Long‐Term Durability and Safety Signals of Systemic AAV Gene Therapy for Haemophilia A and B: A Systematic Review

Background Adeno‐associated virus (AAV) gene therapy can provide sustained endogenous factor expression after a single infusion, but durability and safety differ across products. We synthesised long‐term efficacy and clinically interpretable safety outcomes while avoiding inappropriate class‐level pooling. Methods Five databases were searched from inception to 15 May 2026 for prospective systemic AAV trials in haemophilia A or B. Overlapping reports were linked by trial identifier, vector/transgene, dose, enrolment, sites, sample size and follow‐up. One additional eligible report published within the search window was identified during peer review and incorporated. The primary outcome was product‐specific factor activity at the latest follow‐up with clinical durability. Prophylaxis status, bleeding and safety were synthesised descriptively by product because baseline regimens, outcome definitions and observation windows were not sufficiently harmonised for cross‐product pooling. Risk of bias was assessed with ROBINS‐I. Results Fourteen unique cohorts were included: six in haemophilia A and eight in haemophilia B. Reported long‐term factor activity remained product‐specific. The GS001 Phase 1 study reported median FVIII activity of 5.6 IU/dL at Week 144 in the low‐dose cohort and 42.7 IU/dL at Week 104 in the high‐dose cohort. Prophylaxis and zero‐treated‐bleed outcomes were not pooled because baseline treatment, restart criteria, denominators and observation windows differed. Liver abnormalities, immunosuppressive exposure, treatment‐related serious adverse events and loss of expression varied by product. Rare inhibitor and thrombotic events reported outside the eligible prospective cohort synthesis reinforce the need for ongoing product‐specific surveillance. Conclusions Selected patients experienced sustained haemostatic benefit, and several FIX programmes showed stable multiyear expression. Because assays, products, immune‐management strategies and follow‐up differed, counselling and surveillance should remain product‐specific. Standardised longitudinal reporting is required for stronger comparative conclusions.