Can B-domain deletion alter the immunogenicity of recombinant factor VIII? A meta-analysis of prospective clinical studies

被引:59
作者
Aledort, L. M. [1 ]
Navickis, R. J. [2 ]
Wilkes, M. M. [2 ]
机构
[1] Mt Sinai Sch Med, New York, NY 10029 USA
[2] Hygeia Associates, Grass Valley, CA USA
关键词
blood coagulation factor inhibitors; factor VIII; hemophilia A; incidence; previously treated patients; recombinant proteins; PREVIOUSLY TREATED PATIENTS; HEMOPHILIA-A PATIENTS; PLASMA/ALBUMIN-FREE METHOD; INHIBITOR DEVELOPMENT; FULL-LENGTH; POSTMARKETING SURVEILLANCE; LONG-TERM; MULTITRANSFUSED HEMOPHILIA; SAFETY SURVEILLANCE; JAPANESE PATIENTS;
D O I
10.1111/j.1538-7836.2011.04472.x
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background: As a result of the infrequency of inhibitors in previously treated patients (PTPs) with hemophilia A and the small size of available clinical studies, the immunogenicity of factor (F) VIII products has been difficult to assess. Objectives: A meta-analysis of prospective clinical studies was conducted to test the hypothesis that de novo inhibitor incidence differs between PTPs receiving full-length recombinant FVIII (FL-rFVIII) and B-domain deleted recombinant FVIII (BDD-rFVIII). Methods: Prospective studies with data on inhibitors in PTPs receiving FL-rFVIII or BDD-rFVIII were sought using systematic methods including bibliographic database searches. Data were secured from published study reports and inquiries to investigators. Between-group differences in inhibitor incidence rates were evaluated using mixed effects Cox regression. Results: Twenty-nine studies with 3012 total PTPs were included. Patients were at risk of de novo inhibitor development for a median of 79 exposure days. A total of 35 de novo inhibitors were observed. The cumulative hazard for all de novo inhibitors was 1.25% with a 95% confidence interval (CI) of 0.63-1.88%. The corresponding rate for high-titer de novo inhibitors [> 5 Bethesda units (BU)] was 0.29% (CI, 0.01-0.57%). Exposure to BDD-rFVIII was associated with an increased risk of all de novo inhibitors (hazard ratio, 7.26; CI, 2.12-24.9; P = 0.0016) and of high-titer de novo inhibitors (hazard ratio, 10.8; CI, 2.17-53.7; P = 0.0037), compared with FL-rFVIII. Conclusions: This meta-analysis of prospective clinical studies suggests that recombinant FVIII products may differ in immunogenicity.
引用
收藏
页码:2180 / 2192
页数:13
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