Treatment-related factors, including treatment intensity as briefly mentioned above, therapeutic regimen (i.e. prophylaxis vs. on-demand treatment) and product type have been proposed as possible influences on inhibitor development 7?2. For example, a systematic literature review concluded that inhibitor incidence was lower in patients treated with one pd-FVIII vs. those who had used multiple pd-FVIII concentrates or a single rFVIII product 12. Although a more moderen systematic review using multi-way analysis of variance concluded that source of concentrate did not significantly influence inhibitor development 11, suggestions of an increased incidence of inhibitor development and treatment with rFVIII products, and also those with a B-domain deletion/modification, may continue to contribute to patient and physician reluctance to switch to new rFVIII products.
Three early studies in previously untreated patients (PUPs) suggested that the incidence of inhibitor development was less for those treated with pd-FVIII than in patients treated with rFVIII 13?5. However, significant differences in inhibitor development were only observed in two of these three studies 13,14. Within the UK study, inhibitors developed more frequently in patients initially treated with rFVIII when compared with pd-FVIII (P = 0.006) 13. In a French cohort study, the risk of inhibitor development was reported to be higher in patients treated with rFVIII than those treated with pd-FVIII, no matter other risk factors (e.g. F8 genotype, history of inhibitors in patients with a family history of haemophilia, age at first FVIII infusion) 14. However, in Sweden, no significant increase within the incidence of inhibitors was reported for haemophilia A patients in the 1990s who were mainly treated with recombinant products (n = 10/48, total incidence 21%), as compared with the 1980s (n = 9/52, 17%), when patients received intermediate/high-purity plasma-derived concentrates 15.
The Concerted Action on Neutralising Antibodies in severe haemophilia A (CANAL) study was a retrospective, multi-centre cohort study designed to further describe the relationship between treatment and inhibitor development in 366 PUPs with severe haemophilia (residual FVIII activity <2%) born between 1990 and 2000 9,16. Data available on product type and inhibitor incidence from 316 PUPs were evaluated. A total of 82 patients (26%) developed clinically relevant inhibitors; of 181 patients first treated with rFVIII product, 53 (29%) developed inhibitors, while inhibitors were reported in 29 of the 135 (21%) patients treated with pd-FVIII, and the relative risk (RR) of inhibitors in pd-FVIII vs. rFVIII products was 0.8 (95% confidence interval [CI], 0.5?.3) 16. In addition, switching between FVIII products did not appear to increase the risk of inhibitor development (RR, 1.1; CI, 0.6?.6). Hence, the CANAL study results do not support previous findings suggesting an increased risk of inhibitor development with rFVIII products, nor that switching products may influence inhibitor development 16.
More recently, the potential influence of rFVIII vs. pd-FVIII product type on inhibitor development was also explored within the RODIN (Research Of Determinants of INhibitor development) study, which used data from the PedNet registry that comprised 29 centres in Europe, Canada and Israel. Data were evaluated from 574 PUPs born between 2000 and 2010. Inhibitory antibodies were reported in 177 children (cumulative inhibitor incidence, 32.4%). Overall, there was no difference in inhibitor risk between pd-FVIII and rFVIII products (adjusted hazard ratio 0.96; 95% CI, 0.62?.49), and switching between different FVIII products was not related to an increased risk of inhibitor development (adjusted hazard ratio 0.99; 95% CI, 0.63?.56). However, a significantly increased risk of inhibitor development was found to be associated with second-generation (produced in baby hamster kidney [BHK] cells) vs. third-generation full-length rFVIII products (adjusted hazard ratio 1.60; 95% CI, 1.08?.37) 7. Although this latter finding is intriguing, there isn’t any clear biological explanation for the difference in inhibitor development between second- vs. third-generation full-length rFVIII.
Concerns regarding a possible increase in immunogenicity related to B-domain deleted rFVIII were raised by an early Italian study of previously treated patients (PTPs) 17. Of 25 low-risk PTPs, one patient developed an inhibitor after switching from pd-FVIII to B-domain-deleted rFVIII 17. Results from a more recent meta-analysis by Aledort and colleagues of prospective clinical studies on product switching appeared to demonstrate an increased risk of inhibitor development with B-domain-deleted rFVIII in PTPs 8. However, “good results for meta-analyses come from inclusion of excellent data?18, and on this respect, of the 2 studies that contributed the most to the final odds ratio for the Aledort meta-analysis, one consisted only of case reports 19 and the opposite contained only the prospective arm from the Italian study 17. Caution is therefore warranted when assessing the validity of those findings.
The continued European Haemophilia Safety Surveillance (EUHASS), a prospective adverse event reporting system, is exploring the incidence of inhibitors in PUPs and PTPs and the potential factors that may be contributing to inhibitor development. Data reported from the primary 2 years of the study, provided by 64 haemophilia centres from 27 European countries (caring for 22 242 patients), showed that the inhibitor rate in PUPs with severe haemophilia A was 25% overall, with an analogous incidence of inhibitors in patients treated with rFVIII (25%) as compared with those treated with pd-FVIII (27%) 20. For PTPs, no significant difference was observed in inhibitor incidence between different rFVIII products (including full-length and B-domain-deleted products) 20. A more recent evaluation of data now available from the first 3 years of EUHASS has confirmed that in PUPs, there are no significant differences in inhibitor development between pd-FVIII and rFVIII products, or between different rFVIII products 21. Of note, the second-generation full-length rFVIII product related to increased inhibitor incidence in the RODIN study was also one produced in BHK cells; together, these findings may lead to speculations that products may be associated with inhibitor development in PUPs. However, such speculation ought to be made with caution as many other variables may contribute to immunogenicity.