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

Authors

Mahboob Younus Shaik, Jay Patel, Sunil Kakadia, Stephen Divers

Published in

European journal of haematology. Oct 30, 2026. Epub Oct 30, 2026.

Abstract

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.
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.
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.
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.

PMID:
42963107
Bibliographic data and abstract were imported from PubMed on 31 Oct 2026.

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