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

BACKGROUND: Immune tolerance induction (ITI) is the treatment of choice for eradication of anti-factor VIII (FVIII) neutralizing alloantibodies (inhibitors) in people with inherited hemophilia A and high-responding inhibitor (PwHA-HRi). The association between ITI outcome and time elapsed between inhibitor detection and start of ITI (∆tinhi-ITI ) is debatable. OBJECTIVE: The aim of this study was to evaluate this association among a large cohort of severe PwHA-HRi. METHODS: Severe (factor VIII activity level <1%) PwHA-HRi on ITI (n = 142) were enrolled in 15 hemophilia treatment centers. PwHA-HRi were treated according to the Brazilian ITI Protocol. ITI outcomes were defined as success (i.e., recovered responsiveness to exogenous FVIII) and failure (i.e., no responsiveness to exogenous FVIII and requirement of bypassing agents to control bleeding). RESULTS: Median ages at inhibitor detection and at ITI start were 3.2 years (interquartile range [IQR], 1.6-8.1) and 6.9 years [IQR, 2.6-20.1), respectively. PwHA-HRi were stratified according to ∆tinhi-ITI quartiles: first (0.0-0.6 year), second (>0.6-1.7 year), third (>1.7-9.2 years), and fourth quartile (>9.2-24.5 years). The overall success rate was 65.5% (93/142), with no difference among first, second, third, and fourth quartiles (62.9%, 69.4%, 58.3%, and 71.4%, respectively) even after adjusting the analyses for potential confounders. CONCLUSION: In conclusion, delayed ITI start is not associated with failure of ITI in PwHA-HRi. Therefore, ITI should be offered for these patients, regardless of the time elapsed between the detection of inhibitor and the ITI start.

Access to dental care for patients with inherited bleeding and hemoglobin disorders.

AIM: To identify the main barriers to dental care access for patients with inherited bleeding (IBD) and hemoglobin disorders (HbD). METHODS: Patients with IBD and HbD were invited to participate in this study between August 2019 and March 2020. Data were collected through a questionnaire consisting of socioeconomic and demographic items and questions about access to dental services and history of dental treatment. Univariate and multiple Poisson regression model was used to determine associations between professional refusal of dental care and other co-variables (p < .05). RESULTS: The participants (29.1%) have already had professional refusal of dental care and participants with IBD (53.2%) did not feel confident with their local dentist due to their bleeding tendency. Most (64.6%) felt apprehensive about visiting the local dentist and high prevalence of refusal to provide dental care was associated with age (prevalence ratio [PR] = 1.021; 95% confidence interval [CI] = 1.010-1.032). Individuals with low bleeding risk were less likely to be denied dental care by a professional compared to those with high bleeding risk (PR = 0.536; 95%CI = 0.291-0.990). CONCLUSION: Professional refusal of dental care was high among patients with IBD, particularly older adults and with an increased risk of bleeding.

Extended half-life recombinant factor VIII treatment of hemophilia A in Brazil: an expert consensus statement.

INTRODUCTION: Treatment of hemophilia A in Brazil is offered to all patients at no cost. However, several unmet medical needs exist. METHOD: In this study, we applied the Delphi method to discuss with seven hemophilia A specialists the challenges that patients and the health system face regarding hemophilia A treatment and opportunities for improvement. RESULTS: A consensus was obtained regarding the number of weekly infusions and patient adherence to treatment. The bleeding profile, unfavourable pharmacokinetics (PKs), low adherence and high daily activity were patient profiles that would benefit from using the extended half-life (EHL) recombinant factor VIII (rFVIII). The advantages of treatment with the EHL rFVIII were the lower number of infusions per week, which could increase patient adherence and decrease the risk of bleeds, due to a more constant plasma level, a lower value. Additionally, the EHL rFVIII could improve quality of life, especially in patients with high daily activity, such as adolescents and young adults. The panelists mentioned that EHL rFVIII, if available, could be offered first to the priority group (adolescents between 12 and 19 years old), followed by adults (20 to 64 years old) and elderly people (over 65 years old). CONCLUSION: In summary, the EHL rFVIII offers the optimal prophylaxis by decreasing the dose frequency, increasing the treatment adherence and improving the QoL, without compromising safety and efficacy.

Effect of the First Factor VIII Infusions on Immunological Biomarkers in Previously Untreated Patients with Hemophilia A from the HEMFIL Study.

Hemophilia A (HA) is an inherited bleeding disorder which requires continuous replacement with factor (F) VIII concentrate. The main complication of HA is the development of neutralizing alloantibodies which inhibit FVIII activity (inhibitors). The objective of this study was to investigate the effect of the first FVIII infusions on immunological biomarkers in previously untreated patients with HA. Plasma samples were collected at enrollment before any FVIII infusion (T0) and at inhibitor development (INB +/T1) or up to 35 exposure days without inhibitors (INB -/T1). Anti-FVIII antibodies (immunoglobulin M, immunoglobulin G [IgG] 1, IgG3, and IgG4), chemokines (CCL2, CCL5, CXCL8, CXCL9, and CXCL10), and cytokines (interleukin [IL]-2, IL-4, IL-6, IL-10, interferon-γ, tumor necrosis factor, and IL-17) were assessed. A total of 71 children with severe HA were included, of whom 28 (39.4%) developed inhibitors. Plasma levels of anti-FVIII IgG4, IL-6, and CXCL8 were higher at INB +/T1 when compared with INB -/T1. This group presented a mixed cytokine profile and higher plasma levels of CXCL9 and CXL10 when compared with INB +/T1. We conclude that exposure to FVIII triggers a proinflammatory response mediated by IL-6 and CXCL8 in patients with HA who developed inhibitors. Regardless of inhibitor status, the immune system of all HA patients is stimulated after infusions of FVIII.