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.