Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A

ArticleinHaemophilia 13(2):149-55 · April 2007with10 Reads
DOI: 10.1111/j.1365-2516.2006.01418.x · Source: PubMed
Abstract
Recent reports have suggested that the incidence of inhibitors in haemophilia is the highest in those first exposed to factor VIII under 6 months of age. In this study, we investigated inhibitor development in children first exposed to FVIII as neonates and also examined the effect of other genetic and environmental variables. Three hundred and forty-eight children with severe haemophilia A were investigated. Inhibitors developed in 68 of 348 (20%), with 34 of 348 (10%) high titre inhibitors. The incidence in relation to initial FVIII exposure was: <1 month nine of 35 (26%), 1-6 months 13 of 51 (25%), 6-12 months 27 of 130 (21%), 12-18 months 13 of 66 (20%) and >18 months six of 66 (9%). While we observed a significant difference in inhibitor development and age at first exposure across all age groups (P = 0.018), no significant difference was observed in children treated at different time points during the first year of life (P = 0.44). Similar results were obtained for high titre inhibitors. There was also no difference in the incidence of inhibitors in relation to initial FVIII exposure in a subgroup of 144 children with the intron 22 mutation. Inhibitors developed more frequently in those initially treated with recombinant when compared with plasma-derived FVIII (P = 0.006) and in those with a major molecular defect (P = 0.009). In this study, exposure to FVIII during the neonatal period was not associated with a higher incidence of inhibitors than those treated later during the first year of life. Initial treatment with recombinant FVIII and the presence of a major molecular defect were the most important variables affecting inhibitor development.
    • "There is an ongoing debate as to whether or not the administration of rFVIII concentrates is associated with increased rates of inhibitors in previously untreated patients (PUPs). Wight and Paisley provoked further debate in 2003 with a review that revealed a significant difference in inhibitor incidence between single pdFVIII and rFVIII products; a number of cohort studies followed, which reported a lower inhibitor incidence with pdFVIII than with rFVIII use101112131415 . A review and metaanalysis published in 2010 by Iorio found a significant difference between pdFVIII and rFVIII products in a univariate, but not in a multivariate analysis [16]. "
    Full-text · Article · Jan 2016
    • "There is an ongoing debate as to whether or not the administration of rFVIII concentrates is associated with increased rates of inhibitors in previously untreated patients (PUPs). Wight and Paisley provoked further debate in 2003 with a review that revealed a significant difference in inhibitor incidence between single pdFVIII and rFVIII products; a number of cohort studies followed, which reported a lower inhibitor incidence with pdFVIII than with rFVIII use101112131415 . A review and metaanalysis published in 2010 by Iorio found a significant difference between pdFVIII and rFVIII products in a univariate, but not in a multivariate analysis [16]. "
    Full-text · Article · Jan 2016 · Thrombosis Research
    • "There is an ongoing debate as to whether or not the administration of rFVIII concentrates is associated with increased rates of inhibitors in previously untreated patients (PUPs). Wight and Paisley provoked further debate in 2003 with a review that revealed a significant difference in inhibitor incidence between single pdFVIII and rFVIII products; a number of cohort studies followed, which reported a lower inhibitor incidence with pdFVIII than with rFVIII use [10][11][12][13][14][15] . A review and metaanalysis published in 2010 by Iorio found a significant difference between pdFVIII and rFVIII products in a univariate, but not in a multivariate analysis [16]. "
    [Show abstract] [Hide abstract] ABSTRACT: Introduction: VONCENTO® (CSL Behring) is a plasma-derived, high-concentration, low-volume, high-purity concentrate, which contains a high level of von Willebrand factor (VWF) high-molecular-weight multimers and a VWF/factor VIII (FVIII) ratio of ∼2.4:1, similar to Haemate® P (CSL Behring). Methods: The pharmacokinetic, efficacy and safety profiles of VONCENTO®were investigated in this multicentre, double-blind, randomised study. Subjects aged ≥12 years with haemophilia A who required treatment of nonsurgical bleeds, treatment during surgical events or who were receiving prophylaxis were included. Pharmacokineticswere investigated with a single dose of 50 IU FVIII/kg body weight of either VONCENTO® or BIOSTATE® reference product (Biostate-RP) (Day 1; Day 8 [n= 16], repeated on Day 180 [VONCENTO® only; n=15]). Efficacy and safety analyseswere performed either during on-demand treatment (n=52) or prophylaxis (n=29) for ≥6 months and ≥50 exposure days, respectively. Results: Besides the confirmation of bioequivalence between VONCENTO® and Biostate-RP, which displayed comparable PK profiles, haemostatic efficacy was rated by the investigators as either excellent or good in 96.4% of all bleeding events (96.5% spontaneous, 96.6% traumatic, 96.9% joint bleeds) as well as in 80% of major and 100% of minor surgical procedures at discharge. The median number of annualised bleeding events per subject [range] was significantly lower in the prophylaxis group (2.0 [0.0-34.6]) than in the on-demand group (14.0 [0.0-87.8], p = 0.0013).VONCENTO® was well tolerated and no inhibitory antibodies were identified during the study period. Conclusions: This study demonstrated the bioequivalence of VONCENTO® to Biostate-RP, and its excellent efficacy and safety profile in haemophilia A subjects.
    Full-text · Article · Oct 2015
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