F8 genotype and immune tolerance induction outcome in people with hemophilia A and inhibitors: A systematic review and meta-analysis

Background: F8 genotype is recognized as a risk factor for development of anti-factor VIII (FVIII) neutralizing alloantibodies (inhibitors) in people with hemophilia A (PwHA). However, little is known about the impact of F8 genotype and the outcome of immune tolerance induction (ITI). Since ITI outcome is difficult to predict, identifying its determinants is required. Objectives: To evaluate the impact of the F8 genotype on ITI outcome. Methods: We conducted a literature search (Nov/20/2024 and Jul/31/2025) to identify publications informing PwHA and inhibitors on primary ITI (population), F8 genotype (exposure), ITI success or failure (outcome), from interventional and observational studies. There were no restrictions on language or publication date. Risk of bias was assessed using an adapted Joanna Briggs Institute questionnaire. Results: The systematic review included 22 publications (20 studies) and the meta-analysis encompassed 10 publications (10 studies). We evaluated 586 PwHA, and 541 (92%) reached ITI outcome, of whom 381 (70%) achieved ITI success. The odds ratio (95% confidence interval) of ITI success associated with the presence of F8 large deletion (6 studies, 513 PwHA evaluated) was 0.19 (0.10-0.39 ; I² = 0.0%, p-value = 0.799) compared to the remaining mutations. Intron 22 inversion, non-intron 22 inversion, frameshift, missense, nonsense, and splice site mutations were not associated with ITI outcome. Six (60%) and four (40%) publications were classified as very low and low risk of bias, respectively. Conclusion: F8 large deletions were the only variant type associated with ITI outcome, based on low heterogeneity and very low/low risk of bias.