Updated meta-analysis of inhibitor development in previously untreated patients with severe Hemophilia A: Plasma-derived versus recombinant FVIII products

Abstract

Abstract Background:  Neutralizing inhibitors remain the major complication of replacement therapy in previously untreated patients (PUPs) with severe haemophilia A , affecting up to one-third of this cohort. Earlier meta-analyses, including Kohar et al.  2022 update, suggested a higher inhibitor risk with recombinant FVIII (rFVIII) than with plasma-derived FVIII (pdFVIII) (pooled OR ≈ 1.6; HR ≈ 1.9). Most published work pre-dates 2018 and lacks recent registry-level and product-specific data. We therefore performed a meta-analysis integrating both historic and contemporary studies to compare inhibitor risk between pdFVIII and rFVIII in PUPs with hemophilia A. Methods: A meta-analysis was conducted to compare the risk of factor VIII inhibitor development in previously untreated patients with severe hemophilia A receiving plasma-derived FVIII versus recombinant FVIII. A systematic literature search was performed using PubMed for studies published between 2000 and 2025. The search yielded 285 articles, which were independently screened and reviewed by two investigators. Inclusion criteria: human studies reporting inhibitor counts ≤ 75 exposure days (EDs) in PUPs and directly comparing pdFVIII with rFVIII. Five studies met criteria and included in the meta-analysis: SIPPET trial (Peyvandi et al., 2016), the CANAL study (Gouw et al., 2007), the FranceCoag cohort (Calvez et al., 2018), the PedNet registry (Fischer et al., 2023), and EUHASS/CHESS data (Fischer et al., 2023). Event-level data (number of patients who developed inhibitors and total number treated in each group) were extracted and pooled. The primary outcome was the risk ratio (RR) of inhibitor development. A random-effects model was used to calculate pooled effect estimates. Heterogeneity was assessed using the I² statistic and τ²(tau-squared). All statistical analyses were conducted using Stata/SE 19.5 Results: Five studies comprising a total of 3,236 patients (758 treated with plasma-derived FVIII and 2,478 with recombinant FVIII) were included in the meta-analysis. Using a random-effects model (REML) based on a manually calculated log risk ratios and standard errors, the pooled analysis demonstrated a significantly lower risk of inhibitor development in patients receiving pdFVIII compared to those receiving rFVIII. The pooled risk ratio (RR) was 0.74, with a 95% confidence interval (CI) of 0.57 to 0.96 (p = 0.026), indicating a 26% relative risk reduction associated with pdFVIII. Heterogeneity was observed across the studies (I² = 68.3%). While meta-regression suggested that differences in study size might explain some of this heterogeneity, accounting for around 29% of the between-study differences; this finding was not statistically significant. Nevertheless, the overall pattern of results consistently favored pdFVIII, with all included studies demonstrating a reduction in inhibitor risk relative to rFVIII. Conclusion This updated meta-analysis, incorporating the first post-2021 registry data, confirms a modest but significant reduction in early inhibitor risk with plasma-derived FVIII compared with recombinant FVIII in previously untreated patients with severe hemophilia A. These findings support current shifts in clinical practice, highlight the importance of product-specific pharmacovigilance, and may guide clinicians in selecting first-line products and refining risk-stratified early prophylaxis strategies.