Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Unité Mixte de Recherche en Santé 1136, Institut Pierre Louis d'Épidemiologie et de Santé Publique, Paris, France; INSERM, Unité Mixte de Recherche en Santé 1136, Institut Pierre Louis d'Épidemiologie et de Santé Publique, Paris, France;
Service d'Hématologie Oncologie Pédiatrique, La Timone, Assistance Publique-Hôpitaux de Marseille, Marseille, France; INSERM, Unité Mixte de Recherche 1062, Faculté de Médecine, Aix-Marseille Université, Marseille, France;
Blood. 2014 Nov 27;124(23):3398-408. doi: 10.1182/blood-2014-07-586347. Epub 2014 Sep 24.
Six recombinant factor VIII (rFVIII) products have been marketed worldwide. In 2013, the Research of Determinants of Inhibitor Development (RODIN) study group reported an unexpectedly high risk of inhibitor development with a second-generation full-length rFVIII (Product D) in previously untreated patients (PUPs) with severe hemophilia A (HA). In 1994, French public health authorities established a prospective cohort to monitor hemophilia treatment safety. A PUP subgroup was designed to investigate inhibitor risk factors. We analyzed this subcohort in view of the RODIN findings. After excluding 50 patients who participated in the RODIN study, the primary analysis focused on 303 boys with severe HA first treated with a rFVIII product. A clinically significant inhibitor was detected in 114 boys (37.6%). The inhibitor incidence was higher with Product D vs the most widely used rFVIII product (adjusted hazard ratio [aHR], 1.55; 95% confidence interval [CI], 0.97-2.49). Similar results were found for high-titer inhibitors and in 10 sensitivity analyses. No heterogeneity was observed between RODIN and our results. Combined aHRs were 1.58 (95% CI, 1.17-2.14) for all inhibitors and 1.70 (95% CI, 1.15-2.52) for high-titer inhibitors. Our results confirm the higher immunogenicity of Product D vs other rFVIII products in PUPs with severe HA.
六种重组因子 VIII (rFVIII) 产品已在全球上市。2013 年，研发抑制剂决定因素研究（RODIN）研究小组报告称，在既往未接受治疗的重度 A 型血友病（HA）患者（PUP）中，第二代全长 rFVIII（产品 D）具有意外高的抑制剂发展风险。1994 年，法国公共卫生当局建立了一个前瞻性队列来监测血友病治疗安全性。设立了一个 PUP 亚组来研究抑制剂的危险因素。我们根据 RODIN 的发现分析了这个亚组。在排除了 50 名参加 RODIN 研究的患者后，主要分析集中在 303 名首次接受 rFVIII 产品治疗的重度 HA 的男孩上。在 114 名男孩（37.6%）中检测到临床显著抑制剂。与最广泛使用的 rFVIII 产品相比，产品 D 的抑制剂发生率更高（调整后的危险比[aHR]，1.55；95%置信区间[CI]，0.97-2.49）。高滴度抑制剂也有类似结果，在 10 项敏感性分析中也是如此。RODIN 和我们的结果之间没有观察到异质性。所有抑制剂的合并 aHR 为 1.58（95% CI，1.17-2.14），高滴度抑制剂的合并 aHR 为 1.70（95% CI，1.15-2.52）。我们的结果证实了在重度 HA 的 PUP 中，产品 D 比其他 rFVIII 产品具有更高的免疫原性。
