Time between inhibitor detection and start of immune tolerance induction: Association with outcome in the BrazIT study

Abstract

Hemophilia A (HA) is a rare bleeding disorder caused by reduced or absent clotting factor VIII (FVIII) activity due to mutation in its coding gene (F8). [1] FVIII replacement is required lifelong to treat bleeding, especially in severe cases (FVIII activity below 0.01 international units [IU]/mL). [1] Besides that, up to 44% of people with HA (PwHA) may develop neutralizing antibodies against exogenous FVIII (inhibitors). [2] The presence of inhibitors predispose PwHA to severe bleeding, [3] and increased morbidity and mortality. [4,5] The treatment of choice for persistent, high-responding inhibitors is immune tolerance induction (ITI), which consists of frequent and long-term infusions of FVIII. [1] Success rates among different ITI regimens range from 60%-90%. [6]

Economic Evaluation of Immune Tolerance Induction in Children With Severe Hemophilia A and High-Responding Inhibitors: A Cost-Effectiveness Analysis of Prophylaxis With Emicizumab

“…26 The recommended doses to treat breakthrough bleed in PsHAhri are 75-100 U/kg once or twice daily for aPCC and 90-120 µg/kg every 2-3 h, until the bleeding resolves. 27 According to the Brazilian ITI Protocol, the maximum treatment period is 33 months, 24 although it can last longer according to individual evaluation. Two outcomes can be reached: success is considered if the PsHA re-tolerates FVIII, while failure means permanent high titers of anti-FVIII inhibitor without hemostatic effect with exogenous FVIII.…”

“…For treating breakthrough bleeding, we assumed the mean recommended doses were required for hemostasis: one infusion of aPCC at 87.5 U/kg or two infusions of rFVIIa at 90 µg/kg/dose. 27,33 Since our male population entered the model when 2 years-old, and all treatments are based on the body weight (kg), we considered the age-related weight described previously for the Brazilian male population. 34 We assumed there is no difference between the weight of male PsHAhri and male non-hemophilia age-paired individuals on this age range.…”

High levels of anti–factor VIII immunoglobulin G4 and immunoglobulin G total are associated with immune tolerance induction failure in people with congenital hemophilia A and high-responding inhibitors

“…It affects about 30% of patients with severe hemophilia, leading to inefficient FVIII replacement [ 1 ]. Immune tolerance induction (ITI) is the treatment of choice to eradicate inhibitors, reaching 60% to 90% success rate among people with hemophilia A and inhibitors [ [2] , [3] , [4] , [5] ]. The biological bases related to ITI response are not completely elucidated.…”

“…The biological bases related to ITI response are not completely elucidated. Therefore, investigation of biomarkers associated with ITI outcome is important [ 5 ].…”