Executive summary of the NHLBI State of the Science (SOS) Workshop: Overview and next steps in generating a national blueprint for future research on factor VIII inhibitors

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150611/1/hae13713_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150611/2/hae13713.pd

National surveillance for hemophilia inhibitors in the United States: Summary report of an expert meeting: National Inhibitor Surveillance in the U.S.

On March 12, 2012, the Centers for Disease Control and Prevention (CDC) held a meeting of its partners in hemophilia treatment, community-based organizations, industry, and government to review data and discuss implementation issues relevant to planned United States (U.S.) national inhibitor surveillance. Issues discussed included the current status of inhibitor surveillance in the United Kingdom (UK) and the US, the results of a US inhibitor surveillance feasibility study, proposed national surveillance schemes, laboratory testing and reporting issues and potential opportunities for future inhibitor-related research. It was concluded that implementation of a national program of inhibitor surveillance using standardized testing through an established public health registry along with patient and care provider education and targeted research provide the best opportunity to inform efforts to develop and evaluate effective prevention strategies

Phenotypic Expressions of CCR5-Δ32/Δ32 Homozygosity

Objective: As blockade of CC-chemokine receptor 5 (CCR5) has been proposed as therapy for HIV-1, we examined whether the CCR5-Δ32/Δ32 homozygous genotype has phenotypic expressions other than those related to HIV-1. Design: Study subjects were white homosexual men or men with hemophilia who were not infected with HIV-1. In this study, 15 CCR5-Δ32/Δ32 homozygotes were compared with 201 CCR5 wild-type (+/+) subjects for a wide range of clinical conditions and laboratory assay results ascertained during prospective cohort studies and routine clinical care. CCR5-Δ32 genotype was determined by polymerase chain reaction, followed by single-stranded conformational polymorphism analysis. Results: Hypertension and conditions attributable to hemophilia were the only diagnoses frequently found in clinical records of CCR5-Δ32/Δ32 study subjects. Based on blood pressure measurement and treatment history, CCR5-Δ32/Δ32 homozygotes had a 2.8-fold higher prevalence of hypertension than age-matched CCR5-+/+ study subjects (95% confidence interval [CI], 1.2-6.4; p = .01); none of the homozygotes had severe hypertension. Hematologic measures were generally similar across the genotypes, but total lymphocyte counts were ~20% higher in CCR5-Δ32/Δ32 study subjects than in CCR5-+/+ study subjects (p \u3c .05). Among patients with hemophilia who were infected with hepatitis C virus (HCV), mean alanine aminotransferase levels were 117% higher among CCR5-Δ32/Δ32 homozygotes (p \u3c .05), but serum HCV levels did not differ by CCR5-Δ32 genotype. CCR5-Δ32/Δ32 homozygous study subjects had a lower prevalence of antibodies to measles virus than those with other genotypes, but this association was not confirmed in a group of blood donors. The prevalence of antibodies to nine other common viruses, HBV, and HCV was not related to CCR5 genotype. Conclusions: CCR5-Δ32/Δ32 homozygotes are generally similar to wild-type persons. Confirmatory investigations are required to determine whether hypertension, increased lymphocyte counts, and higher hepatic enzyme levels in the presence of HCV infection represent true phenotypic expressions of this genotype. CCR5-Δ32/Δ32 homozygosity does not provide broad protection against viral infections

The Author Journal Compilation ª

Summary Factor IX (FIX) inhibitors develop in 1AE5-3% of haemophilia B patients. Due to its low incidence compared with that in haemophilia A, few comparable data exist on host and treatment-related risk factors, and immunological processes associated with FIX inhibitor development. Moreover, the safety and efficacy of bypass therapy as well as the outcome predictors of successful inhibitor eradication have been poorly characterised. The lack of a useful evidence-based approach to the diagnosis and management of FIX inhibitors complicates their significant morbidity due to the frequency of allergic reactions that often herald antibody development. This review discusses what is currently known about the epidemiology, natural history and immunology of anti-FIX antibody development. It addresses several special considerations in the approach to the treatment of bleeding and inhibitor eradication. A case is made for moving forward with an integrated international collaboration for the further study of the nature and treatment of this problem. Keywords: haemophilia B, factor IX deficiency, inhibitors, inhibitor treatment, immune tolerance. Factor IX (FIX) inhibitors develop in 1AE5-3% of haemophilia B patients, with geographically isolated pockets of higher incidence This review discusses what is currently known about the epidemiology, the natural history, the host and treatmentrelated risk factors, and the immunology of anti-FIX antibody development. It also addresses several special considerations in the clinical approach to both the safe and efficacious treatment of bleeding in the presence of antibody as well as inhibitor eradication, i.e. immune tolerance. A case is made for moving forward with an integrated international collaboration for the scientific and clinical study of the nature and treatment of this orphan disease in need of our attention. Epidemiology of FIX inhibitors: potential reasons for a low incidence disorder The published incidence of FIX inhibitors is between 1AE5 and 3% of all patients with haemophilia B and between 9 and 23% of severely affected FIX deficient patient

Navigating Speed Bumps on the Innovation Highway in Hemophilia Therapeutics

Abstract. The unprecedented emergence of novel therapeutics for both hemophilia A and B during the last half decade has been accompanied by the promise of even more extraordinary progress in ameliorative and curative strategies for both disorders. Paradoxically, the speed of innovation has created new dilemmas for persons with hemophilia and their physicians with respect to optimizing individual choices from the expanding menu of standard and novel therapies and approaches to symptom or risk reduction, and ultimately, to normalizing the hemophilia phenotype. Among the most disruptive new approaches, challenges remain in the form of the adverse reactions that have been observed with nonfactor therapies, as well as in the uncertain long-term safety profile of potentially curative gene therapy. Together, these challenges have generated uncertainty as to how to adopt novel therapies and treatment strategies across a diverse patient population, creating speed bumps on the hemophilia innovation highway. It is from this perspective that this article discusses the current state of gene therapy and bleeding prophylaxis for hemophilia A and B, as well as prevention and treatment of the factor VIII inhibitor phenotype in hemophilia A. It further posits that these speed bumps may provide important clues to the mechanistic understanding of both symptom manifestation and resilience within the hemophilia phenotype, as well as opportunities to reconsider and reconfigure the current paradigms for symptom prediction and individualized therapeutic decision making

A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor.

The development of inhibitory antibodies to factor VIII is a serious complication of hemophilia. FEIBA (factor VIII inhibitor-bypassing activity), an activated prothrombin complex concentrate (aPCC), and NovoSeven, recombinant factor Vila (rFVIIa), are used as hemostatic bypassing agents in treating patients with inhibitors. The FENOC study was designed to test equivalence of the products in the treatment of ankle, knee, and elbow joint bleeding. A prospective, open-label, randomized, crossover, equivalency design was used. The parameters of interest were the percentage of patients who reported efficacy in response to FEIBA and the percentage that reported efficacy in response to NovoSeven. A difference in these percentages of no more than 15% was determined to be a clinically acceptable magnitude for equivalence of the 2 products. The primary outcome was evaluation 6 hours after treatment. Data for 96 bleeding episodes contributed by 48 participants were analyzed. The criterion for declaring the 2 products equivalent at 6 hours was not met; however, the confidence interval of the difference in percentages of efficacy reported for each product only slightly exceeded the 15% boundary (-11.4%-15.7%), P=.059. FEIBA and NovoSeven appear to exhibit a similar effect on joint bleeds, although the efficacy between products is rated differently by a substantial proportion of patients. This trial was registered at www.clinicaltrials.gov as #NCT00166309