Early intrahepatic recurrence of HBV infection in liver transplant recipients despite antiviral prophylaxis
François Villeret,
Fanny Lebossé,
Sylvie Radenne,
Didier Samuel,
Bruno Roche,
Jean-Yves Mabrut,
Vincent Leroy,
Georges-Philippe Pageaux,
Rodolphe Anty,
Sylvie Thevenon,
Sinafa Si Ahmed,
Aaron Hamilton,
Marintha Heil,
Caroline Scholtès,
Massimo Levrero,
Barbara Testoni,
Fabien Zoulim,
Françoise Berby,
Isabelle Bordes,
Daniel Cherqui,
Tarek Debs,
Christian Ducerf,
Jean-Charles Duclos-Valle,
Marie-Noëlle Hilleret,
Antonio Iannelli,
Kayvan Mohkam,
Francis Navarro
Affiliations
François Villeret
Service d’Hépatologie, Hôpital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France; Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052, CNRS UMR 5286, Université Claude Bernard Lyon 1, Lyon, France
Fanny Lebossé
Service d’Hépatologie, Hôpital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France; Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052, CNRS UMR 5286, Université Claude Bernard Lyon 1, Lyon, France
Sylvie Radenne
Service d’Hépatologie, Hôpital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France
Didier Samuel
Centre Hépato-Biliaire, Université Paris-Saclay, Unité Inserm 1193, Hôpital Paul-Brousse, Assistance Publique-Hôpitaux de Paris (AP-HP), Villejuif, France
Bruno Roche
Centre Hépato-Biliaire, Université Paris-Saclay, Unité Inserm 1193, Hôpital Paul-Brousse, Assistance Publique-Hôpitaux de Paris (AP-HP), Villejuif, France
Jean-Yves Mabrut
Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052, CNRS UMR 5286, Université Claude Bernard Lyon 1, Lyon, France; Service de Chirurgie Générale et Transplantation Hépatique, Hôpital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France
Vincent Leroy
Service d’Hépato-gastro-entérologie, Hôpital Grenoble-Alpes, Grenoble, France
Georges-Philippe Pageaux
Département d’Hépatologie et Transplantation Hépatique, CHU Saint-Eloi, Montpellier, France
Rodolphe Anty
Université Côte d’Azur, pôle digestif CHU de Nice, INSERM, U1065, C3M, Nice, France
Sylvie Thevenon
Centre de Recherche Clinique, Hôpital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France
Sinafa Si Ahmed
Service d’Hépatologie, Hôpital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France
Aaron Hamilton
Roche Molecular Diagnostics, Pleasanton, CA, USA
Marintha Heil
Roche Molecular Diagnostics, Pleasanton, CA, USA
Caroline Scholtès
Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052, CNRS UMR 5286, Université Claude Bernard Lyon 1, Lyon, France; Service de Virologie, Hôpital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France
Massimo Levrero
Service d’Hépatologie, Hôpital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France; Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052, CNRS UMR 5286, Université Claude Bernard Lyon 1, Lyon, France
Barbara Testoni
Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052, CNRS UMR 5286, Université Claude Bernard Lyon 1, Lyon, France; Corresponding authors. Address: INSERM U1052, 151, Cours Albert Thomas, 69008 Lyon, France. Tel.: +33-4-72-68-19-70; Fax: +33-4-72-68-19-71.
Fabien Zoulim
Service d’Hépatologie, Hôpital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France; Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052, CNRS UMR 5286, Université Claude Bernard Lyon 1, Lyon, France; Corresponding authors. Address: INSERM U1052, 151, Cours Albert Thomas, 69008 Lyon, France. Tel.: +33-4-72-68-19-70; Fax: +33-4-72-68-19-71.
Background & Aims: Prophylaxis with nucleos(t)ide analogues (NUCs) and hepatitis B immunoglobulin (HBIG) has decreased the rate of HBV recurrence after orthotopic liver transplantation (OLT), but the duration of this prophylaxis remains debated. Our aim was to investigate the recurrence of both intrahepatic and serum HBV markers after OLT in patients receiving long-term NUC and HBIG prophylaxis. Methods: A total of 31 HBV-positive patients benefiting from OLT were prospectively enrolled in five French centres between 2012 and 2015. Tissue samples from the native liver, liver reperfusion biopsy, and 12-month post-OLT (M12) biopsy were collected. Intrahepatic HBV markers were quantified using Droplet Digital PCR. Serum hepatitis B core-related antigen (HBcrAg) and HBsAg were quantified using the Lumipulse platform. Results: Among the 31 patients, 26 were HBeAg negative and 28 had undetectable serum HBV DNA at OLT. All patients received HBIG and NUC after OLT, and serum HBV DNA was undetectable at M12. Of the 27 available native livers, 26 had detectable total HBV DNA (median, 0.045 copies/cell), 21 were positive for cccDNA (0.001 copies/cell), and 19 were positive for 3.5-kb HBV RNA (0.0004 copies/cell). Among the 14 sequential reperfusion and M12 biopsies, seven were positive for HBV markers on the reperfusion sampling, and six of them were also positive at M12. Of the 27 patients with available serum samples at M12, eight were positive for HBcrAg and five were positive for HBsAg by ultrasensitive quantification, although they were negative by conventional techniques. Overall, among the 17 patients having a matched biopsy and serum sample at M12, only one had undetectable HBV markers in both the liver and serum. Conclusions: Our results demonstrate a very early detection of viral genome in the graft and intrahepatic viral recurrence despite NUC and HBIG prophylaxis. Clinical Trials Registration: This study is registered at ClinicalTrials.gov (NCT02602847). Impact and Implications: In this work, we show that, despite the recommended prophylaxis based on NUC and HBIG, HBV can infect the new liver very rapidly after transplantation. Twelve months after transplantation, the majority of patients had at least one HBV marker detected in either serum or the liver. Therefore, our results demonstrate early intrahepatic viral recurrence despite NUC and HBIG therapy and underline the importance of an optimal patient compliance to the antiviral prophylaxis to prevent viral rebound.