An Early Viral Response Predicts the Virological Response to Ribavirin in Hepatitis E Virus Organ Transplant Patients Nassim Kamar, MD, PhD, 1,2,3 Sebastien Lhomme, PhD, PharmD, 2,3,4 Florence Abravanel, PhD, PharmD, 2,3,4 Olivier Cointault, MD, 1 Laure Esposito, MD, 1 Isabelle Cardeau-Desangles, MD, 1 Arnaud Del Bello, MD, 1,3 Gaëlle Dörr, MD, 1,3 Laurence Lavayssière, MD, 1 Marie Béatrice Nogier, MD, 1 Joelle Guitard, MD, 1 David Ribes, MD, 1 Anne Laure Goin, MD, 5 Pierre Broué, MD, 6 David Metsu, MD, 7 Karine Sauné, PhD, PharmD, 2,3,4 Lionel Rostaing, MD, PhD, 1,2,3 and Jacques Izopet, PhD, PharmD 2,3,4 Background. Ribavirin is efficient at treating chronic hepatitis E virus infection in solid-organ transplant patients. However, the early kinetics of viral replication under therapy and the impact of immunosuppressant regimens on viral replication are unknown: thus, determining the aim of our study. Methods. Thirty-five patients with a solid-organ transplant and chronic hepatitis E virus infection were given ribavirin for 3 months. The hepatitis E virus (HEV) RNA concentrations were determined before treatment, at days 7, 15, and 21 and at months 1, 2, and 3 during therapy and after ribavirin cessation. Results. A sustained virological response (SVR) occurred in 63%. Decreased viral concentration within the first week post-ribavirin therapy was an independent predictive factor for SVR, and a decreased HEV concentration of 0.5 log copies/mL or greater had an 88% positive predictive value. No correlation between ribavirin trough level on day 7 or at month 2 with a virological response or an SVR was observed. Before therapy, HEV RNA concentration was significantly greater in patients receiving mechanistic target of rapamycin inhibitor- based immunosuppression compared to patients given calcineurin inhibitors. The use of mycophenolic acid did not impact on the response to ribavirin. Conclusion. An early response to ribavirin can be used to define the optimal duration of therapy in the setting of HEV infection. (Transplantation 2015;99: 2124–2131) I t has been now clearly demonstrated that hepatitis E virus (HEV) infection can lead to chronic hepatitis in immuno- suppressed patients. 1,2 In patients with a solid-organ trans- plant (SOT) HEV can cause rapid progression to fibrosis, neurological symptoms, and kidney injury. 2 Decreasing im- munosuppression allows clearance of the virus in nearly one-third of patients with chronic hepatitis. 3 In the remaining patients with chronic HEV infection, anti-viral therapies, such as interferon or ribavirin, have been successfully used. 4 In case reports and small series, ribavirin has been found to be efficient at treating SOT patients with chronic HEV in- fection. 5-14 More recently, this was confirmed in a large retro- spective multicenter study that included 59 SOT patients treated by ribavirin alone for HEV infection. 15 In this later study, a sustained virological response (SVR) was observed in 78% of treated patients. This rate increased to 85% when four relapsers were retreated for a longer period. 15 A higher lymphocyte count at ribavirin initiation was the sole indepen- dent predictive factor for an SVR. In univariate analysis, neg- ative HEV viremia at month 1 was associated with a higher rate of SVR. However, in this previous multicenter study, the early kinetics of viral replication under therapy and riba- virin levels were not assessed in a large number of patients and, therefore, were not reported. 15 In our present single-center study, we describe the early virological response to ribavirin. We looked for a correla- tion between the decrease in HEV viral load and ribavirin trough levels, and analyzed their impact on SVR rate. We also analyzed the impact of immunosuppressive regimen on HEV clearance. MATERIALS AND METHODS Between September 2009 and December 2013, 38 SOT patients were treated with ribavirin as a monotherapy for HEV infection. Thirty-seven patients had a chronic HEV Received 20 February 2015. Revision requested 18 March 2015. Accepted 28 March 2015. 1 Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France. 2 INSERM U1043, IFR-BMT, CHU Purpan, Toulouse, France. 3 Université Paul Sabatier, Toulouse, France. 4 Laboratory of Virology, CHU Purpan, Toulouse, France. 5 Department of Thoracic Surgery and Lung Transplantation, CHU Rangueil-Larrey, Toulouse, France. 6 Pediatric Hepatology, Hôpital des enfants, Toulouse, France. 7 Laboratory of Toxicology, CHU Purpan, Toulouse, France. The authors declare no funding or conflict of interest. N.K. designed the study, collected the data and wrote the article. S.L., F.A., K.S. did the virological work-up and reviewed the article. O.C., L.E., I.C.-D., A.D., G.D., L.L., M.B.N., J.G., D.R., A.L.G., P.B., L.R. participated in the patients’ follow-up and re- viewed the paper. D.M. did the pharmacology work-up. J.I. participated in the study's design and reviewed the paper. Correspondence: Nassim Kamar, MD, PhD, Department of Nephrology and Organ Transplantation, CHU Rangueil, TSA 50032, 31059 Toulouse Cedex 9, France. (kamar.n@chu-toulouse.fr). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0041-1337/15/9910–2124 DOI: 10.1097/TP.0000000000000850 Original Clinical ScienceçLiver 2124 www.transplantjournal.com Transplantation ■ October 2015 ■ Volume 99 ■ Number 10 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.