Incidence of inhibitors to recombinant factor VIII products – A meta-analysis of 1,852 previously untreated patients

Aim: This study aimed to evaluate the risk of inhibitor development and to clarify the relationship between rFVIII product used and inhibitor development in previously untreated patients (PUPs) and minimally treated patients (MTPs). Methods: Prospective and retrospective clinical studies, published from 1 January 1988 to 31 August 2015, with PUPs and MTPs with severe and moderate hemophilia A were identified in a systematic literature search in electronic databases. The primary outcome measure was development of clinically relevant inhibitors. The secondary outcome measure was development of a high-titer inhibitor, defined as peak titer of at least 5 BU/mL up to the 75th exposure day. We computed pooled meta-analytic estimates according to the rFVIII product used by applying the inverse-variance method, assuming a fixed, or a random-effects model if significant between-studies heterogeneity was present. Results: We identified 728 unique papers, of which 664 papers were excluded because (duplicates; not relevant for the endpoint; review articles; letter to the editor; case-reports; animal studies; and others). Sixty-four full-text papers were evaluated, plus ten additional papers identified through review of references of the retrieved articles. Of these, 57 articles were excluded after full-text review (incompleteness of data, overlapping cohort); 17 studies were included in the final meta-analysis. The pooled estimate of all inhibitors (548 inhibitors out of 1,852 PUPs/MTPs) in the overall population considered was 0.27 (95% CI 0.24–0.31) with significant heterogeneity (I-squared: 67.5%, p< 0.01). Also in only PUPs with severe hemophilia (331 inhibitors out of 1,153 PUPs), the pooled estimate of all inhibitors was 0.27 (0.22–0.32) with significant heterogeneity (I-squared: 63.5%, p< 0.01). The observed heterogeneity was due to differences in inhibitor incidence among studies using the same product. Pooled inhibitor incidence estimates among products ranged from 0.20 to 0.42 with overlapping confidence intervals, in the absence of heterogeneity (p=0.18). Similar patterns were observed in subpopulations of patients with high or low titer inhibitors. A few studies reported inhibitor hazard ratios with the different products used, taking into account potential risk factors. A meta-analysis of these studies showed PUPs/MTPs treated with Antihemophilic Factor (Recombinant, 3rd generation) had a pooled inhibitor hazard ratio estimate of 0.63 (95% CI 0.48–0.83) as compared to Antihemophilic Factor (Recombinant, 2nd generation). The pooled estimates of other rFVIII were not significantly different. Conclusion: The overall incidence of inhibitors in PUPs/MTPs included in this meta-analysis was 27%. Although significant heterogeneity among studies was observed, no significant differences among products were found. Differences between products used were found only by considering hazard ratios considering potential risk factors.