Recombinant factor VIII products and inhibitor development in previously untreated boys with severe hemophilia A

Thierry Calvez, Hervé Chambost, Ségolène Claeyssens-Donadel, Roseline d'Oiron, Véronique Goulet, Benoît Guillet, Virginie Héritier, Vanessa Milien, Chantal Rothschild, Valérie Roussel-Robert, Christine Vinciguerra and Jenny Goudemand

Key points

  • A currently marketed recombinant FVIII product is associated with a higher risk of inhibitor development in boys with severe hemophilia A

  • This result, validated by extensive sensitivity analyses, confirms a recently published study and cannot be explained by identified biases


Six recombinant factor VIII (rFVIII) products have been marketed worldwide. In January 2013 the Research of Determinants of Inhibitor Development (RODIN) study group reported an unexpectedly high risk of inhibitor development with a so-called second-generation full-length rFVIII (Product "D") in previously untreated patients (PUPs) with severe hemophilia A (HA). A prospective cohort was established by French public health authorities in 1994 to monitor hemophilia treatment safety. A PUP subgroup was specifically designed to investigate risk factors for inhibitor development. We analyzed our cohort dataset in view of the RODIN findings. After excluding 50 patients who also participated in the RODIN study, the primary analysis focused on 303 severe HA boys 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 versus the most widely used rFVIII product (adjusted-HR 1.55, 95%CI 0.97-2.49). Similar results were found for high-titer inhibitors and in ten sensitivity analyses. No heterogeneity was observed between RODIN and FranceCoag 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 versus other rFVIII products in PUPs with severe HA.

  • Submitted July 2, 2014.
  • Accepted September 7, 2014.