Lusher J, Abildgaard C, Arkin S, Mannucci P M, Zimmermann R, Schwartz L, Hurst D
Children's Hospital of Michigan, Detroit 48201, USA.
J Thromb Haemost. 2004 Apr;2(4):574-83. doi: 10.1111/j.1538-7933.2004.00646.x.
Development of recombinant factor VIII (rFVIII) replacement therapy represents a milestone in the treatment of hemophilia A.
The objective of this long-term, multicenter study was to assess the safety, efficacy and rate of inhibitor formation of rFVIII (Kogenate) in the treatment of hemophilia A in a group of previously untreated patients (PUPs).
Between January 1989 and October 1997, 102 evaluable patients (mean age 3.9 years) were treated with rFVIII as sole therapy for prophylaxis against bleeding or for hemorrhage. Patients with mild hemophilia were treated for > or =2 years, while those with moderate or severe hemophilia were treated for > or =5 years or 100 exposure days.
All patients responded well to therapy, so that 82% of bleeding episodes required a single infusion for treatment. Only four mild drug-related adverse events were recorded during the study for an overall rate of 0.03% (4/13 464 infusions). No viral seroconversions were observed. The inhibitor incidence in PUPs with severe hemophilia was 29% (19/65). Overall, inhibitory antibodies developed in 21 patients (20.6%). Inhibitor titers were low (<10 Bethesda Units) in nine of the 21 patients despite continued episodic treatment with rFVIII and transient in eight patients receiving episodic treatment (seven low titer, one high titer). Eight high-titer inhibitor patients were treated with immune-tolerance induction therapy; five had successful outcomes.
The observed incidence of inhibitor formation is similar to studies of PUPs receiving plasma-derived FVIII. These results demonstrate the safety and efficacy of rFVIII in long-term treatment of hemophilia A.
重组凝血因子VIII（rFVIII）替代疗法的发展是A型血友病治疗中的一个里程碑。
这项长期、多中心研究的目的是评估rFVIII（拜科奇）在一组既往未接受治疗的患者（PUPs）中治疗A型血友病的安全性、疗效及抑制剂形成率。
1989年1月至1997年10月，102例可评估患者（平均年龄3.9岁）接受rFVIII作为预防出血或治疗出血的唯一疗法。轻度血友病患者治疗≥2年，中度或重度血友病患者治疗≥5年或100个暴露日。
所有患者对治疗反应良好，82%的出血事件单次输注即可治疗。研究期间仅记录到4例轻度药物相关不良事件，总发生率为0.03%（4/13464次输注）。未观察到病毒血清学转换。重度血友病PUPs中抑制剂发生率为29%（19/65）。总体而言，21例患者（20.6%）产生了抑制性抗体。21例患者中有9例尽管继续接受rFVIII间歇性治疗，但抑制剂滴度较低（<10贝塞斯达单位），8例接受间歇性治疗的患者中抑制剂滴度为短暂性（7例低滴度，1例高滴度）。8例高滴度抑制剂患者接受了免疫耐受诱导治疗；5例获得成功。
观察到的抑制剂形成发生率与接受血浆源性FVIII的PUPs研究相似。这些结果证明了rFVIII在长期治疗A型血友病中的安全性和有效性。
