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

The development of inhibitors to factor VIII or IX is the most serious comp lication of haemophilia therapy. While early surveys revealed inhibitor pre valences of 3.6-25%, recent studies, especially those using recombinant DNA -derived products, have prompted speculation as to whether ultrapurified pr oducts may cause a higher incidence of inhibitors. Although studies of ultr apure rFVIII in previously treated patients have not shown an increased inh ibitor risk, in previously untreated patients (PUPs) with severe haemophili a A (factor VIII < 2%), cumulative incidences of approximately 30% have bee n reported. The majority of these inhibitors are low responders; many have disappeared spontaneously despite continued treatment with the study produc t (i.e. transient inhibitors), and were most probably detected as a consequ ence of frequent inhibitor testing. The mutation causing haemophilia has re cently been shown to be a significant risk factor for developing an inhibit or; mutations leading to the absence of endogenous factor VIII protein (for example, large multidomain deletions, nonsense mutations, isochromosomal i ntron 22 inversions) are associated with the highest risk of inhibitor deve lopment. Furthermore, recent prospective studies of plasma-derived products reveal inhibitor incidences (i.e. 21-52%) that are comparable to those obt ained with recombinant products. When comparing the incidences of high-resp onder inhibitors (> 10 BU) among recent prospectively studied severe haemop hilia A cohorts (i.e. 11-41%), differences between plasma-derived and recom binant products cannot be discerned. New studies of either recombinant or p lasma-derived products should consider all known parameters influencing inh ibitor formation, thereby facilitating meaningful comparisons of inhibitor risk.