How Should Hepatitis E Virus Infection Be Defined in Organ-Transplant Recipients?

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 (1Kamar N Selves J Mansuy JM et al.Hepatitis E virus and chronic hepatitis in organ-transplant recipients.N Engl J Med. 2008; 358: 811-817Crossref PubMed Scopus (1063) Google Scholar,2Kamar N Bendall R Legrand-Abravanel F et al.Hepatitis E.Lancet. 2012; 379: 2477-2488Abstract Full Text Full Text PDF PubMed Scopus (748) Google Scholar). However, if immunosuppressive-drug doses are decreased or a short course of ribavirin therapy is given, then sustained HEV clearance can be achieved (3Kamar 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: 353-360Crossref PubMed Scopus (191) Google Scholar,4Kamar N Rostaing L Abravanel F et al.Ribavirin therapy inhibits viral replication in patients with chronic hepatitis E virus infection.Gastroenterology. 2010; 139: 1612-1618Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar). Hence, these therapeutic strategies are recommended for patients who develop chronic HEV infection (5Wedemeyer H Pischke S Manns MP. Pathogenesis and treatment of hepatitis E virus infection.Gastroenterology. 2012; 142 (e1381.): 1388-1397Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar). 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 (1Kamar N Selves J Mansuy JM et al.Hepatitis E virus and chronic hepatitis in organ-transplant recipients.N Engl J Med. 2008; 358: 811-817Crossref PubMed Scopus (1063) Google Scholar). 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 diagnosedResolving group1The 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. (n = 21)Chronic group1The 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. (n = 48)p-ValueAge (years)51 ± 1348 ± 13NSGender: male/female22/629/12NSTransplanted organKidney2222NSLiver613Kidney–pancreas03Heart02Lung01Liver/nonliver transplant6/2213/28NSInduction therapy21/730/10NSRATG/anti-IL2R blockers12/921/9NSCalcineurin inhibitors: Y/N20/835/6NSCyclosporine A/tacrolimus5/152/330.08Cyclosporine A C2 level (ng/mL)523 ± 164352 ± 248NSTacrolimus trough level (ng/mL)7.6 ± 3.710.5 ± 5.70.08Belatacept1/271/40NSmTOR inhibitors8/209/32NSMycophenolic acid22/629/12NSMycophenolic dose (mg/kg/day)17.7 ± 7.719.2 ± 8.2NSAzathioprine1/273/38NSSteroids18/1031/10NSSteroid dose (mg/kg/day)0.08 ± 0.040.12 ± 0.11NSTime since transplantation (months)68 ± 5045 ± 40NSAST (IU/L)104 (20–1435)81 (16–436)NSALT (IU/L)275 (22–922)147 (14–874)0.004γGT (IU/L)205 (28–2337)130 (30–3480)NSBilirubin (µmol/L)15 (6–54)13 (5–277)NSWBCC (/mm3)6901 ± 29776298 ± 2616NSLymphocyte count (/mm3)1287 ± 6631265 ± 667NSPositive CD4 lymphocyte count (/mm3)538 ± 334551 ± 420NSPositive CD8 lymphocyte count (/mm3)387 ± 250463 ± 284NSPositive CD19 lymphocyte count (/mm3)101 ± 107106 ± 117NSPlatelet count (/mm3)202 582 ± 72 567201 195 ± 78 508NSHEV RNA concentration (log copies/mL)5.1 (2.06–6.85)5.85 (2.5–7.76)0.04RATG, 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. Open table in a new tab 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. 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 (1Kamar N Selves J Mansuy JM et al.Hepatitis E virus and chronic hepatitis in organ-transplant recipients.N Engl J Med. 2008; 358: 811-817Crossref PubMed Scopus (1063) Google Scholar). After 2008, specific therapeutic strategies were developed and given to patients with persistent HEV replication for more than 6 months (3Kamar 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: 353-360Crossref PubMed Scopus (191) Google Scholar,4Kamar N Rostaing L Abravanel F et al.Ribavirin therapy inhibits viral replication in patients with chronic hepatitis E virus infection.Gastroenterology. 2010; 139: 1612-1618Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar). 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. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.