Incidence of inhibitors in haemophilia A patients – a review of recent studies of recombinant and plasma‐derived factor VIII concentrates

Abstract

The development of inhibitors to factor VIII or IX is the most serious complication of haemophilia therapy. While early surveys revealed inhibitor prevalences of 3.6-25%, recent studies, especially those using recombinant DNA-derived products, have prompted speculation as to whether ultrapurified products may cause a higher incidence of inhibitors. Although studies of ultrapure rFVIII in previously treated patients have not shown an increased inhibitor risk, in previously untreated patients (PUPs) with severe haemophilia A (factor VIII < 2%), cumulative incidences of approximately 30% have been reported. The majority of these inhibitors are low responders; many have disappeared spontaneously despite continued treatment with the study product (i.e. transient inhibitors), and were most probably detected as a consequence of frequent inhibitor testing. The mutation causing haemophilia has recently been shown to be a significant risk factor for developing an inhibitor; mutations leading to the absence of endogenous factor VIII protein (for example, large multidomain deletions, nonsense mutations, isochromosomal intron 22 inversions) are associated with the highest risk of inhibitor development. Furthermore, recent prospective studies of plasma-derived products reveal inhibitor incidences (i.e. 21-52%) that are comparable to those obtained with recombinant products. When comparing the incidences of high-responder inhibitors (> 10 BU) among recent prospectively studied severe haemophilia A cohorts (i.e. 11-41%), differences between plasma-derived and recombinant products cannot be discerned. New studies of either recombinant or plasma-derived products should consider all known parameters influencing inhibitor formation, thereby facilitating meaningful comparisons of inhibitor risk.

Prevalence of small rearrangements in the factor VIII gene F8C among patients with severe hemophilia A

“…Up to 35-40% of subjects with severe hemophilia A develop a factor VIII inhibitor at some stage in their treatment [reviewed by Scharrer et al, 1999 andOldenburg et al, 2000]. Collection of more data on possible factors influencing the inhibitor formation is therefore very important on order to allow correct assessment of inhibitor risk.…”

“…Moderate (factor VIII activity 2-5% of normal) and mild hemophilia A (factor VIII activity 5-30% of normal) occur in about 10% and 30-40% of patients respectively. It has been reported that individuals receiving recombinant factor VIII therapy develop antibodies (s.c. "inhibitors" of factor VIII), leading to autoantibody production against the endogenous protein [reviewed by Scharrer et al, 1999]. The question of correlation between autoimmune response and type of molecular defect in this coagulation factor is still open.…”

Muscle creatine kinase/SV40 hybrid promoter for muscle-targeted long-term transgene expression

“…SEAP activity can be monitored in a plasma-based assay that allows longterm surveillance of the gene expression profile without sacrificing the animals. We chose the human gene, and not mouse SEAP, due to the immunogenicity of human SEAP in mice (28,29); this protocol mimics the conditions in gene therapy for congenital protein deficiencies, since proteins responsible for congenital deficiencies are often recognized as foreign by the immune system (30)(31)(32). SEAP expression profiles in mice that received intramuscular electrotransfer of a human SEAP expression plasmid are shown in Fig.…”

Therapeutic choices for patients with hemophilia and high‐titer inhibitors

“…The incidence of inhibitors in severe hemophilia A is reported to be as high as 20%-52% [1,2] and in hemophilia B is 1.5%-3% [3]. Therapeutic approaches are often based on inhibitor titers as well as response to factor challenge.…”