Of the 234 non-RODIN inhibitor-free patients, 220 (94%) were followed for 13

Of the 234 non-RODIN inhibitor-free patients, 220 (94%) were followed for 13.3 months and 209 (89.3%) for 19.1 months (all brands GSK547 of rFVIII). a surrogate for rFVIII exposure. An inhibitor developed in 118 (29%) patients, 60 high and 58 low titer, after a median (interquartile range) of 7.8 (3.3-13.5) months from first exposure and 16 (9-30) EDs. Of 128 patients treated with Kogenate Bayer/Helixate NexGen, 45 (35.2%, 95% confidence interval [CI] 27.4-43.8) developed an inhibitor compared with 42/172 (24.4%, 95% CI 18.6% to 31.4%) with Advate (= .04). The adjusted hazard ratio (HR) (95% CI) for Kogenate Bayer/Helixate NexGen compared with Advate was 2.14 (1.12-4.10) (= .02) for high titer and 1.75 (1.11-2.76) (= .02) for all inhibitors. When excluding UK-RODIN patients, the adjusted HR (95% CI) for high-titer inhibitors was 2.00 (0.93-4.34) (= .08). ReFacto AF was associated with a higher incidence of all, but not high-titer, inhibitors than Advate. These results will help inform debate around the relative immunogenicity and use of rFVIII brands. Introduction The Research Of Determinants of INhibitor development (RODIN) group reported that a second-generation full-length recombinant factor VIII (rFVIII) (Kogenate Bayer/Helixate NexGen; Bayer AG, Bayer Healthcare, Berkeley, CA) was associated with an increased risk of inhibitor development in previously untreated patients (PUPs) compared with a third-generation full-length rFVIII (Advate; Baxter International, Thousand Oaks, CA). The adjusted hazard ratio (HR) (95% confidence interval [CI]) was 1.60 (1.08-2.37) for all inhibitors and 1.79 (1.09C2.94) for high-titer inhibitors.1 The authors discussed whether this association may be a biased finding (through confounding, selection or information bias), or may be a chance finding, or a causal effect. They argued at the time1 and later2 that bias was an unlikely explanation for the observation. Other experts have raised questions relating to study methodology and analysis,3-5 but these have been defended by the authors.2 Previous publications, including the Kogenate Bayer licensing studies and a systematic review, had suggested that the inhibitor risk associated with Kogenate Bayer might be lower than average,6,7 although the inclusion of minimally treated patients in the licensing study may have influenced this observation. The European Medicines Agency (EMA) reviewed the available evidence and concluded on 6 December 2013 that current evidence does not confirm increased risk of inhibitor development compared with other factor VIII products GSK547 (EMA/741427/2013; http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Kogenate_Bayer_Helixate_Nexgen_20/Recommendation_provided_by_Pharmacovigilance_Risk_Assessment_Committee/WC500157065.pdf). Further studies are needed to provide additional information about the incidence of inhibitor development in PUPs associated with different rFVIII brands. The United Kingdom (UK) Haemophilia Centre Doctors Organization (UKHCDO) therefore investigated the risk factors, including brand of rFVIII, for inhibitor formation in all patients with severe hemophilia A born in the UK between 1 January 2000 and 31 GSK547 December 2011. Methods Data reported to the GSK547 UKHCDO National Haemophilia Database (NHD) were analyzed under an agreement with the UK Data Protection Registrar. The following data were Mouse monoclonal to Histone 3.1. Histones are the structural scaffold for the organization of nuclear DNA into chromatin. Four core histones, H2A,H2B,H3 and H4 are the major components of nucleosome which is the primary building block of chromatin. The histone proteins play essential structural and functional roles in the transition between active and inactive chromatin states. Histone 3.1, an H3 variant that has thus far only been found in mammals, is replication dependent and is associated with tene activation and gene silencing. extracted from the NHD or requested to be reported to the NHD from all UK Haemophilia Centres: date of birth, ethnicity, family history (FH) of hemophilia, FH of a FVIII inhibitor in any relative, FVIII mutation, date of first FVIII treatment, brand of FVIII first infused, intensive treatment event at first exposure or during the first 50 exposure days (EDs) but before inhibitor detection (intensive treatment after an inhibitor had developed was excluded), units of FVIII used annually prior to 2005 or quarterly after 2005, date of inhibitor diagnosis, peak inhibitor titer, and EDs prior to inhibitor formation. Data on the rFVIII usage and time from first treatment to reach 75 EDs were known for 50 noninhibitor patients entered into RODIN and were compared with rFVIII usage in the noninhibitor patients in the rest of the cohort. Ethnicity is reported as white or nonwhite; FVIII mutations were categorized as high risk (large deletions, nonsense mutations, intron 1 and 22 inversions), low risk (small deletions and insertions, missense mutations, splice site mutations), or unknown (no mutation detected or unknown).8 This definition of high-risk/low-risk genotype replicates that used in RODIN. Inhibitor titres were measured locally using standard Bethesda or Nijmegen assays. All laboratories participated in national external quality-control schemes. High-titer inhibitors were categorized as 5 BU and low titer as <5 BU. Intensive treatment was 5 or more consecutive EDs. The frequency of inhibitor testing was at the discretion.