Evolving perspectives in product safety for haemophilia

Abstract

The past decade has seen a consolidation of the safety measures built into the manufacture of coagulation factor concentrates for people with haemophilia. The scientific developments of the 1980s have been fully reflected in the manufacturing principles and the regulatory control of concentrate production, so that the safety of concentrate therapy now exceeds the safety of normal blood transfusion. A clear understanding of the epidemiology of the transfusion-transmitted viruses allows the selection of donors with a satisfactory safety profile. Source material for plasma-derived concentrates is now screened with sensitive tests that detect viral infection in donors at a very early phase in the viral life cycle. This decreases the potential viral load to levels that are easily eliminated by well-accredited viral inactivation procedures. These measures have ensured a high level of assurance regarding the safety of products from the traditional transfusion-transmitted infections. However, testing for some transfusion-transmitted viruses does not yet form part of mainstream blood screening; alternative strategies based upon the particular needs of pooled plasma product recipients may be more feasible. Whereas the risk of emerging pathogens has to be kept constantly under review, four such viruses identified over the 1990s have proven to be of little relevance to plasma product recipients and the need for measures specifically directed against them is debatable. The risk of variant Creuzfeldt-Jakob Disease (vCJD) is a special case of an emerging infection that is insufficiently well characterized to allow a conclusive assessment of its role in the safety of concentrates; however, data regarding the capacity of concentrate manufacturing methods to clear the putative agent are encouraging. The relative uncertainty surrounding vCJD has caused the influential regulatory authorities of North America to take a precautionary approach regarding the selection of blood donors. This is having an effect on the supply of factor VIII concentrates and has possibly affected the rate at which developed countries have switched to recombinant products. The safety of recombinant products continues to be supported through patient monitoring, and the new generation of plasma protein-free products will further enhance the role of these products as the treatment of choice with people with haemophilia. However, their cost-effectiveness relative to the current generation of plasma-derived products makes it unlikely that they will be accessible by developing countries. The dependence of most of the world's population of people with haemophilia on a safe and sufficient blood supply will therefore continue into the foreseeable future, and with it the need to maintain constant vigilance on blood safety matters.

The History and Evolution of the Clinical Effectiveness of Haemophilia Type A Treatment: A Systematic Review

“…In contrast a cohort that evaluated 62 patients treated with the same brand of high-purity plasma-derived FVIII (pFVIII) containing Von Willebrand factor (VWF) and 86 patients treated with full-length rFVIII concluded that the risk of inhibitor development was higher in patients treated with rFVIII than in patients treated with pFVIII, regardless of other risk factors (F8 genotype; non-white origin; history of inhibitors in patients with a family history of haemophilia; age at first FVIII infusion). The adjusted relative risk (RR) for inhibitor development with rFVIII versus pFVIII was 2.4 [36,37].…”

Detection of EBV, HBV, HCV, HIV-1, HTLV-I and -II, and SMRV in Human and Other Primate Cell Lines

“…A considerable percentage of cell lines was established before viral contaminations had been routinely assayed or even before those viruses had been discovered. Additionally, the risk of emerging pathogens has to be kept under constant review [3]. …”

Therapy for haemophilia: recent advances and goals for the future

“…Although most inhibitors are either transient or resolve with immune tolerance therapy, ∼ 15% of FVIII-deficient patients and 3% of FIX-deficient patients have persistent clinically significant inhibitors, which result in severe morbidity [13,14]. Finally, although the risk of transmission of infectious agents has been largely overcome by the development of recombinant factor products, there still exists at least the theoretical risk of infection from prions and unforeseen infectious agents perhaps from the use of mammalian cells in the production of factor concentrates [15]. Future treatment for haemophilia revolves around improving on these negative aspects of therapy.…”