The emergence of non-factor therapies has fundamentally changed inhibitor management in haemophilia. Historically, immune tolerance induction (ITI) was considered indispensable for eradicating factor VIII (FVIII) or IX inhibitors and restoring responsiveness to replacement therapy. However, the introduction of rebalancing therapies (TFPI inhibitors, tissue factor pathway inhibitors) and emicizumab, a bispecific antibody mimicking factor VIIIa activity, provides highly effective bleed protection regardless of inhibitor status, challenging the traditional paradigm of universal ITI. Subcutaneous emicizumab and TFPI inhibitors enable safe, convenient prophylaxis without the need for central venous access or intensive FVIII respectively IX exposure, raising the question of whether ITI remains necessary in all patients with haemophilia A or B with inhibitors.

Current ITI practice increasingly favours combined ITI–emicizumab strategies, which reduce treatment burden and bleeding risk. Interim data from the MOTIVATE study and registry data indicate that combined approaches can achieve inhibitor eradication, yet success rates and optimal protocols remain uncertain. Moreover, the clinical relevance of tolerance is debated: while FVIII treatment is effective and safe to treat major bleeds or to cover major surgery compared to bypassing agents, many patients achieve good bleed protection with emicizumab prophylaxis without inhibitor eradication, but data on long-term joint health are still lacking. In haemophilia B, ITI feasibility is further limited by allergic reactions and nephrotic syndrome, making rebalancing therapies as a promising alternative for long-term care. This review explores whether ITI continues to be justified in the era of non-factor prophylaxis, summarizing evolving strategies, real-world evidence and unresolved questions.

Received: 02 December 2025

Accepted after revision: 01 June 2026

Article published online:
06 July 2026

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