title: Recombinant factor VIII products and inhibitor development in previously untreated boys with severe hemophilia A.
abstract: Six recombinant factor VIII (rFVIII) products have been marketed worldwide. In 2013, the Research of Determinants of Inhibitor Development (RODIN) study group reported an unexpectedly high risk of inhibitor development with a second-generation full-length rFVIII (Product D) in previously untreated patients (PUPs) with severe hemophilia A (HA). In 1994, French public health authorities established a prospective cohort to monitor hemophilia treatment safety. A PUP subgroup was designed to investigate inhibitor risk factors. We analyzed this subcohort in view of the RODIN findings. After excluding 50 patients who participated in the RODIN study, the primary analysis focused on 303 boys with severe HA first treated with a rFVIII product. A clinically significant inhibitor was detected in 114 boys (37.6%). The inhibitor incidence was higher with Product D vs the most widely used rFVIII product (adjusted hazard ratio [aHR], 1.55; 95% confidence interval [CI], 0.97-2.49). Similar results were found for high-titer inhibitors and in 10 sensitivity analyses. No heterogeneity was observed between RODIN and our results. Combined aHRs were 1.58 (95% CI, 1.17-2.14) for all inhibitors and 1.70 (95% CI, 1.15-2.52) for high-titer inhibitors. Our results confirm the higher immunogenicity of Product D vs other rFVIII products in PUPs with severe HA.
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Unité Mixte de Recherche en Santé 1136, Institut Pierre Louis d'Épidemiologie et de Santé Publique, Paris, France; INSERM, Unité Mixte de Recherche en Santé 1136, Institut Pierre Louis d'Épidemiologie et de Santé Publique, Paris, France;
authors.forename: Thierry
authors.initials: T
authors.lastname: Calvez
authors.affiliation: Service d'Hématologie Oncologie Pédiatrique, La Timone, Assistance Publique-Hôpitaux de Marseille, Marseille, France; INSERM, Unité Mixte de Recherche 1062, Faculté de Médecine, Aix-Marseille Université, Marseille, France;
authors.forename: Hervé
authors.initials: H
authors.lastname: Chambost
authors.affiliation: Centre Régional d'Hémophilie, Centre Hospitalier Universitaire, Toulouse, France;
authors.forename: Ségolène
authors.initials: S
authors.lastname: Claeyssens-Donadel
authors.affiliation: Centre Régional d'Hémophilie, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Le Kremlin Bicêtre, France;
authors.forename: Roseline
authors.initials: R
authors.lastname: d'Oiron
authors.affiliation: French Institute for Public Health Surveillance, Saint-Maurice, France;
authors.forename: Véronique
authors.initials: V
authors.lastname: Goulet
authors.affiliation: Centre Régional de Traitement des Maladies Hémorragiques de Rennes-Bretagne, Centre Hospitalier Universitaire de Rennes et Rennes 1 Université, Faculté de Médecine, Rennes, France;
authors.forename: Benoît
authors.initials: B
authors.lastname: Guillet
authors.affiliation: French Institute for Public Health Surveillance, Saint-Maurice, France;
authors.forename: Virginie
authors.initials: V
authors.lastname: Héritier
authors.affiliation: Service d'Hématologie Oncologie Pédiatrique, La Timone, Assistance Publique-Hôpitaux de Marseille, Marseille, France;
authors.forename: Vanessa
authors.initials: V
authors.lastname: Milien
authors.affiliation: Centre Régional d'Hémophilie, Assistance Publique-Hôpitaux de Paris, Centre Hospitalier Universitaire de Necker, Paris, France;
authors.forename: Chantal
authors.initials: C
authors.lastname: Rothschild
authors.affiliation: Centre Régional d'Hémophilie, Assistance Publique-Hôpitaux de Paris, Centre Hospitalier Universitaire de Cochin, Paris, France;
authors.forename: Valérie
authors.initials: V
authors.lastname: Roussel-Robert
authors.affiliation: Service d'Hématologie Biologique, Hospices Civils de Lyon, Equipe d'Accueil Mixte 4174, Université de Lyon, Lyon, France;
authors.forename: Christine
authors.initials: C
authors.lastname: Vinciguerra
authors.affiliation: Service d'Hématologie et de Transfusion, Centre Hospitalier Universitaire de Lille, Université Lille 2, Equipe d'Accueil 2693, Faculté de Médecine, Lille, France.
authors.forename: Jenny
authors.initials: J
authors.lastname: Goudemand
mesh_terms: D000917:Antibody Formation; D002675:Child, Preschool; D015331:Cohort Studies; D005169:Factor VIII / Q000276:immunology* / Q000627:therapeutic use*; D005602:France / Q000453:epidemiology; D006467:Hemophilia A / Q000188:drug therapy* / Q000453:epidemiology / Q000276:immunology*; D006801:Humans; D007223:Infant; D008297:Male; D015201:Meta-Analysis as Topic; D011358:Product Surveillance, Postmarketing; D011994:Recombinant Proteins / Q000276:immunology / Q000627:therapeutic use; D012720:Severity of Illness Index
chemical_list: D011994:Recombinant Proteins; C078147:F8 protein, human; D005169:Factor VIII