Adeno-associated virus-based gene therapy for hemophilia A and B: a systematic review and meta-analysis.

Adeno-associated virus (AAV)-based gene therapy is an emerging treatment for hemophilia A (HA) and hemophilia B (HB). In this systematic review and meta-analysis, we searched for studies of adult males with severe or moderately severe HA or HB who received AAV-based gene therapy. Annualized bleeding rate (ABR), annualized infusion rate (AIR), total factor use, factor levels, and adverse events (AEs) were extracted. Eight HA trials representing 7 gene therapies and 211 patients and 12 HB trials representing 9 gene therapies and 184 patients were included. For HA, gene therapy resulted in an annualized decrease of 7.58 bleeding events (95% confidence interval [CI], -11.50 to -3.67) and 117.2 factor infusions (95% CI, -151.86 to -82.53) compared with before gene therapy. Factor VIII level at 12 months ranged from 10.4 to 70.31 IU/mL by 1-stage assay. HB gene therapies were associated with an annualized decrease of 5.64 bleeding events (95% CI, -8.61 to -2.68) and 58.92 factor infusions (95% CI, -68.19 to -49.65). Mean factor IX level at 12 months was 28.72 IU/mL (95% CI, 18.78-38.66). Factor expression was more durable for HB than HA; factor IX levels remained at 95.7% of their peak whereas factor VIII levels fell to 55.8% of their peak at 24 months. The pooled percentage of patients experiencing a serious AE was 19% (10%-31%) and 21% (10%-37%) for HA and HB gene therapies, respectively. No thrombosis or inhibitor formation was reported. AAV-based gene therapies for both HA and HB demonstrated significant reductions in ABR, AIR, and factor use.