Background: Continuous prophylaxis, or the routine replacement of deficient clotting factor, is the standard of care therapy for individuals with severe hemophilia A and joint bleeding. In the United States (US), the majority of eligible patients are prescribed continuous prophylaxis, including approximately 75% of children < 20 years of age. However, up to 30% of severe hemophilia A patients develop neutralizing alloantibodies that render factor replacement ineffective requiring inhibitor eradication through induction of immune tolerance (ITI) therapy. Tolerized patients demonstrate successful elimination of inhibitors and normal response to FVIII concentrates. Non-tolerized patients can also be treated on prophylaxis using bypassing agents.
Aim: This analysis used national surveillance data to compare joint and other outcomes in persons with severe hemophilia A on continuous prophylaxis in three groups: no history of an inhibitor, likely tolerized inhibitor and active (non-tolerized) inhibitor.
Methods: The Community Counts bleeding disorders surveillance project is funded by the Centers for Disease Control and Prevention (CDC) through a cooperative agreement awarded to the American Thrombosis and Hemostasis Network (ATHN) in partnership with the US Hemophilia Treatment Center Network (USHTCN). The Registry for Bleeding Disorders Surveillance component collects detailed medical information on patients with bleeding disorders who receive treatment within the USHTCN. Likely tolerized inhibitors were defined as having a history of a previous inhibitor and currently being treated with FVIII concentrate; active inhibitors were defined as having a history of a previous inhibitor and being treated with bypassing agents. Using the Registry component, the following data elements, stratified by age and inhibitor status, were extracted from the initial visit form: demographics, treatment regimen, mobility, cumulative joint bleeding, invasive joint procedures, pain and opioid use.
Results: Data on 1,300 persons with severe hemophilia A were analyzed including: 739 with a negative inhibitor history; 410 likely tolerized inhibitor patients; and 151 with an active inhibitor. The 410 patients represented 73% of participants with a positive inhibitor history, similar to the North American Inhibitor Registry (DiMichele D, Haemophilia 2009;15:320-8). Participants with likely tolerized inhibitors were treated using continuous prophylaxis in similar proportion to participants with no history of inhibitor (83% vs 78%, respectively), and more often than participants with active inhibitor (83% vs 65%); however outcomes of participants on continuous prophylaxis were similar in all three groups (Table 1). Patients < 20 years of age had less disability, and fewer joint bleeds, invasive procedures, pain and opioid use compared with adult participants.
Conclusions: Improved outcomes on preventive strategies may be best determined prospectively in younger patients due to the lesser degree of established morbidity. Persons with severe hemophilia A on continuous prophylaxis with likely tolerized inhibitors (using FVIII) or with active inhibitors (using bypassing agents) demonstrate outcomes similar to those without inhibitors. However, more age- and treatment regimen- stratified analysis is needed for more precise comparisons. Future findings may contribute to the perspective that prophylaxis should be the standard of care for all hemophilia patients regardless of inhibitor status.
Manco-Johnson:Bayer: Honoraria, Research Funding; Baxalta: Honoraria; NovoNordisk: Honoraria; BiogenIdec: Honoraria; CSL Behring: Honoraria. Kulkarni:Baxter: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; BPL: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Biogen: Research Funding, Speakers Bureau. Buckner:Novo Nordisk: Consultancy; Genentech: Consultancy; Baxalta: Consultancy.
Asterisk with author names denotes non-ASH members.