Predictors of the outcome of immune tolerance induction in patients with haemophilia A and inhibitors: The Brazilian Immune Tolerance (BrazIT) Study protocol.

Ricardo Mesquita Camelo,Suely Meireles Rezende,Daniel Gonçalves Chaves,Luciana Werneck Zuccherato,Dominique Heymann

doi:10.1371/journal.pone.0256265

Abstract

The development of inhibitors is the main complication of haemophilia A (HA) treatment. Immune tolerance induction (ITI) is the treatment of choice for inhibitor eradication. We describe the methodology of the Brazilian Immune Tolerance Induction (BrazIT) Study, aimed to identify clinical, genetic, and immune biomarkers associated with response to ITI and inhibitor recurrence. This cohort study includes people with HA (PwHA) and inhibitors (a) who require bypassing agents to treat and/or prevent bleeding, and (b) who are at any stage of ITI treatment. Patients are included in each haemophilia treatment centre (HTC). Factor VIII (FVIII) and inhibitor assessments are performed at local laboratories of each HTC. The ITI regimen followed the national protocol of the Brazilian Ministry of Health. All PwHA starts with low-dose ITI (50 IU/kg three times weekly); high-dose regimen (100 IU/kg daily) is used if there is lack of response to the low-dose ITI. Outcomes are classified as total or partial success, and failure. Standardized case report forms with clinical, laboratory, and treatment data are collected from medical files and interviews. Blood samples are collected for genetic and immune biomarkers at the time of inclusion in the study and at the end of ITI. The study is ongoing and, currently, 202/250 (80.8%) PwHA from 15 HTCs have been included. BrazIT Study is the largest cohort of PwHA and inhibitor under treatment with the same ITI regimen reported to date. This study is likely to contribute with novel predictors of ITI response.

Highlights

Haemophilia A is a rare inherited disorder caused by diminished/absent coagulation factor VIII (FVIII) activity, which result in spontaneous haemorrhages [1]
Patients are included in each haemophilia treatment centre (HTC); FVIII and inhibitor assessments are performed at the local haemostasis laboratories of each HTC
The Brazilian Immune Tolerance Induction (BrazIT) Study is a non-interventional study, safety concerns related to medicines, blood products, and treatments are reported according to the haemophilia directives and the Brazilian regulation [36–40]

Summary

Introduction

Haemophilia A is a rare inherited disorder caused by diminished/absent coagulation factor VIII (FVIII) activity, which result in spontaneous haemorrhages [1]. The only treatment capable of eradicating inhibitors is the immune tolerance induction (ITI), which consists of frequent infusions of FVIII to induce anergy [9]. This treatment is long-lasting, expensive, and can be troublesome, due to the need of high adherence, good venous access, adequate medical support, and continuous monitoring [9–11]. This study demonstrated that the risk of inhibitor recurrence after successful ITI was associated with a low recovery of FVIII and the use of immunomodulatory therapy [24]. About 450 PwHA have been included in this program This large population of PwHA on ITI provided us an outstanding opportunity to initiate a cohort study: the Brazilian Immune Tolerance (BrazIT) Study. Tolerant PwHA are followed for at least one year after finishing ITI to evaluate inhibitor recurrence

Methodology

Study design and ethical approval

Discussion

Findings

Conclusion