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The Authors’ Reply

Mazzola, Alessandra, MD, PhD1; Tran Minh, Margherita, MD1,2; Charlotte, Frédéric, MD3; Hdiji, Aisha, MD1; Bernard, Denis, MD4; Wendum, Dominic, MD, PhD5; Calmus, Yvon, MD, PhD1; Conti, Filomena, MD, PhD1

doi: 10.1097/TP.0000000000001995
Letters to the Editor

1 APHP, Hôpital Pitié-Salpêtrière, Unité Médicale de Transplantation Hépatique, Hépato-Gastro-Enterologie. Hôpital Pitié-Salpétrière UPMC Paris VI, Boulevard de l’Hôpital 75013 Paris, France.

2 Medicina Traslazionale, Università Piemonte Orientale Amedeo Avogrado, Italy.

3 APHP, Hôpital Pitié-Salpêtrière, Service d’Anatomie et Cytologie Pathologique, Paris, France.

4 APHP, Hôpital Pitié-Salpêtrière, Service d’Anesthésie-Réanimation, Paris, France.

5 APHP, Hôpital Saint Antoine, Service d’Anatomie et Cytologie Pathologique, Paris, France.

Received 6 October 2017.

Accepted 11 October 2017.

The authors declare no funding or conflicts of interest.

C.F. made substantial contributions to the conception and design of the work. C.F. and M.A. participated in drafting the work and revising it critically for important intellectual content. C.F. and W.D. participated in the interpretation of histological liver biopsies. C.Y. participated in the final approval of the version to be published. T.M.M., H.A., and B.D. made the agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Correspondence: Alessandra Mazzola, MD, PhD, Hôpital Pitié-Salpêtrière, Unité Médicale de Transplantation Hépatique, 47-83 Boulevard de l’Hôpital, 75013 Paris, France. (

We read with interest the letter to the editor from Kamar et al1 regarding our article which reported a case of chronic hepatitis E virus (HEV) infection in a liver transplant patient who had experienced a progression of liver fibrosis, leading to cirrhosis.2 This patient received several courses of ribavirin (RBV) with or without pegylated interferon. Although HEV replication continued, a regression of liver fibrosis was observed, and we concluded that long-term RBV therapy was safe in this setting, it did not achieve a sustained HEV virological response.2

Several interesting points have been raised in this letter and require a response to better understand our meaning. The first concerns the usefulness of reporting results on HEV RNA viral loads during therapy, although, unfortunately, only qualitative results were available for our patient.

Second, to clarify why the patient failed to clear the virus, Kamar et al proposed specifying RBV trough levels, kidney function, and hemoglobin levels. RBV levels were not evaluated during the treatment, but doses were adapted as a function of his tolerance and the presence of anemia. In 2009, in the context of antiviral therapy (pegylated interferon and RBV), treatment with recombinant erythropoietin was initiated for anemia (hemoglobin, 11 g/L). Also, during long-term RBV monotherapy, hemoglobin levels remained stable (hemoglobin, 11 g/L) with iron supplementation; lower hemoglobin levels were not tolerated by the patient because of asthenia and a generally poor condition. Renal function remained stable throughout treatment (creatinine clearance, 87 mL/min; serum creatinine, 79 μmol/L, without proteinuria). It should also be noted that immunosuppressive therapy was based on mammalian target of rapamycin inhibitors3; these were required because of epidermoid cancer of the tongue that was diagnosed after liver transplantation.4 The patient never presented with iron overload, and all the liver biopsies performed between 2006 and 2013 revealed only low and nonsignificant liver iron deposition. Hepatic iron levels remained stable, and no signs of histological fibrosis progression were observed.

We tried repeatedly to increase the RBV doses but this proved impossible because of poor patient tolerance. The data suggested that 800 mg daily of RBV was the highest dose tolerated by the patient, but this was insufficient to clear HEV, and his treatment could not be further improved.

We also agree with the comment on HEV RNA mutation but this was not investigated during antiviral therapy. The deep sequencing of HEV RNA is now in progress.

Finally, we agree wholly with the writer’s conclusion that HEV clearance is mandatory in chronically infected patients, and clinicians should strive to achieve HEV clearance, particularly to prevent extrahepatic manifestations of HEV.5 However, when HEV clearance proves impossible after reducing immunosuppression as much as possible and increasing the RBV dose up to the maximum threshold tolerated by the patient, along with the concomitant administration of erythropoietin as in our case, our message is that RBV should be pursued at a safe dose to prevent the progression of liver fibrosis.

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1. Kamar N, Del Bello A, Izopet J. Should persistent hepatitis E virus replication in transplant patients be tolerated? [published online November 10, 2017]. Transplantation. doi: 10.1097/TP.0000000000001994.
2. Mazzola A, Tran Minh M, Charlotte F, et al. Chronic hepatitis E viral infection after liver transplantation: a regression of fibrosis after antiviral therapy. Transplantation. 2017;101:2083–2087.
3. Saliba F, Duvoux C, Gugenheim J, et al. Efficacy and safety of everolimus and mycophenolic acid with early tacrolimus withdrawal after liver transplantation: a multicenter randomized trial. Am J Transplant. 2017;17:1843–1852.
4. Holdaas H, De Simone P, Zuckermann A. Everolimus and malignancy after solid organ transplantation: a clinical update. J Transplant. 2016;2016:4369574.
5. Kamar N, Marion O, Abravanel F, et al. Extrahepatic manifestations of hepatitis E virus. Liver Int. 2016;36:467–472.
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