Comparative effectiveness of full‐length and B‐domain deleted factor VIII for prophylaxis – a meta‐analysis

Abstract

Recently reported data suggest the possibility of differences in clinical efficacy between full-length factor VIII (FL-FVIII) and B-domain deleted recombinant factor VIII (BDD-rFVIII). To address this question, we conducted a meta-analysis of studies reporting the incidence of bleeding under prophylaxis, as well as studies of FL-FVIII and BDD-rFVIII half-life. The pooled cumulative weekly prophylactic dose of BDD-rFVIII (81.3 +/- 13.8 IU kg(-1) week(-1)) was greater by 36% (P = 0.11) than that of FL-FVIII (60.0 +/- 5.9 IU kg(-1) week(-1)). The pooled incidence of bleeding in BDD-rFVIII recipients [16.8 bleeds per patient year; confidence interval (CI), 9.5-24.2 bleeds per patient year] was more than 2.5-fold larger (P < 0.0005) than that in patients receiving FL-FVIII (6.6 bleeds per patient year; CI, 4.7-8.5 bleeds per patient year). In a multivariate analysis, the incidence rate ratio was 2.10 (CI, 1.98-2.24), indicating that breakthrough bleeding under prophylaxis was more than twice as likely with BDD-rFVIII than FL-FVIII at equivalent doses and ages. The pooled half-life for plasma-derived FL-FVIII (13.7 h; CI, 12.8-14.6 h) was closely similar to that for recombinant FL-FVIII (14.3 h; CI, 13.3-15.4 h). By contrast, the pooled half-life for BDD-rFVIII (11.3 h; CI, 9.9-12.7 h) was shorter by approximately 3 h compared with FL-FVIII. Although the results of the meta-analysis need to be interpreted with caution, the pooled data suggest that breakthrough bleeding under prophylaxis may occur more frequently in patients receiving BDD-rFVIII than FL-FVIII and may at least partly reflect a more abbreviated half-life of BDD-rFVIII. Several biochemical differences between BDD-rFVIII and FL-FVIII may underlie the observed disparities in bleeding incidence and half-life. This meta-analysis should be confirmed by further studies.

Increased breakthrough bleeding during prophylaxis with B‐domain deleted factor VIII – a robust meta‐analytic finding

“…Keywords: factor VIII, haemophilia A, haemorrhage, half-life, meta-analysis, protein engineering We earlier reported the results of a meta-analysis suggesting reduced haemostatic efficacy during prophylaxis and shortened half-life of B-domain deleted factor VIII (BDD-rFVIII) when compared with fulllength (FL)-FVIII [1]. We included 13 studies in the meta-analysis and extracted data on annual incidence of bleeding episodes during prophylaxis.…”

An engineered EBV vector expressing human factor VIII and von Willebrand factor in cultured B‐cells

“…Functional activity of FVIII secreted in culture medium from the cells carrying the vector as confirmed by a chromogenic assay, (COATEST VIII: C/4, Chromogenix) indicated that even full-length FVIII is processed in these B-cell lines. Recent prophylaxis analysis comparing the effectiveness of full-length and B-domaindeleted factor VIII indicates that bleeding may occur more frequently in patients receiving B-domain-deleted recombinant FVIII than full-length FVIII and suggests the effectiveness and stability of the full-length version [16]. Although a 10% increase in FVIII level in our in vitro cell model is rather modest, clinical application of this technology would be through a hematopoietic stem cell transplant.…”

Functional roles of the factor VIII B domain

“…Accelerated inactivation of BDD-rFVIII, as well as accelerated activation by thrombin, would necessitate either higher doses or more frequent dosing. A 2003 meta-analysis did demonstrate increased bleeding incidence associated with the use of BDD-rFVIII compared with full-length FVIII for prophylaxis [40].…”

“…While some explanatory factors, such as ABO blood group, have been identified, the reasons for this variability are still poorly understood. A metaanalysis of 27 pharmacokinetic studies suggested that BDD-rFVIII may have a shorter circulating half-life than full-length FVIII [40]. An acknowledged limitation of the meta-analysis was the scarcity of available data derived from direct comparison between FVIII types in the same study.…”