When Should Ribavirin Be Started to Treat Hepatitis E Virus Infection in Transplant Patients?

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To the Editor: Meisner et al reported a case of hepatitis E virus (HEV) infection that occurred in a liver transplant patient who was cleared of the virus at 4 months after diagnosis, following a flu-like syndrome (1Meisner S Polywka S Memmler M Definition of chronic hepatitis E after liver transplant conforms to convention.Am J Transplant. 2015; 15 (et al): 3011-3012Crossref PubMed Scopus (10) Google Scholar). Based on this single case, they concluded that, in solid organ transplant recipients, chronic HEV infection should be defined as persistent HEV replication for at least 6 months rather than 3 months, as we have previously suggested (2Kamar N Rostaing L Legrand-Abravanel F Izopet J. How should hepatitis E virus infection be defined in organ-transplant recipients?.Am J Transplant. 2013; 13: 1935-1936Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). In a large series that included 69 solid organ transplant patients, we reported that 41 patients evolved to chronic hepatitis (defined by the persistence of HEV replication ≥6 months) but that 28 patients were spontaneously cleared of the virus. All of these 28 patients were cleared of the virus within the first 3 months after diagnosis without any modification to immunosuppressive therapy (2Kamar N Rostaing L Legrand-Abravanel F Izopet J. How should hepatitis E virus infection be defined in organ-transplant recipients?.Am J Transplant. 2013; 13: 1935-1936Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). Unfortunately, the case report by Meisner et al does not provide sufficient and robust data to support their conclusion (1Meisner S Polywka S Memmler M Definition of chronic hepatitis E after liver transplant conforms to convention.Am J Transplant. 2015; 15 (et al): 3011-3012Crossref PubMed Scopus (10) Google Scholar). Indeed, it has been previously shown that HEV clearance requires a specific anti-HEV T cell response and that reduced immunosuppression therapy, especially of drugs that target T cells, enables HEV clearance in one third of solid organ transplant patients with chronic HEV infection (3Kamar N Abravanel F Selves J Influence of immunosuppressive therapy on the natural history of genotype 3 hepatitis-E virus infection after organ transplantation.Transplantation. 2010; 89 (et al): 353-360Crossref PubMed Scopus (182) Google Scholar). In these patients, tacrolimus trough levels and steroid doses were significantly lower compared to those observed in patients who remained viremic and chronically infected (3Kamar N Abravanel F Selves J Influence of immunosuppressive therapy on the natural history of genotype 3 hepatitis-E virus infection after organ transplantation.Transplantation. 2010; 89 (et al): 353-360Crossref PubMed Scopus (182) Google Scholar). Hence, reduction of immunosuppressive therapy is the first-line therapeutic option against HEV in solid organ transplant patients. In the report by Meisner et al, no data regarding the management of immunosuppressive therapy were provided. One wonders whether the authors had reduced doses of immunosuppressants after HEV diagnosis or during the flu-like symptoms, since this would have increased the immunological response and, thus, HEV clearance. The authors need to provide details about doses and levels of immunosuppressive drugs taken before diagnosis, at diagnosis, and during HEV infection. Solid organ transplant patients with HEV have accelerated progression of liver fibrosis (3Kamar N Abravanel F Selves J Influence of immunosuppressive therapy on the natural history of genotype 3 hepatitis-E virus infection after organ transplantation.Transplantation. 2010; 89 (et al): 353-360Crossref PubMed Scopus (182) Google Scholar) and can present with severe HEV-associated extrahepatic manifestations (neurological manifestations and kidney injuries) that can occur whatever the duration of HEV infection (4Kamar N Bendall R Legrand-Abravanel F Hepatitis E.Lancet. 2012; 379 (et al): 2477-2488Abstract Full Text Full Text PDF PubMed Scopus (733) Google Scholar). Ribavirin is an efficient, safe, and inexpensive treatment of HEV infection (5Kamar N Izopet J Tripon S Ribavirin for chronic hepatitis E virus infection in transplant recipients.N Engl J Med. 2014; 370 (et al): 1111-1120Crossref PubMed Scopus (342) Google Scholar). Hence, we suggest that, when possible, as soon as HEV infection is diagnosed in transplant patients, immunosuppressive therapy should be reduced, targeting tacrolimus and mammalian target of rapamycin inhibitors trough levels ≤5 ng/mL, and cyclosporine A trough level ≤100 ng/mL. If HEV replication persists 3 months later, then patients should be offered ribavirin therapy. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.