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The basic science that made possible production of recombinant factor (F)VIII and factor IX was seminal. For hemophiliacs, it offered the hope of unlimited affordable therapy that would be safer than existing products. However, continued concerns about product contamination by agents such as new variant Creutzfeldt-Jakob Disease (NVCJD) have led to further refinements through removal of human and bovine proteins in an attempt to minimize or eliminate the potential for transfusion-transmitted disease.

As with all new technologies, there are both perceived and actual risks. One of the complications of any replacement therapy is the induction of inhibitors. The prevalence of inhibitors has been demonstrated to be 15%[1–3] from human-derived products. When the prospective multicenter previously untreated patients (PUP) studies were initiated (using all recombinant FVIII products), between 30 and 35%[4,5] of patients developed inhibitors. In some studies, as many as 50%[6] of the inhibitors remained high titer, while the rest either disappeared or remained low titer. Many of the high-titered patients required expensive, long-term immune tolerance induction. For some patients, success was not achieved. It has been posited that the prevalence of 30–35% from recombinant is no different from the 15% prevalence from human-derived products because the studies are not comparable. The question at hand remains: do recombinant products produce more inhibitors?

We have learned from these studies that many factors play a role in predilection for inhibitor development. The severity of disease (i.e. severe hemophiliacs are more likely to develop inhibitors), gene defect (e.g. inversions, deletions), in addition to African-Americans having twice the prevalence of inhibitor induction than Caucasians, are factors leading to higher likelihood of developing an inhibitor[1]. Altering human-derived products has also produced neoantigens that produced a higher unexpected prevalence of inhibitors in previously treated patients. Two different products added a second viral inactivation step to their process, producing a more immunogenic concentrate [7].

We already know that recombinant proteins have led to a higher rate of antibody induction than human- or animal-derived counterparts. Insulin and human growth hormone are such examples. The Dutch [8], Belgians, and Scandinavians [9], who keep excellent data on their hemophilia patient population, report that 6–10% of patients treated with human-derived products over a long period of time developed inhibitors. In England [10], one study demonstrated that PUPs studied on the English virally inactivated 8Y VIII produced no inhibitors. The Turkish data showed that cryoprecipitate- and plasma-treated patients had a minimal prevalence of inhibitors. The same was true in Iowa (CT Kisker, personal communication) with patients treated with cryoprecipitate derived from family members. Recently, the French have reported that 14% of their PUPs on human-derived products developed inhibitors, whereas 30% did so on recombinant products [11]. There is an ongoing German study taking all comers that compares treatment with either human or recombinant products. These data are not complete but suggest that differences exist and that a lower prevalence of inhibitors occurs with human-derived products.

In summary, it is unlikely that in the near future we will have sufficient prospective randomized studies to resolve definitively the dilemma of inhibitor induction. Therefore, both physicians and patients need to recognize that choosing a recombinant therapeutic product may well increase the risk of this major complication of therapy.

References

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  2. References
  • 1
    Aledort LM. Inhibitors in hemophilia patients: current status and management. Am J Hematol 1994; 47: 20817.
  • 2
    Rasi V, Ikkala E. Haemophiliacs with factor VIII inhibitors in Finland: prevalence, incidence and outcome. Br J Haematol 1990; 76: 36971.
  • 3
    Schwarzinger I, Pabinger I, Korninger C, Haschke F, Kundi M, Niessner H, Lechner K. Incidence of inhibitors in patients with severe and moderate hemophilia A treated with factor VIII concentrates. Am J Hematol 1987; 24: 2415.
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    Lusher JM, Arkin S, Abildgaard CF, Schwartz RS. Kogenate Previously Untreated Patient Study Group; Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. Safety, efficacy, and the development of inhibitors. N Engl J Med 1993; 328: 4539.
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    Bray G, Gomperts ED, Courter S, Gruppo R, Gordon EM, Manco-Johnson M, Shapiro A, Scheibel E, White G III, Lee M, Recombinate® Study Group. A multicenter study of recombinant factor VIII (Recombinate): safety, efficacy and inhibitor risk in previously untreated patients with hemophilia A. Blood 1994; 83: 242835.
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    Ehrenforth S, Kreuz W, Scharrer I, Linda R, Funk M, Gungor T, Krackhardt B, Kornhuber B. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 1992; 339: 5948.
  • 7
    Rosendaal FR, Nieuwenhuis HK, Van den Berg HM, Heijboer H, Mauser-Bunschoten EP, Van der Meer J, Smit C, Strengers PFW, Briët E, Dutch Hemophilia Study Group. A sudden increase in factor VIII inhibitor development in multitransfused hemophilia A patients in the Netherlands. Blood 1993; 81: 21806.
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    Peerlinck K, Rosendaal FR, Vermylen J. Incidence of inhibitor development in a group of young hemophilia A patients treated exclusively with lyophilized cryoprecipitate. Blood 1993; 81: 33325.
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    Nilsson IM. Recent Developments in the Study of Inhibitors to Factor VIII Therapy, Monograph. Washington, DC: American Red Cross, 1993: 1520.
  • 10
    Yee TT, Williams MD, Hill FG, Lee CA, Pasi KJ. Absence of inhibitors in previously untreated patients with severe haemophilia A after exposure to a single intermediate purity factor VIII product. Thromb Haemost 1997; 78: 10279.
  • 11
    Rothschild C, Goudemand J, Demiguel V, Lambert T, Calvez T. Effect of type of treatment (recombinant vs. plasmatic) on FVIII inhibitor incidence according to known risk cofactors in previously untreated severe hemophilia A patients (Pups). J Thromb Haemost 2003; 1 (Suppl) : Abstract OC215.