycophenolic dose (mg/kg/day)||17.7 ± 7.7||19.2 ± 8.2||NS|
|Steroid dose (mg/kg/day)||0.08 ± 0.04||0.12 ± 0.11||NS|
|Time since transplantation (months)||68 ± 50||45 ± 40||NS|
|AST (IU/L)||104 (20–1435)||81 (16–436)||NS|
|ALT (IU/L)||275 (22–922)||147 (14–874)||0.004|
|γGT (IU/L)||205 (28–2337)||130 (30–3480)||NS|
|Bilirubin (µmol/L)||15 (6–54)||13 (5–277)||NS|
|WBCC (/mm3)||6901 ± 2977||6298 ± 2616||NS|
|Lymphocyte count (/mm3)||1287 ± 663||1265 ± 667||NS|
|Positive CD4 lymphocyte count (/mm3)||538 ± 334||551 ± 420||NS|
|Positive CD8 lymphocyte count (/mm3)||387 ± 250||463 ± 284||NS|
|Positive CD19 lymphocyte count (/mm3)||101 ± 107||106 ± 117||NS|
|Platelet count (/mm3)||202 582 ± 72 567||201 195 ± 78 508||NS|
|HEV RNA concentration (log copies/mL)||5.1 (2.06–6.85)||5.85 (2.5–7.76)||0.04|
Forty-one of our 69 patients (59.4%) evolved to chronic infection, confirmed by persistent positive serum HEV RNA for at least 6 months. In these patients, HEV RNA concentration remained stable, that is 5.85 (2.5–7.76), 5.8 (3.65–7.37) and 4.95 log copies/mL (3.55–7.61), respectively, at acute phase, and at 3 and 6 months later. The other 28 patients were spontaneously cleared of the virus either at 1 month (n = 21) or between months 1 and 3 (n = 7). Thereafter, serum HEV RNA remained undetectable. Until 2008, because little was known about this disease, patients with persistent HEV infection did not receive a specific therapeutic strategy. Patients remained viremic and most rapidly developed severe fibrosis and/or cirrhosis . After 2008, specific therapeutic strategies were developed and given to patients with persistent HEV replication for more than 6 months [3, 4].
In this cases series, no HEV clearance was observed between months 3 and 6 after infection. Hence, chronic HEV infection can be defined as persisting HEV replication beyond 3 months after infection, at least in SOT patients.
N. Kamar1,2,3,*, L. Rostaing1,2,3
F. Legrand-Abravanel2,3,4 and J. Izopet2,3,4
1 Department of Nephrology, Dialysis and Organ Transplantation, CHU Rangueil, Toulouse, France
2 Université Paul Sabatier, Toulouse, France
3 INSERM U1043, IFR–BMT, CHU Purpan, Toulouse, France
4 Department of Virology, CHU Purpan, Toulouse, France
* Corresponding author: Nassim Kamar, email@example.com
The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.
- 1Hepatitis E virus and chronic hepatitis in organ-transplant recipients. N Engl J Med 2008; 358(8): 811–817., , , et al.
- 2Hepatitis E. Lancet 2012; 379: 2477–2488., , , et al.
- 3Influence of immunosuppressive therapy on the natural history of genotype 3 hepatitis-E virus infection after organ transplantation. Transplantation 2010; 89(3): 353–360., , , et al.
- 4Ribavirin therapy inhibits viral replication in patients with chronic hepatitis E virus infection. Gastroenterology 2010; 139(5): 1612–1618., , , et al.
- 5Pathogenesis and treatment of hepatitis E virus infection. Gastroenterology 2012; 142(6): 1388–1397; e1381., ,