Response: Immunogenicity of factor VIII concentrates in patients with hemophilia: the next sensible step

Ever since the introduction of recombinant factor VIII products in the late 1980s, physicians have wondered whether such products carry a higher risk of inhibitory antibodies than the factor VIII products derived from human plasma. The reported incidences of inhibitors in the cohorts of patients in whom the effectiveness and safety of recombinant products was assessed were higher than the reported incidences in cohorts that were treated with plasma-derived products. Yet, this may have been due to more frequent and more sensitive testing for the presence of inhibitors in the cohorts on recombinant products. At present, the clinical significance of these otherwise undetected inhibitors is unclear.

Thus far, 3 observational studies have directly compared the incidence of inhibitors in patients on either product type. All 3 studies revealed a point estimate in the same direction, namely a higher risk of inhibitors in the patients on recombinant products. However, the size of these point estimates differed considerably.^1-3 Table 1 presents the risk of developing inhibitors according to the use of plasma-derived or recombinant factor VIII products in the 3 reports. The challenge now is to combine the knowledge derived from these 3 studies in order to increase the relevance of our future studies on the topic.

Considering the specific critiques of Gringeri and Mannucci, we agree that our demonstration of equivalent immunogenicity of products with considerable contents of von Willebrand factor compared with recombinant products did not definitively settle the issue of plasma-derived versus recombinant products.³  Yet, our findings clearly show that, on average, the incidence of inhibitors among patients on a large variety of plasma-derived products is not much lower than the incidence among patients on different recombinant products. These findings combined with the know-ledge derived from the studies of Goudemand et al¹  and Chalmers et al²  suggest that some, but not all, plasma-derived products may indeed carry a lower risk of inhibitor development than other products. In addition, we have learned from the Concerted Action on Neutralizing Antibodies in severe hemophilia A patients (CANAL) study³  that it may be a fallacy to believe that the presence of von Willebrand factor in a product prevents the occurrence of inhibitors.

Gringeri and Mannucci suggest that a randomized clinical trial will provide a definite answer on the comparison of immuno-genicities of factor VIII products. In our view, the next relevant question is not whether plasma-derived products have a lower risk of inhibitors but rather which plasma-derived products carry a lower risk of inhibitors and why. It may be worth reanalyzing the CANAL study³  data in order to explore the potential effects of different production processes of the plasma-derived products on the risk of inhibitors.

Finally, it may be questioned whether plasma-derived products should be studied for their effects on the risk of developing inhibitors at all. Many countries have abandoned the use of plasma-derived products in young children because of the, albeit small, risk of transmission of infectious agents. It may be more relevant to compare the different recombinant products and to further examine the effect of genetic and nongenetic risk factors for inhibitor development, such as the potentially preventive effect of early prophylaxis. Findings from the latter studies may have a major impact on the prevention of inhibitors of future patients with severe hemophilia.