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In the last two decades, great advances in our understanding of the genetic and molecular bases of haemophilia, along with the results of extensive clinical research, have led to dramatic improvements in the management of people with this inherited bleeding disorder. The period from the 1990s onward has been characterised by an increase in the availability and quality of recombinant coagulation factors and the broad implementation of prophylactic treatment regimens1. In parallel, progressive improvement of virus-inactivation methods in plasma products, as well as of methods used to screen viruses in blood donations and plasma pools (i.e., polymerase chain reaction testing) led to an impressive increase in the safety of plasma-derived factor concentrates, as clearly documented by the fact that no blood-borne transmission of hepatitis viruses or human immunodeficiency virus has occurred in the last 20 years2. As a consequence, the quality of life of haemophiliacs has dramatically improved and their life expectancy has progressively approached that of their non-haemophilic peers3. In this context, the most challenging complication of current therapy has become the development of inhibitory alloantibodies, which renders replacement therapies ineffective, limit the access of patients to a safe and effective standard of care and predispose them to an unacceptably high risk of morbidity and mortality4.
Despite intensive research, particularly focused on inhibitory antibodies against factor VIII (FVIII) which are much more frequent than those directed against factors IX and XI, the mechanism of this complication still remains incompletely understood. Patient-related, non-modifiable risk factors as well as environmental, modifiable risk factors have been identified5,6. Debate on the role of the source of product used for therapy started soon after several reports on previously untreated patients (PUPs) demonstrated a higher incidence of inhibitors in patients treated with recombinant FVIII concentrates than in those treated with plasma-derived products7. In vitro studies suggested that the presence of von Willebrand factor (VWF) in plasma-derived FVIII concentrates plays a role in decreasing FVIII immunogenicity, via epitope masking and protection of the FVIII molecule from endocytosis by antigen-presenting cells8,9. Other investigators however maintain that the putative lower immunogenicity of plasma-derived FVIII is related to a number of immunomodulatory substances contained in these products, which are much less purified than recombinant factors10.
In 2003, a systematic review was carried out to investigate more comprehensively the epidemiology of inhibitors in haemophilia A in relation to the source of FVIII11. Patients treated with a single plasma-derived FVIII had a lower cumulative incidence of inhibitors than those treated with a single recombinant FVIII product. In patients treated only with plasma-derived FVIII, the cumulative incidence of inhibitors ranged from 0% to 12.4% (weighted mean, 6.8%) for all inhibitors and from 0% to 2.5% (weighted mean, 1.4%) for high-responder inhibitors (>5 Bethesda units). In comparison, in patients treated exclusively with recombinant FVIII, cumulative incidence rates between 36% and 38.7% (weighted mean, 37.5%) were reported for all inhibitor patients whereas for high responders the inhibitor incidence ranged from 11.3% to 18% (weighted mean, 15.1%)11.
Other studies carried out after the publication of the systematic review were consistent with these results. In 2006, Gringeri and colleagues retrospectively evaluated the occurrence of inhibitors in PUPs or minimally treated patients with severe haemophilia A treated with plasma-derived, VWF-containing FVIII concentrates and found an inhibitor incidence of 9.8%12. This low inhibitor incidence using plasma-derived VWF-containing FVIII products was confirmed in other cohorts of PUPs/minimally treated patients13,14. In particular, a retrospective French study cohort of PUPS with severe haemophilia A given a single high-purity plasma-derived VWF/FVIII or first generation full-length recombinant FVIII concentrates found a 2.4-higher risk of inhibitors in patients treated with a recombinant FVIII than in those treated with a plasma-derived VWF/FVIII13. Similarly, in a retrospective UK cohort study that included 348 PUPs, the overall incidence of new inhibitors was 14% among those treated exclusively with plasma-derived FVIII versus 27% in those treated with recombinant FVIII15. There are, however, also recent results in contrast with these findings, because a retrospective analysis of data obtained in 316 PUPs enrolled in the CANAL study found no difference between plasma-derived and recombinant products16. These discrepancies led European and North American investigators to carry out a more recent systematic review and meta-analysis that included as many as 2094 PUPs (1167 on plasma-derived and 927 on recombinant FVIII concentrates) from 24 prospective and retrospective studies. In this analysis, 14.3% of patients treated with plasma-derived FVIII concentrates and 27.4% of patients treated with recombinant FVIII products developed inhibitors17 and the rate of high-titre inhibitors was higher in the recombinant FVIII arm (17.4% versus 9.3%), even though the higher immunogenicity of recombinant FVIII decreased when a number of possible confounders were included in the analysis17.
Unfortunately, no randomised clinical trials are currently available to provide definite evidence on whether or not a difference in immunogenicity does exist between plasma-derived and recombinant FVIII concentrates. For this reason, the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) has been started recently (http://www.clinicaltrials.gov, study NCT 01064284; EUDRACT n. 2009-011186-88). SIPPET is an investigator-driven, prospective, randomised, open-label clinical trial investigating inhibitor frequency in PUPs or minimally treated patients first exposed to plasma-derived VWF/FVIII concentrates or recombinant FVIII18. The main objective of SIPPET is to compare the immunogenicity of VWF/FVIII and of recombinant FVIII products by determining the cumulative incidence of inhibitor development in the first 50 exposure days. Secondary objectives include the identification of risk factors potentially associated with inhibitor development (e.g. age at first treatment, severity of bleeding, surgery, intensity of treatment, modality of treatment delivery, time of treatment in relation to vaccinations, concurrent viral infections and/or medications) and laboratory variables, such as gene defects, FVIII antigen level, MHC HLA phenotype, interleukin-10 and tumor necrosis factor-a genotypes18. Other large prospective cohorts that investigate PUPs with severe haemophilia, such as the European PedNet Registry19 and the French cohort (FranceCoag Network)20, may also contribute to fulfil these objectives.
Another important issue related to the choice of plasma-derived versus recombinant FVIII is that of the comparative efficacy of the two sources of replacement therapy in achieving immune tolerance, the best method to eradicate inhibitors through the long-term treatment of patients with replacement therapy with coagulation factors. After several in vitro studies showed a decrease in inhibitor activity against FVIII complexed with VWF (VWF/FVIII) compared with recombinant FVIII21–26 a number of clinical studies have explored the role of FVIII product type in immune tolerance induction (ITI), and some clinical experience in Europe and the USA suggest that FVIII concentrates rich in VWF may increase the likelihood of successful ITI. A retrospective study conducted in Frankfurt showed that the success rates using a high-dose ITI protocol (the so-called Bonn protocol) declined from 91% to 37.5% following the introduction, in the early 1990s, of monoclonal FVIII concentrates that contain very little VWF27. When patients who had an unsatisfactory response to ITI using monoclonal or recombinant FVIII were switched to concentrates containing large amounts of VWF, 80% of them achieved complete inhibitor eradication. Similarly, a compilation of data from two haemophilia centres in Germany showed that before 1990 ITI was successful in 87% of patients treated exclusively with VWF/FVIII products, whereas later, i.e., between 1990 and mid-1999 when monoclonal FVIII products were largely used, success rates dropped to 54%28. With the return to use of the VWF/FVIII products in the mid 1999s, 82% of patients were successfully tolerised28. These results are strengthened by the findings of a number of investigators in Europe and the USA, who observed the enhanced efficacy of VWF-containing concentrates used for ITI, particularly in patients with poor prognostic factors and resistant to previous tolerisation with monoclonal or recombinant products29–31. In this context, the results of two ongoing prospective trials, the Rescue Immune Tolerance Study (RESIST)-naive (ITI-naive patients with poor prognostic factors randomly assigned to VWF/FVIII or recombinant FVIII at a dose of 200 IU/kg/day) and RESIST-experienced (patients who have previously failed ITI with monoclonal or recombinant FVIII undergoing ITI with VWF/FVIII products at a dose of 200 IU kg/day), should help to elucidate the role of the source of FVIII in ITI.
Thus, taking in account these clinical and experimental findings on inhibitor development, inhibitor eradication using plasma-derived VWF/FVIII products and also considering their lower costs and the high degree of safety reached now, I conclude that plasma-derived VWF/FVIII products should be strongly considered as an adequate therapeutic choice not only in patients already being treated with these products, but also in previously untreated or minimally treated children. In particular, they should also be more widely used to induce immune tolerance, not only because of in vitro data and of the striking clinical data collected in Germany27,28, but also because I find it more biologically plausible to attempt to induce immunotolerance with a product different from that used at the time of inhibitor development (which, in Western Europe and North America, is mainly recombinant FVIII).