Gene therapy reduces bleeding rates and factor use in adults with severe hemophilia A

INTRODUCTION: Gene therapy (GT) is an emerging one-time treatment for people with hemophilia A (PwHA). We conducted a systematic review and meta-analysis to evaluate the efficacy, effectiveness, and safety of GT versus factor VIII (FVIII) or emicizumab prophylaxis. METHODS: Searches of MEDLINE/PubMed, Embase, Cochrane Library, LILACS and trial registries were run to Aug/02/2025. Eligible studies enrolled adults with severe/moderately hemophilia A treated with GT. Outcomes involved annualized bleeding rate (ABR), FVIII activity, FVIII/emicizumab consumption, annualized infusion rate, health-related quality of life (HRQoL), and adverse events. Risk of bias was assessed with MINORS. (CRD42024562798). RESULTS: Fourteen publications from five studies evaluated valoctocogene roxaparvovec, giroctocogene fitelparvovec, and dirloctocogene samoparvovec. GT reduced ABR [SMD -0.72 (95% CI: -0.96 to -0.48);  < 0.00001] versus FVIII prophylaxis. Mean FVIII activity rose to 8.3-67.5 IU/dL in year 1, then declined over follow-up. FVIII prophylaxis use decreased by >96% in year 4, with marked improvements HRQoL. Return to prophylaxis after GT ranged from 0%-33%. Adverse events were common but mostly mild to moderate, particularly transient liver enzyme elevations managed with corticosteroids. Risk of bias was moderate. CONCLUSIONS: GT offered meaningful reductions in bleeding and treatment burden in PwHA. Durability of FVIII expression and long-term safety require further investigation. REGISTRATION: This study was prospectively registered at PROSPERO (CRD42024562798).