title: Treatment characteristics and the risk of inhibitor development: a multicenter cohort study among previously untreated patients with severe hemophilia A.
abstract: BACKGROUND
  The development of inhibitory antibodies against infused factor (F) VIII is a major complication of treatment of patients with severe hemophilia A.
  
  
  OBJECTIVE
  This study was set up to examine the effects of treatment-related factors on inhibitor development among previously untreated patients with severe hemophilia A.
  
  
  METHODS
  In this multicenter cohort study, we combined individual patient data obtained from four recombinant FVIII product registration studies (Kogenate, Kogenate Bayer, Recombinate, ReFacto) that were performed between 1989 and 2001. From the databases we selected all 236 previously untreated patients with severe hemophilia A who were subsequently treated with FVIII on at least 50 days.
  
  
  METHODS
  Clinically relevant inhibitor development, defined as the occurrence of at least two positive inhibitor titers and a decreased recovery.
  
  
  RESULTS
  67 patients (28%) developed clinically relevant inhibitors (44 high-titer) at a median of ten exposure days. Age at first exposure was not associated with inhibitor development. Peak treatment moments and surgical procedures were related to an increased inhibitor risk [adjusted relative risk 1.6 (95% confidence interval 1.0-2.6) and 2.7 (95% confidence interval 1.3-5.7), respectively]. A shorter duration between exposure days was associated with an increased risk of inhibitor development. There was a possible association between dosing of FVIII and inhibitor development, which largely disappeared after adjustment for confounding factors.
  
  
  CONCLUSIONS
  These findings show that intensive treatment periods are associated with an increased risk of inhibitor development in previously untreated patients with severe hemophilia A. Our results do not support the notion that age at first exposure is associated with the risk of developing inhibitors.
authors: Van Creveldkliniek, and Department of Pediatrics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: S C
authors: SC
authors: Gouw
authors: H M
authors: HM
authors: van den Berg
authors: S
authors: S
authors: le Cessie
authors: J G
authors: JG
authors: van der Bom
mesh_terms: D002675:Child, Preschool; D015331:Cohort Studies; D004342:Drug Hypersensitivity / Q000209:etiology / Q000276:immunology; D005169:Factor VIII / Q000009:adverse effects / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000627:therapeutic use; D006467:Hemophilia A / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D007223:Infant; D007518:Isoantibodies / Q000097:blood; D008297:Male; D011994:Recombinant Proteins / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000276:immunology / Q000627:therapeutic use; D012307:Risk Factors
chemical_list: D007518:Isoantibodies; D011994:Recombinant Proteins; D005169:Factor VIII