Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK.
Arthur Bloom Haemophilia Centre, School of Medicine, Cardiff University, Cardiff, UK.
Haemophilia. 2018 Nov;24(6):896-901. doi: 10.1111/hae.13551. Epub 2018 Jul 13.
Factor VIII inhibitor development is currently the most serious complication of the treatment of haemophilia A. Differences in manufacturing and the molecular structure of brands of recombinant factor VIII have led to speculation that concentrates may differ in immunogenicity. This has led to a regulatory focus on the immunogenicity of factor VIII concentrates both before and after licensure.
To investigate the immunogenicity of ReFacto AF post licensure in a real-world setting in previously untreated patients (PUPs) treated exclusively with this product until at least 50 exposure days (EDs).
The United Kingdom Haemophilia Centre Doctors' Organisation (UKHCDO) National Haemophilia Database (NHD) identified a consecutive cohort of patients with severe haemophilia A (<0.01 IU/L) whose first treatment was with ReFacto AF, monitored time to inhibitor development and described associated risk factors.
One hundred and three boys reached 50 EDs within the study period, of whom 35 developed an inhibitor (P(t ≤ 50) = 0.33, [95% CI: 0.25-0.43]), of which 15 (P(t ≤ 50) = 0.16, [95% CI: 0.10-0.25]) were high titre. Inhibitors arose after a median (interquartile range) 11 (7-16) EDs. Inhibitors were significantly associated with high-risk mutations and non-significantly associated with non-white ethnicity. Inhibitors were negatively associated with a family history of haemophilia A. High-titre inhibitors were significantly associated with a family history of inhibitors.
Inhibitor incidence in a single country population of ReFacto AF PUPs was similar to that previously described. Low- and high-titre inhibitors were detected after a similar number of EDs, contrasting with previous data, probably reflecting standardized inhibitor monitoring within the United Kingdom.
目前，因子 VIII 抑制剂的发展是血友病 A 治疗中最严重的并发症。由于重组因子 VIII 品牌在制造和分子结构上存在差异，人们推测其在免疫原性方面可能存在差异。这导致监管部门在许可前后都将重点放在因子 VIII 浓缩物的免疫原性上。
在真实环境中，调查瑞福（ReFacto AF）在既往未接受治疗的患者（PUP）中的免疫原性，这些患者在至少 50 个暴露日（ED）内仅接受该产品治疗。
英国血友病中心医生组织（UKHCDO）国家血友病数据库（NHD）确定了一个连续队列的患有严重血友病 A（<0.01 IU/L）的患者，他们的首次治疗是使用 ReFacto AF，监测抑制剂的发展时间，并描述相关的危险因素。
在研究期间，有 103 名男孩达到了 50 个 ED，其中 35 名（P(t ≤ 50) = 0.33，[95% CI：0.25-0.43]）出现了抑制剂，其中 15 名（P(t ≤ 50) = 0.16，[95% CI：0.10-0.25]）为高滴度抑制剂。抑制剂出现在中位数（四分位距）11（7-16）ED 后。抑制剂与高危突变显著相关，与非白种人种族无显著相关性。抑制剂与血友病 A 的家族史呈负相关。高滴度抑制剂与抑制剂的家族史显著相关。
在瑞福 AF PUP 的单一国家人群中，抑制剂的发生率与之前描述的相似。低和高滴度抑制剂在相似数量的 ED 后被检测到，这与之前的数据相反，可能反映了英国标准化的抑制剂监测。
