title: Nonneutralizing antibodies against factor VIII and risk of inhibitor development in severe hemophilia A.
abstract: The development of anti-factor VIII (FVIII) neutralizing antibodies (inhibitors) is the major complication in hemophilia A. Nonneutralizing antibodies (NNAs) have been detected in hemophilia patients and also in unaffected individuals. The aim of this study was to assess the prevalence of NNAs and to evaluate whether their presence is associated with the development of inhibitors in a cohort of previously untreated or minimally treated patients with hemophilia A; plasma samples of 237 patients with severe hemophilia A enrolled in the SIPPET trial were collected before any exposure to FVIII concentrates and analyzed for the presence of anti-FVIII NNAs. Patients were observed for the development of neutralizing antibodies. NNAs were found in 18 (7.6%) of 237 patients at screening, and there was a clear age gradient. Of those with NNAs, 7 patients subsequently developed an inhibitor for a cumulative incidence of 45.4% (95% confidence interval [CI], 19.5% to 71.3%); among the 219 patients without NNAs, 64 (29%) developed an inhibitor (cumulative incidence, 34.0%; 95% CI, 27.1%-40.9%). In Cox regression analyses, patients with NNAs at screening had an 83% higher incidence of inhibitor development than patients without NNAs (hazard ratio [HR], 1.83; 95% CI, 0.84-3.99). For high-titer inhibitors, the incidence rate had an almost threefold increase (HR, 2.74; 95% CI, 1.23-6.12). These associations did not materially change after adjustment. The presence of anti-FVIII NNAs in patients with severe hemophilia A who were not previously exposed to FVIII concentrates is associated with an increased incidence of inhibitors.
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico Ca'Granda Ospedale Maggiore Policlinico and Luigi Villa Foundation, Milan, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Cannavò
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico Ca'Granda Ospedale Maggiore Policlinico and Luigi Villa Foundation, Milan, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Valsecchi
authors.affiliation: Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy; and.
authors.forename: Isabella
authors.initials: I
authors.lastname: Garagiola
authors.affiliation: Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy; and.
authors.forename: Roberta
authors.initials: R
authors.lastname: Palla
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico Ca'Granda Ospedale Maggiore Policlinico and Luigi Villa Foundation, Milan, Italy.
authors.forename: Pier Mannuccio
authors.initials: PM
authors.lastname: Mannucci
authors.affiliation: Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Frits R
authors.initials: FR
authors.lastname: Rosendaal
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico Ca'Granda Ospedale Maggiore Policlinico and Luigi Villa Foundation, Milan, Italy.|Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy; and.
authors.forename: Flora
authors.initials: F
authors.lastname: Peyvandi
mesh_terms: D002675:Child, Preschool; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005169:Factor VIII / Q000276:immunology* / Q000627:therapeutic use*; D006467:Hemophilia A / Q000188:drug therapy*; D006801:Humans; D007223:Infant; D007518:Isoantibodies / Q000276:immunology*; D008297:Male; D016016:Proportional Hazards Models
chemical_list: D007518:Isoantibodies; C427184:recombinant factor VIII SQ; D005169:Factor VIII