Risk Differential in Inhibitor Development in the First Days of Treatment By Product Class: A Sippet Analysis
Authors: Peyvandi Flora , Cannavò Antonino , Garagiola Isabella , Palla Roberta , Rosendaal Frits , Mannucci Piermannuccio 
Published: October 2019

Abstract
BACKGROUND: Administration of factor VIII (FVIII) concentrates to patients with severe hemophilia A has nearly normalized their life expectancy; however, a substantial number of previously untreated patients (PUPs) develop neutralizing alloantibodies (inhibitors) against FVIII that complicate the benefits of treatment and make the management of these patients difficult and costly. Recently a randomized clinical trial (SIPPET) showed that the risk of inhibitor development is nearly doubled in previously untreated and minimally treated patients with severe hemophilia A treated with recombinant products (rFVIII) compared with plasma-derived (pdFVIII) products containing von Willebrand factor (VWF).
AIM: The aim of this post-hoc analysis of the SIPPET study was to assess the early risk of inhibitor development every 5 exposure days (EDs) and to see whether or not there was a difference between the two arms of plasma-derived FVIII and recombinant FVIII products over the course of time of FVIII exposure.
METHODS: 251 children were enrolled in the SIPPET study and randomized to receive a single pd or rFVIII (4 different brands of each). The outcomes were any FVIII inhibitor levels ≥ 0.4 Bethesda Units (BU) and high-titer inhibitors (peak levels > 5 BU). Patients were tested for inhibitors before entry and at regular intervals during 50 EDs, 3 years or the development of an inhibitor. Patients who had not reached 50 EDs by the time of study termination were censored. To study the risk over time, survival analysis by Kaplan-Meier and Cox regression were repeated for every 5 EDs to assess the association of source of FVIII with inhibitor development over time.
RESULTS: 76 out of 251 patients developed an inhibitor and of those 50 were high-titer; all occurred before 40 EDs.
Over the complete observation period, users of rFVIII products had a 87% higher rate of inhibitor development than users of pdFVIII (hazard ratio (HR) 1.87; 95% confidence interval (CI95) 1.17-2.96). The hazard ratio was particularly high during the first 5 EDs, both for all (HR 3.14, CI95% 1.01-9.74) and high-titer inhibitor development (HR 4.19, CI95% 1.18-14.8). After the first 5 EDs, the difference between two arms was less pronounced and quickly dropped to the overall difference of 1.87. Table 1 shows the cumulative incidence per time interval for each of the product classes.
CONCLUSION : The risk of inhibitor development during replacement therapy occurs more early (0-5 EDs) in patients treated with rFVIII than in those treated with pdFVIII, and remains high until 15 EDs. For pdFVIII, the highest risk came later (6-10 EDs) and this peak lasted shorter. The results of this analysis shows the relevance of the early exposure days for inhibitor development.
Table 1. Table 1.

Disclosures
Peyvandi: Alexion: Other: research funding paid to Luigi Villa Foundation, Research Funding; Novo Nordisk: Other: research funding paid to Luigi Villa Foundation, Research Funding, Speakers Bureau; Bayer: Speakers Bureau; Kedrion Biopharma: Consultancy, Other: research funding paid to Luigi Villa Foundation, Research Funding; LFB: Consultancy; CSL Behring: Speakers Bureau; Biotest: Other: research funding paid to Luigi Villa Foundation, Research Funding, Speakers Bureau; Octapharma: Consultancy; Ablynx: Membership on an entity's Board of Directors or advisory committees, Other: research funding paid to Luigi Villa Foundation, Research Funding; SOBI: Speakers Bureau; Grifols: Speakers Bureau. Palla:Pfizer: Other: travel support . Mannucci:Bayer: Speakers Bureau; Grifols: Speakers Bureau; Kedrion: Speakers Bureau; NovoNordisk: Speakers Bureau.