A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A

作者：Peyvandi, F.^*; Mannucci, P. M.; Garagiola, I.; El-Beshlawy, A.; Elalfy, M.; Ramanan, V.; Eshghi, P.; Hanagavadi, S.; Varadarajan, R.; Karimi, M.; Manglani, M. V.; Ross, C.; Young, G.; Seth, T.; Apte, S.; Nayak, D. M.; Santagostino, E.; Mancuso, M. E.; Sandoval Gonzalez, A. C.; Mahlangu, J. N.; Bonanad Boix, S.; Cerqueira, M.; Ewing, N. P.; Male, C.; Owaidah, T.; Soto Arellano, V.; Kobrinsky, N. L.; Majumdar, S.; Perez Garrido, R.; Sachdeva, A.; Simpson, M.; Thomas, M.; Zanon, E.

来源：New England Journal of Medicine, 2016, 374(21): 2054-2064.

DOI：10.1056/NEJMoa1516437

• PREVIOUSLY UNTREATED PATIENTS
• INHIBITOR DEVELOPMENT
• UNITED-STATES
• PLASMA
• PRODUCTS
• FVIII
• RECOMBINANT
• CONCENTRATE
• MORTALITY
• CHILDREN

BACKGROUND @@@ The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy. @@@ METHODS @@@ We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites. @@@ RESULTS @@@ Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (>= 5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00). @@@ CONCLUSIONS @@@ Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII. (Funded by the Angelo Bianchi Bonomi Foundation and others; ClinicalTrials.gov number, NCT01064284; EudraCT number, 2009-011186-88.)

• 出版日期2016-5-26
• 单位河北医科大学