Immune tolerance induction in adult patients with hemophilia A and inhibitor

Orientador: Margareth Castro OzeloDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: Introdução: Uma das principais complicações associadas ao tratamento da hemofilia A consiste no desenvolvimento de inibidores, que são anticorpos direcionados contra o fator VIII infundido. O tratamento de eleição para pacientes com hemofilia e inibidor é a imunotolerância (IT), que consiste na infusão do concentrado de fator deficiente, na tentativa de dessensibilizar o paciente, com taxas de sucesso de aproximadamente 70%. A presença de inibidores de longa duração na população adulta tem sido associada a uma menor chance de resposta à IT. No Brasil, a IT tornou-se disponível apenas em 2011. Dessa forma, quase todos os pacientes com inibidores permaneceram com essa complicação por muito tempo. Objetivos: a) descrever a resposta ao tratamento de imunotolerância em pacientes adultos, com Hemofilia A e inibidor nos diferentes centros de hemofilia no Brasil; b) determinar o custo-efetividade da IT; c) analisar os episódios de sangramentos pré, durante e após a IT. Métodos: estudo multicêntrico, observacional, retrospectivo e prospectivo, realizado entre maio e novembro de 2015, em pacientes adultos, com hemofilia A e inibidor de alta resposta (>5UB/mL), submetidos ao tratamento de IT pela primeira vez. Os dados demográficos e clínicos foram coletados a partir dos prontuários e da avaliação clínica. O protocolo de baixas doses foi inicialmente utilizado para todos (25-50UI/kg, 3 vezes por semana), com diferentes concentrados de fator VIII derivados de plasma, contendo ou não fator de von Willebrand, ou concentrado de Fator VIII recombinante. Resultados: 56 pacientes adultos foram submetidos à IT no Brasil e, destes, 30 foram incluídos neste estudo. Foram analisados a frequência de episódios de sangramento, o consumo total de fatores de coagulação, incluindo concentrados de fator VIII e agentes de bypass, nos 12 meses pré-IT, durante a IT e durante cada ano de acompanhamento após a IT, bem como o custo desses produtos. A mediana de idade ao início da IT foi de 33 anos (19-51), e a mediana do título de inibidor foi de 6,1UB/mL (0,9-20,8). A mediana do pico histórico foi de 48UB/mL (5-590), com mediana de tempo de presença de inibidor de 13 anos (5-22). Apresentaram sucesso completo à IT 14 pacientes (46,6%) e sucesso parcial 9 (30%), com título de inibidor 5BU.mL-1) submitted to this treatment for the first time. Demographic and clinical data were collected from medical records and clinical evaluation. The low dose protocol was initially used for all (25-50UI / kg 3 times / week) with different plasma derived factor VIII concentrates, containing or not von Willebrand containing factor or recombinant factor VIII concentrate. Results: 56 patients underwent to ITI in Brazil, and among these patients, 30 were included in this study. We analyzed the frequency of bleeding episodes, the total consumption of coagulation factors, including factor VIII concentrate and bypassing agents in the 12 months pre ITI, during ITI and each year of follow-up after IT and the cost of these products. The median age of ITI onset was 33 years (19-51), and median inhibitor titer was 6.1BU.mL-1 (0.9-20.8). The median historical peak titre was 48BU.mL-1 (5.5-590), with median history of inhibitor for 13 years (5-22). Fourteen patients (46.6%) achieved complete response to ITI with median of 5.5 months (0.5-27). Nine patients achieved partial success to ITI, with inhibitor titre <5BU.mL-1 and are no longer using bypassing agents. Thus, 23/30 (76.7%) patients discontinued use of bypassing agents in a median period of 2 months (0-18). Among all 30 patients, the annualized bleeding rate (ABR) decreased more than three times comparing 12 months pre and during ITI. Notably, among patients with complete and partial success, no significant difference was observed between the median cost of 12 months before and during ITI period. Conclusion: Collectively, these data support the indication of ITI to poor risk group defined by age and duration of inhibitor. This study indicated that ITI treatment in adult HA patients is clinically effective and cost-effectiveMestradoClinica MedicaMestra em Ciência

Immunogenicity of Current and New Therapies for Hemophilia A

Anti-drug antibody (ADA) development is a significant complication in the treatment of several conditions. For decades, the mainstay of hemophilia A treatment was the replacement of deficient coagulation factor VIII (FVIII) to restore hemostasis, control, and prevent bleeding events. Recently, new products have emerged for hemophilia A replacement therapy, including bioengineered FVIII molecules with enhanced pharmacokinetic profiles: the extended half-life (EHL) recombinant FVIII products. However, the main complication resulting from replacement treatment in hemophilia A is the development of anti-FVIII neutralizing alloantibodies, known as inhibitors, affecting approximately 25&ndash;30% of severe hemophilia A patients. Therefore, the immunogenicity of each FVIII product and the mechanisms that could help increase the tolerance to these products have become important research topics in hemophilia A. Furthermore, patients with inhibitors continue to require effective treatment for breakthrough bleedings and procedures, despite the availability of non-replacement therapy, such as emicizumab. Herein, we discuss the currently licensed treatments available for hemophilia A and the immunogenicity of new therapies, such as EHL-rFVIII products, compared to other products available

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