Surveillance for factor VIII inhibitor development in the Canadian Hemophilia A population following the widespread introduction of recombinant factor VIII replacement therapy.

In the Fall of 1994 the majority of Canadian Hemophilia A (Factor VIII (F.VII) deficiency) patients who were receiving replacement therapy were converted to Recombinant Factor VIII (rF.VIII) from plasma derived products. This decision was taken and funded by the Canadian Blood Agency following the advice of the Association of Hemophilia Centre Directors of Canada (AHCDC) who considered this to be the safest replacement therapy available. Although it was the considered opinion of the AHCDC that there was no evidence available to support the theoretical concern that rF.VIII may prove more immunogenic than plasma derived products, patient follow up included intensive surveillance of all patients converted for this complication. A central reference laboratory was established and plasma specimens obtained before and 6-12 months following conversion to rF.VIII were referred for evaluation for inhibitor development by the classical Bethesda Assay. By concensus of the referring centers a Bethesda Unit (BU)/activity of 0.5 or greater was considered to be clinically significant. No increase in the incidence of inhibitor development has been recorded in 478 patients followed for one year after conversion. This pattern has not changed in 339 of these patients followed for a further year. Of interest was the finding by the reference laboratory that 8.0% of patients had BU activity of 0.5 or greater before conversion to rF.VIII. Many of these individuals lost this activity after conversion to rF.VIII as did others who appeared to have developed inhibitory activity during the first year of follow up but became inhibitor free in the second year of therapy. Overall, the incidence of true inhibitor development, i.e. negative pre-/positive post-conversion to rF.VIII, in this population of Hemophilia A patients was 2-3% over 2 years. This is similar to the incidence in patients treated with plasma derived products. These data emphasize the need for rigorous baseline evaluation in such investigations and the heterogeneity of the inhibitor response as assessed by in vitro assay. It was concluded that, although no attempt was made to correlate these in vitro data with clinical observations including F.VIII recovery and survival, the use of rF.VIII in hemophiliacs previously treated with plasma derived products was not associated with an increase in F.VIII inhibitor development.