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NEJM Article, Factor VIII Products and Inhibitor Development in Severe Hemophilia A

BACKGROUND

For previously untreated children with severe hemophilia A, it is unclear whether the type of factor VIII product administered and switching among products are associated with the development of clinically relevant inhibitory antibodies (inhibitor development).

METHODS

We evaluated 574 consecutive patients with severe hemophilia A (factor VIII activity, <0.01 IU per milliliter) who were born between 2000 and 2010 and collected data on all clotting-factor administration for up to 75 exposure days. The primary outcome was inhibitor development, which was defined as at least two positive inhibitor tests with decreased in vivo recovery of factor VIII levels.

RESULTS

Inhibitory antibodies developed in 177 of the 574 children (cumulative incidence, 32.4%); 116 patients had a high-titer inhibitory antibody, defined as a peak titer of at least 5 Bethesda units per milliliter (cumulative incidence, 22.4%). Plasma-derived products conferred a risk of inhibitor development that was similar to the risk with recombinant products (adjusted hazard ratio as compared with recombinant products, 0.96; 95% confidence interval [CI], 0.62 to 1.49). As compared with third-generation full-length recombinant products (derived from the full-length complementary DNA sequence of human factor VIII), second-generation full-length products were associated with an increased risk of inhibitor development (adjusted hazard ratio, 1.60; 95% CI, 1.08 to 2.37). The content of von Willebrand factor in the products and switching among products were not associated with the risk of inhibitor development.

CONCLUSIONS

Recombinant and plasma-derived factor VIII products conferred similar risks of inhibitor development, and the content of von Willebrand factor in the products and switching among products were not associated with the risk of inhibitor development. Second-generation full-length recombinant products were associated with an increased risk, as compared with third-generation products. (Funded by Bayer Healthcare and Baxter BioScience.)

Samantha C. Gouw, M.D., Ph.D., Johanna G. van der Bom, M.D., Ph.D., Rolf Ljung, M.D., Ph.D., Carmen Escuriola, M.D., Ana R. Cid, M.D., Ségolène Claeyssens-Donadel, M.D., Christel van Geet, M.D., Ph.D., Gili Kenet, M.D., Anne Mäkipernaa, M.D., Ph.D., Angelo Claudio Molinari, M.D., Wolfgang Muntean, M.D., Rainer Kobelt, M.D., George Rivard, M.D., Elena Santagostino, M.D., Ph.D., Angela Thomas, M.D., Ph.D., and H. Marijke van den Berg, M.D., Ph.D. for the PedNet and RODIN Study Group.

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