Rate of inhibitor development in previously untreated hemophilia A patients treated with plasma‐derived or recombinant factor VIII concentrates: a systematic review

Abstract

previously untreated hemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates: a systematic review. J Thromb Haemost 2010; 8: 1256-65.Summary. Background: Different rates of inhibitor development after either plasma-derived (pdFVIII) or recombinant (rFVIII) FVIII have been suggested. However, conflicting results are reported in the literature. Objectives: To systematically review the incidence rates of inhibitor development in previously untreated patients (PUPs) with hemophilia A treated with either pdFVIII or rFVIII and to explore the influence of both study and patient characteristics. Methods: Summary incidence rates (95% confidence interval) from all included studies for both pdFVIII and rFVIII results were recalculated and pooled. Sensitivity analysis was used to investigate the effect of study design, severity of disease and inhibitor characteristics. Meta-regression and analysis-of-variance were used to investigate the effect of covariates (testing frequency, follow-up duration and intensity of treatment). Results: Two thousand and ninety-four patients (1167 treated with pdFVIII, 927 with rFVIII; median age, 9.6 months) from 24 studies were investigated and 420 patients were observed to develop inhibitors. Pooled incidence rate was 14.3% (10.4-19.4) for pdFVIII and 27.4% (23.6-31.5) for rFVIII; high responding inhibitor incidence rate was 9.3% (6.2-13.7) for pdFVIII and 17.4% (14.2-21.2) for rFVIII. In the multi-way ANOVA study design, study period, testing frequency and median follow-up explained most of the variability, while the source of concentrate lost statistical significance. It was not possible to analyse the effect of intensity of treatment or trigger events such as surgery, and to completely exclude multiple reports of the same patient or changes of concentrate. Conclusions: These findings underscore the need for randomized controlled trials to address whether or not the risk of inhibitor in PUPs with hemophilia A differs between rFVIII and pdFVIII.

Current Controversies in the Formation and Treatment of Alloantibodies to Factor VIII in Congenital Hemophilia A

“…Two systematic reviews published in 2003 showed a significantly lower incidence of inhibitor development with the use of single pdFVIII product over a single rFVIII product; these reviews are summarized in Table 3. 15,16 However, after adjusting for study design, study period, testing frequency, and median follow-up, these data lost statistical significance in the second larger review. 16 The above data are largely retrospective, and a multivariate analysis of the studies in the second review showed an overestimation of inhibitor development in the retrospective studies.…”

Prevalence of Inhibitors to Factor VIII after 25 Exposures to Factor VIII Concentrates and/or Blood Products in Persons with Hemophilia A

“…The suggestion that monoclonal antibody-purified or recombinant preparations might cause higher inhibitor rates than those seen with plasma-derived preparations has not been proven. [20][21][22][23] Patient age at the time of initial replacement treatment, treatment intensity, and the early use of prophylaxis may influence inhibitor formation.…”

The role of natural VWF/FVIII complex concentrates in contemporary haemophilia care: a guideline for the next decade

“…1. Meta-analysis of the relative risk of inhibitor development between recombinant FVIII (rFVIII) and plasma-derived FVIII (pd-FVIII) concentrate in previously-untreated patients with haemophilia A [7].…”

“…To delve further into this issue, a meta-analysis was conducted on 24 studies which involved a total of 2094 patients, 1965 of whom were treated with pd-FVIII and 887 with rFVIII [7]. In line with the crude data, the combined random effect in the meta-analysis indicated that the risk of inhibitor development with rFVIII was approximately twice that with plasmaderived product (27.4 vs. 14.3%) within a narrow confidence interval (1.46-2.65).…”