Timing and severity of inhibitor development in recombinant versus plasma-derived factor VIII concentrates: a SIPPET analysis
Inhibitor development remains a significant problem in congenital hemophilia, with a multi-factorial etiology. The SIPPET trial demonstrated that the risk of inhibitors was nearly twice as high with recombinant products as compared to plasma-derived. While most inhibitors developed within the first 20 exposure days (ED), there is little data in the literature on the time course of inhibitor development.
SIPPET was a randomized trial comparing recombinant and plasma-derived (von Willebrand containing) factor replacement products for their risk of inhibitor development. This post-hoc analysis examined the results of frequent inhibitor testing done on the included patients. Inhibitors were assessed every 3-4 EDs for patients treating on demand and every 2 weeks for patients on prophylaxis, or as clinically indicated.
All inhibitors occurred within 39 ED and 90% within 20 ED (34 and 16 ED respectively for high-titre inhibitors). Inhibitors occurred earlier with recombinant products, peaked at a higher level, and persisted longer. In the first 5 EDs, the hazard ratio for recombinant products was 3.14 for all inhibitors and 4.19 for high-titre. Evaluation of the severity of the immunogenic effect also revealed an increasing hazard ratio for recombinant products with increasing Bethesda titres.
This is a post-hoc analysis of a relatively small sample pool. Because the comparison is between high-purity recombinant product and von Willebrand containing plasma derived product, the role of von Willebrand factor cannot be determined (which may be a relevant consideration in immunogenicity).