title: Evaluation of safety and effectiveness of factor VIII treatment in haemophilia A patients with low titre inhibitors or a personal history of inhibitor. Patient Data Meta-analysis of rAFH-PFM Post-Authorization Safety Studies.
abstract: There is no prospective evidence on inhibitor recurrence among haemophilia A patients with low titre inhibitors or history of inhibitors, and whether or how therapeutic choices affect the risk of recurrence. The aims of this study were to synthesise safety data in patients with moderate-severe haemophilia A and with low titre inhibitors or inhibitor history enrolled in the rAHF PFM (ADVATE) - Post-Authorization Safety Studies (ADVATE-PASS) international programme. The study was conducted in clinics participating to the ADVATE PASS programme. The patient population consisted of patients entering the studies with low titre (≤ 5 BU) inhibitors or a positive personal history of inhibitors. Patients on Immune Tolerance Induction at study entry were excluded. Primary outcome was new or recurrent inhibitor titre > 5 BU. Secondary outcomes were any increase of inhibitor titre not reaching 5 BU; any unexplained change in treatment regimen. Primary analysis was done by two-stage random effects meta-analysis. Secondary analysis was done by a hierarchical Bayesian random effects logistic model. A total of 219 patients from seven studies were included. Of these 214 (97.7 %) patients had been previously treated for more than 50 exposure days. Two hundred ten patients had positive history for inhibitors, nine a baseline measurable titre. No patient presented a primary outcome event (95 % confidence interval [CI] 0-1.6 %). Six patients with previous history developed a low titre recurrence (overall rate 2.2, 95 %CI 0-4.8 %). When any increase of inhibitor titre or any treatment change was accounted for, overall 3.7 % (95 % CI 0 %-8.0 %) of patients experienced the outcome. In conclusion, the observed rate of events does not support the definition of this population as at high risk for inhibitor development.
authors.forename: Vadim
authors.initials: V
authors.lastname: Romanov
authors.forename: Maura
authors.initials: M
authors.lastname: Marcucci
authors.forename: Ji
authors.initials: J
authors.lastname: Cheng
authors.forename: Lehana
authors.initials: L
authors.lastname: Thabane
authors.affiliation: Alfonso Iorio, MD, PhD, FRCP(C), HIRUCRL-140, Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada, Tel.: +1 905 525 9140 ext 22421, E-mail: iorioa@mcmaster.ca.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Iorio
mesh_terms: D000906:Antibodies / Q000097:blood*; D001499:Bayes Theorem; D015415:Biomarkers / Q000097:blood; D016208:Databases, Factual; D005169:Factor VIII / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D006467:Hemophilia A / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology; D006470:Hemorrhage / Q000097:blood / Q000175:diagnosis / Q000276:immunology / Q000628:therapy*; D006490:Hemostatics / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D006801:Humans; D016015:Logistic Models; D009010:Monte Carlo Method; D064887:Observational Studies as Topic; D016017:Odds Ratio; D011159:Population Surveillance; D011358:Product Surveillance, Postmarketing; D012307:Risk Factors; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000906:Antibodies; D015415:Biomarkers; D006490:Hemostatics; C078147:F8 protein, human; D005169:Factor VIII
keywords: ADVATE; Haemophilia A; PASS; low titre inhibitors; switching