Risk of inhibitors in haemophilia and the type of factor replacement

Abstract

Inhibitors in haemophilia are a serious complication that may render usual replacement therapy ineffective. The risk is greatest in previously untreated children with severe haemophilia A. The role of replacement factor VIII in this group is an important issue. Until now, few clinical studies have correctly taken into account the variety of cofactors involved in inhibitor development: genetic (familial antecedents, ethnicity, F8 and immune response genotypes), and environmental cofactors (age at first infusion, prophylaxis and intensity of treatment). This is a prerequisite to correctly evaluating the putative role of the type of factor replacement. Prospective cohort studies are therefore urgently needed. Depending on the expected inhibitor risk in the reference group, the intensity of the relationship between risk factor and endpoint, the duration of patient follow up, and the design of the study (balanced or unbalanced groups), cohorts including 200-500 previously untreated children should be sufficient to demonstrate an increased intensity of risk of about 2 or more with one product compared with another. Aside from clinical studies, fundamental research is essential to test the multiple hypotheses that could explain a difference in inhibitor risk between the currently available factor VIII concentrates in order to develop less immunogenic factor VIII.