title: Can B-domain deletion alter the immunogenicity of recombinant factor VIII? A meta-analysis of prospective clinical studies.
abstract: BACKGROUND
  As a result of the infrequency of inhibitors in previously treated patients (PTPs) with hemophilia A and the small size of available clinical studies, the immunogenicity of factor (F)VIII products has been difficult to assess.
  
  
  OBJECTIVE
  A meta-analysis of prospective clinical studies was conducted to test the hypothesis that de novo inhibitor incidence differs between PTPs receiving full-length recombinant FVIII (FL-rFVIII) and B-domain deleted recombinant FVIII (BDD-rFVIII).
  
  
  METHODS
  Prospective studies with data on inhibitors in PTPs receiving FL-rFVIII or BDD-rFVIII were sought using systematic methods including bibliographic database searches. Data were secured from published study reports and inquiries to investigators. Between-group differences in inhibitor incidence rates were evaluated using mixed effects Cox regression.
  
  
  RESULTS
  Twenty-nine studies with 3012 total PTPs were included. Patients were at risk of de novo inhibitor development for a median of 79 exposure days. A total of 35 de novo inhibitors were observed. The cumulative hazard for all de novo inhibitors was 1.25% with a 95% confidence interval (CI) of 0.63-1.88%. The corresponding rate for high-titer de novo inhibitors [> 5 Bethesda units (BU)] was 0.29% (CI, 0.01-0.57%). Exposure to BDD-rFVIII was associated with an increased risk of all de novo inhibitors (hazard ratio, 7.26; CI, 2.12-24.9; P = 0.0016) and of high-titer de novo inhibitors (hazard ratio, 10.8; CI, 2.17-53.7; P = 0.0037), compared with FL-rFVIII.
  
  
  CONCLUSIONS
  This meta-analysis of prospective clinical studies suggests that recombinant FVIII products may differ in immunogenicity.
authors.affiliation: Mount Sinai School of Medicine, New York, NY 10029-6574, USA. louis.aledort@mountsinai.org
authors.forename: L M
authors.initials: LM
authors.lastname: Aledort
authors.forename: R J
authors.initials: RJ
authors.lastname: Navickis
authors.forename: M M
authors.initials: MM
authors.lastname: Wilkes
mesh_terms: D000906:Antibodies / Q000032:analysis; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data*; D003625:Data Collection; D005169:Factor VIII / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D006467:Hemophilia A / Q000188:drug therapy / Q000276:immunology; D006801:Humans; D055261:Immunogenetic Phenomena; D011994:Recombinant Proteins; D017384:Sequence Deletion
chemical_list: D000906:Antibodies; D011994:Recombinant Proteins; D005169:Factor VIII