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Developments in the production of plasma-derived factor VIII and recombinant factor VIII have improved safety and increased the availability of these products for people with haemophilia A
Pier M Mannucci Angelo Bianchi Bonomi
Haemophilia and Thrombosis Centre
Department of Medicine and Medical Specialties
University of Milan and IRCC S Maggiore
Hospital Foundation, Milan
Modern treatment of haemophilia A, the most common and severe inherited coagulation disorder, began in the early 1970s, when a few commercial manufacturers made available factor VI (FVI)-containing products purified from human plasma pooled from thousands of donors. These products, lyophilised and soluble in small amounts of fluid, could be easily administered to patients by slow intravenous injections, making feasible home care by caregivers, parents and patients themselves. In turn, home care made possible early treatment of incident bleeding episodes, and even their prevention through the administration of FVI at regular intervals (primary prophylaxis).
If the 1970s were a landmark in the path towards modern treatment of haemophilia, the picture changed dramatically in the early 1980s when a large proportion of patients treated with pooled plasma concentrates became infected with bloodborne agents such as the hepatitis C and B viruses and the newly identified human immunodeficiency virus (HIV).[2,3]
Many patients infected with HIV died, while others died as a consequence of chronic viral hepatitis. The scientific community reacted rapidly to these unpredicted scourges that had hit people with haemophilia at a time when replacement therapy had dramatically improved their quality of life.
The first step towards improving safety was the introduction of virus inactivation methods that, added to the processes employed to manufacture plasma derived FVI, progressively rendered them safer and safer.
Since the late 1980s, when effective virucidal methods were fully adopted by all manufacturers of coagulation factors, no viral infection has been recorded. Neither has the abnormal prion responsible for new variant Creutzfeldt–Jakob disease been transmitted by coagulation factor concentrates, as was feared.[1,4,5]
Another advance has made available a safer therapy to people with haemophilia: FVI produced through recombinant DNA technology. The first recombinant FVI was clinically evaluated and made commercially available by Baxter in 19917 followed by those produced by Bayer[8,9] and Wyeth. Clinical experience with recombinant FVI in the treatment of people with haemophilia now spans over a quarter of century: not only are these products very efficacious, but they also have an impeccable safety record. This article features the main characteristics of plasma-derived and recombinant FVI products currently available in Europe.
Plasma-derived factor VIII
To assure safety, manufacturers perform plasma serologic tests for HIV1–2, HbsAg and HCVA b on individual donors. The adoption of other tests (such as ALT , HbcAb and HbsAb) are much less widespread. Other measures such as plasma inventory hold – that is, retention of plasma after donation and before fractionation to acquire more information about a donor – and nucleic acid testing (NAT ) are also applied by manufacturers, even though there is some variability between them for the length of inventory hold, plasma mini-pool size and the viruses that are looked for by NAT in mini-pools.
In all, the requirement for viral testing of donor plasma used to manufacture plasma-derived FVI has become more and more stringent and has considerably contributed to the current safety status of these products.
Table 1 (page 40) lists plasma-derived FVI products available in European countries and provides information on brand name, manufacturer, plasma source, fractionation and viral inactivation methods. The costs of these products vary between different countries.
In general, the per-unit cost of plasma-derived FVI is approximately two-thirds or less that of recombinant FVI. On the whole, plasma-derived concentrates have been clinically evaluated to an extent sufficient to demonstrate their efficacy and safety convincingly. The available products vary to a relatively large degree in terms of purification and content of other plasma proteins (Table 1).
At the moment there is less preference than in the early 1990s for high-purity products, because there is little evidence that protein contaminants negatively affect the safety and efficacy of FVIII (see below).
Recombinant factor VIII products
Five brands are currently licensed and available: Recombinate and Advate (Baxter BioScience)[7,11] Refacto (Wyeth), Helixate FS (CSL Behring) and Kogenate FS (Bayer). Helixate FS and Kogenate FS are the same product manufactured by Bayer Healthcare and made commercially available as two different brands.
Table 2 shows the main characteristics of recombinant FVI. Notwithstanding the fact that no clinically significant adverse event has ever been recorded for recombinant FVI products since their first availability, and that the different brands appear to be equally effective and safe, there has been a tendency by manufacturers to progressively increase the purity of their products and to eliminate from the manufacturing process, as well as from the final formulation, human- or animal-derived plasma proteins other than FVI.
However, all currently available products still use immunoaffinity chromatography with mouse monoclonal antibodies to purify FVI. The recombinant FVI products containing large amounts of human albumin in the final formulation are conventionally called first-generation products. Of these, only Recombinate is still produced and available. The production of Kogenate and Helixate has been discontinued and replaced by the corresponding brands targeted as FS, that contain no albumin in the final formulation and that are considered second-generation recombinant FVI. To the second generation of FVI products also belongs Refacto, which is engineered without the disposable B domain of the FVI molecule.
The only third-generation FVI currently licensed is Advate, which is produced without any contact with human- or animal-derived proteins during the purification process. However, Advate comes into contact with heterologus proteins during its manufacture: hamster cells, that secrete human FVI in the culture medium, and mouse monoclonal antibody, used in one of the purification steps. Wyeth is in the advanced stages of clinically evaluating a fourth generation FVI that avoids the latter step, and hence any contact with mouse proteins (but hamster cells are still being used).
These efforts to further purify recombinant FVI stand as a monument of ingenuity and high technology, notwithstanding the impeccable record of safety and efficacy of first-generation FVI. What about the future? Several manufacturers are developing newer products that aim to extend the half-life of FVI in the circulation. At least one of these products, which would offer substantial advantages in regular primary prophylaxis, is in an advanced phase of clinical testing for licensing.
The dramatic problems created in the 1980s by the appearance of HIV infection in people with haemophilia, as well as the first awareness of the long-term ominous consequences of chronic infections with the hepatitis viruses, have led to a tremendous thrust towards the development of safer and safer FVI. Another step forward is increased availability, as shown by the selection of products available in several different European countries. Recombinant FVI is an exciting development and stands as one of the main examples of the success of biotechnologies in producing plasma proteins for therapeutic use.
Which product should be chosen? In some European countries (such as the United Kingdom, Ireland, The Netherlands, Sweden and Denmark) only – or almost only – recombinant FVI is used, in spite of its higher cost. This choice is driven by factors such as the more advanced technology behind these products and the associated perception of greater safety. Greater safety is only perceived though, because there has been no report of breaches of safety for plasma-derived FVI since the agonies of the 1980s. For instance, no HIV or hepatitis A, B or C viruses have been transmitted by any FVI product since 1987, as demonstrated in the USA by the Centers for Disease Control and Prevention, which has implemented an ongoing programme of broad surveillance of treated people with haemophilia. Neither have viral transmissions been recorded in Europe, where the same products are used.
Accordingly, plasma-derived FVI is still largely used in such countries as Spain, Italy and France, and the countries of Eastern Europe. This attitude is driven not only by the lower cost coupled with documented safety, but perhaps also by the availability of data indicating that these products are less likely to trigger the development of FVI alloantibodies (inhibitors) in previously untreated or minimally treated boys with severe haemophilia A.[14–17] Available data are suggestive but not conclusive, so that a randomised clinical trial comparing plasma derived, VWF-containing FVI with recombinant FVI is about to start in three different continents (the SIPET Study).[18,19]
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