Incidence and risk factors for inhibitor development in previously untreated severe haemophilia A patients born between 2005 and 2010

Abstract

The objective of this study was to evaluate the inhibitor development (ID) in previously untreated patients (PUPs) with severe haemophilia A (FVIII ≤ 0.01 IU mL(-1) ). All Canadian Haemophilia Treatment Centres completed a questionnaire on patients born between September 2005 and August 2010 and followed for up to 7 years. Eligible patients had at least 20 exposure days (ED) or had developed an inhibitor. The odds ratio (OR) and 95% confidence intervals (95% CI) for risk factors to develop an inhibitor were estimated using unconditional logistic regression. A total of 99 haemophilia A PUPs were studied. Thirty-four (34%) developed an inhibitor (24/34 of high titre). Inhibitors developed in 25/63 (40%) patients with a high-risk mutation. ID was most frequent in Aboriginals (86%). Dose intensity (IU kg(-1) day(-1) X number of ED) at first exposure to factor VIII (FVIII) was associated with a crude OR increase of 1.10 (95% CI: 0.99-1.23) with each increase of 100 dose-intensity units. Haemarthrosis and intracranial bleeding as the indication for first exposure to FVIII concentrate were associated with a crude OR for ID of 7.63 (95% CI: 2.14-27.17) and 5.08 (95% CI: 1.11-23.31) respectively. ID according to FVIII concentrate used was: Advate (®) 18/50 (36%), Kogenate FS(®) or Helixate FS(®) 15/36 (42%), Wilate(®) 0/11 and Xyntha(®) 1/2. In multivariate analysis, Aboriginal ethnicity (OR = 11.69; 95% CI: 1.11-122.86) and haemarthrosis (OR = 4.49; 95% CI: 1.08-18.61) were statistically significant. The cumulative incidence of ID in severe haemophilia A PUPs was 34% and varied according to ethnicity, type of bleeding at first ED, type of FVIII product and dose intensity at first exposure.

Product type and other environmental risk factors for inhibitor development in severe hemophilia A

“…Subsequently, this higher immunogenicity observed for second‐generation full‐length recombinant products was confirmed in a cohort of patients included in the Rèseau FranceCoag and in the UK children registered in the UKHCDO National Haemophilia Database (NHD) and most recently in the FranceCoag PUP cohort . Two additional studies, the EUHASS study and a Canadian cohort study, who also investigated the higher immunogenicity of the second‐generation recombinant products, did not confirm the RODIN data, but were small or did not inform adjustment for confounding. Subsequently, an attempt was made to reconcile these contrasting results.…”

An update on the ‘danger theory’ in inhibitor development in hemophilia A

“…• Peak treatment for bleeding is not unequivocal related to an increased inhibitor risk in cohort studies of PUPs with severe hemophilia. [4,22,80,81] Conflictory results…”

Recombinant factor VIII products and inhibitor development in previously untreated patients with severe haemophilia A: Combined analysis of three studies

“…There is an ongoing debate whether certain brands of factor VIII may be associated with an increased risk of inhibitor development in previously untreated patients (PUPs) with severe haemophilia A . The results of the Research of Determinants of Inhibitor Development (PedNet study group) , the FranceCoag Network and the UK Haemophilia Centre Doctors' Organisation (UKHCDO) study groups consistently indicated an increased risk for inhibitor development following treatment with the second‐generation full‐length recombinant factor VIII product (rFVIII).…”