Inhibitors more likely to develop against recombinant factor VIII than plasma-derived factor VIII: The SIPPET study

1. Early replacement therapy with plasma-derived factor VIII were associated with a lower incidence of inhibitor development than recombinant factor VIII.

2. The difference in inhibitor development is speculated to be associated with decreased immunogenicity due to the presence of von Willebrand factor in plasma-derived factor VIII products.

Evidence Rating Level: 2 (Good)

Study Rundown: Hemophilia A is an inherited coagulopathy in which coagulation factor VIII is deficient. Current management of this condition relies on replacement of factor VIII with an exogenous source. However, in about 30% of patients who receive exogenous factor VIII, alloantibodies (inhibitors) are known to develop. Several explanations for why this occurs in select patients have been put forward, one of which is varying composition between plasma-derived factor VIII, which contains von Willebrand factor, and recombinant factor VIII, which contains no von Willebrand factor. The authors of this paper carried out the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) study to assess differences in the development of factor VIII inhibitors. Males younger than 6-years old that were diagnosed with hemophilia A received between 1 and 50 infusions of plasma-derived factor VIII or recombinant factor VIII. The primary outcome was the development of an inhibitor with a prespecified titer (0.4 to <5 Bethesda units). Secondary outcome was development of high-titer inhibitor (≥5 Bethesda units).

A greater percentage of patients treated with recombinant factor VIII had a positive primary and secondary outcome compared to patients treated with plasma-derived factor VIII. Persistence of the inhibitor, defined as disappearing spontaneously within 6 months, did not differ significantly between the groups.

This study draws strength from its use of regression models, multivariable models, and sensitivity analyses to verify the validity of their raw data. One limitation of the study, though, was the decision to use only one plasma-derived factor VIII and one recombinant factor VIII per country. Another was that the trial was terminated prematurely.

Click to read the study, published today in NEJM

Relevant Reading: Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study

In-Depth [ prospective cohort]: In the SIPPET study, a total of 251 males younger than 6-years-old were randomly assigned in a 1:1 ratio to receive either plasma-derived factor VIII or recombinant factor VIII. Patients who underwent randomization were followed for 50 consecutive exposure days or 3 years or until inhibitor development was confirmed, whichever occurred first. Among the patients treated with plasma-derived factor VIII, 29 out of the 125 had a positive primary outcome (23.2%) and 20 of these had a positive secondary outcome (16.0%). Among the patients treated with recombinant factor VIII, 47 out of the 126 had a positive primary outcome (37.3%) and 30 of these had a positive secondary outcome (23.8%). In Cox regression models, the rate of inhibitor development was 87% higher with recombinant factor VIII than with plasma-derived factor VIII (HR=1.87; 95% [CI], 1.17 to 2.96). For high-titer inhibitors, the HR was 1.69 (95% [CI], 0.96 to 2.98).

Applying a multivariable model to adjust for age, mutation, country, and previous exposure to blood components revealed a HR of 1.95 (95% [CI], 1.21 to 3.15). Applying a multivariable model to adjust for age, mutation, country, and family history revealed a HR of 1.88 (95% [CI], 1.16 to 3.04). For high-titer inhibitors, a model including age, mutation, previous exposure, and country yielded a HR of 1.73 (95% [CI], 0.97 to 3.10); in the second multivariable model, the HR was 1.64 (95% [CI], 0.91 to 2.95).

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