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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 [5]. 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 [1]. 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.

Table 1. Patients' characteristics when hepatitis-E virus-infection was diagnosed
 Resolving group1 (n = 21)Chronic group1 (n = 48)p-Value
  • 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.

  • 1

    The resolving group was composed of patients having HEV replication of less than 6 months duration. Chronic HEV infection was defined by the presence of persistently HEV replication for at least 6 months.

Age (years)51 ± 1348 ± 13NS
Gender: male/female22/629/12NS
Transplanted organ
Kidney2222NS
Liver613 
Kidney–pancreas03 
Heart02 
Lung01 
Liver/nonliver transplant6/2213/28NS
Induction therapy21/730/10NS
RATG/anti-IL2R blockers12/921/9NS
Calcineurin inhibitors: Y/N20/835/6NS
Cyclosporine A/tacrolimus5/152/330.08
Cyclosporine A C2 level (ng/mL)523 ± 164352 ± 248NS
Tacrolimus trough level (ng/mL)7.6 ± 3.710.5 ± 5.70.08
Belatacept1/271/40NS
mTOR inhibitors8/209/32NS
Mycophenolic acid22/629/12NS
Mycophenolic dose (mg/kg/day)17.7 ± 7.719.2 ± 8.2NS
Azathioprine1/273/38NS
Steroids18/1031/10NS
Steroid dose (mg/kg/day)0.08 ± 0.040.12 ± 0.11NS
Time since transplantation (months)68 ± 5045 ± 40NS
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 ± 29776298 ± 2616NS
Lymphocyte count (/mm3)1287 ± 6631265 ± 667NS
Positive CD4 lymphocyte count (/mm3)538 ± 334551 ± 420NS
Positive CD8 lymphocyte count (/mm3)387 ± 250463 ± 284NS
Positive CD19 lymphocyte count (/mm3)101 ± 107106 ± 117NS
Platelet count (/mm3)202 582 ± 72 567201 195 ± 78 508NS
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 [1]. 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, kamar.n@chu-toulouse.fr

Disclosures

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

References

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  • 1
    Kamar N, Selves J, Mansuy JM, et al. Hepatitis E virus and chronic hepatitis in organ-transplant recipients. N Engl J Med 2008; 358(8): 811817.
  • 2
    Kamar N, Bendall R, Legrand-Abravanel F, et al. Hepatitis E. Lancet 2012; 379: 24772488.
  • 3
    Kamar N, Abravanel F, Selves J, et al. Influence of immunosuppressive therapy on the natural history of genotype 3 hepatitis-E virus infection after organ transplantation. Transplantation 2010; 89(3): 353360.
  • 4
    Kamar N, Rostaing L, Abravanel F, et al. Ribavirin therapy inhibits viral replication in patients with chronic hepatitis E virus infection. Gastroenterology 2010; 139(5): 16121618.
  • 5
    Wedemeyer H, Pischke S, Manns MP. Pathogenesis and treatment of hepatitis E virus infection. Gastroenterology 2012; 142(6): 13881397; e1381.