Long-term safety of treatment of hemophilia A: a comprehensive review.

Abstract

Introduction: Hemophilia A is an inherited bleeding disorder caused by factor VIII (FVIII) deficiency, resulting in recurrent bleeding and progressive joint damage. Treatment has expanded beyond FVIII replacement to extended-half-life products, non-factor therapies, rebalancing agents, and gene therapy. These advances improve outcomes but introduce distinct long-term safety considerations.

Areas covered: This review evaluates long-term safety evidence from pivotal trials, extension studies, real-world registries, and recent international congress reports. It examines standard- and extended-half-life FVIII concentrates, efanesoctocog alfa, emicizumab, emerging rebalancing agents targeting natural anticoagulant pathways, and adeno-associated virus vector-based gene therapies.

Expert opinion: Established hemophilia A treatments generally have favorable long-term safety profiles and reduce treatment burden; however, mature safety data remain limited for newer agents. Inhibitor development remains the principal complication of FVIII replacement. Non-factor and rebalancing therapies carry potential thrombotic risks requiring appropriate monitoring. Gene therapy may provide durable FVIII expression after a single administration but raises concerns regarding hepatotoxicity, durability of expression, and uncertain long-term effects. Continued pharmacovigilance and individualized treatment selection are therefore essential as therapeutic options expand.