Safety of Recombinant Factor VIII Therapy: Focus on Inhibitor Development

Introduction

Treatment of hemophilia A entails replacing missing or low levels of clotting factor VIII (FVIII). The evolution of FVIII replacement therapy began more than 60 years ago with infusion of fresh or frozen plasma to replace FVIII,1 but only low FVIII concentrations could be achieved with this method because of the risk of hypervolemia.1 Higher FVIII concentrations were subsequently achieved in the 1960s through use of cryoprecipitation and glycine precipitation techniques.1 However, the source of FVIII remained as fresh human plasma, placing recipients of FVIII replacement therapy at risk for blood-borne diseases.2 In the late 1970s and early 1980s, transmission of hepatitis B and C virus and HIV reached epidemic levels among patients with hemophilia treated with plasma-derived FVIII (pdFVIII) products, which, at that time, did not undergo a viral inactivation step during manufacture.3

Abstract

INTRODUCTION

Pathogen transmission and inhibitor development are the principal safety concerns when treating hemophilia A with factor VIII (FVIII) replacement therapy. The availability of recombinant FVIII (rFVIII) products, which are manufactured using little or no plasma-derived proteins, has minimized the risk of pathogen transmission but has not eliminated the possibility of FVIII inhibitor development.

OBJECTIVES

To review the safety issues related to use of second- and third-generation rFVIII products with a focus on incidence of inhibitor development.

METHODS

A Medline search was conducted using the search terms “recombinant factor VIII” and “safety.” Articles from this search were selected based on their relevance to the topic and supplemented with papers identified by reviewing the reference lists of published work.

RESULTS

The manufacture of rFVIII products differs from that of plasma-derived FVIII products in that plasma-derived proteins are used only in the culture medium (second-generation rFVIII products) or not at all (third-generation rFVIII products), limiting the risk of blood-borne pathogen transmission. In clinical trials involving previously untreated patients (PUPs), the incidence of inhibitor development for the second-generation rFVIII product formulated with sucrose (rFVIII-FS) was 15%, which compares favorably with the incidence range reported for clinical trials in PUPs receiving other rFVIII products (19%–35%).

CONCLUSION

Differences in study design and patient populations complicate comparisons of inhibitor formation among rFVIII products, but the incidence of inhibitor development with rFVIII products generally appears to be low.

Keywords

factor VIII, hemophilia, inhibitor, recombinant, pathogen safety