The case for wider use of recombinant factor VIII concentrates

Critical Reviews in Oncology/Hematology 83 (2012) 11–20

The case for wider use of recombinant factor VIII concentrates Cedric Hermans a,∗ , Hans-Hermann Brackmann b , Piercarla Schinco c , Günter Auerswald d a

c

Hemostasis and Thrombosis Unit, Haemophilia Clinic, CliniquesUniversitaires Saint-Luc, Catholic University of Louvain, 1200 Brussels, Belgium b Institute of Experimental Hematology and Transfusion Medicine, University of Bonn, Germany Hemostasis/Thrombosis Unit and Hemophilia Centre, Azienda Ospedaliera/Universitaria S. Giovanni Battista – Molinette, Turin, Italy d Klinikum Bremen Mitte Prof.-Hess-Kinderklinik, St.-Jürgen-Str. 1, 28205 Bremen, Germany Accepted 5 August 2011

Contents 1. 2.

3.

4.

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Current concerns with factor concentrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Pathogen safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. The parvovirus experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. The variant Creutzfeldt–Jakob disease experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.3. Presence of impurities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Neutralizing inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. Interpretation of clinical studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. Results from pooled analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.3. Evidence from the CANAL study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.4. Impact of treatment modality on inhibitor development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Increased immunogenicity related to manufacture of plasma-derived factor VIII . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Factors that may influence product choice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Guideline recommendations on choice of concentrate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Cost considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Scientific validation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Practical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Pressures on the blood supply . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12 13 13 13 14 14 14 15 15 15 16 16 16 16 16 17 17 17 18 18 18 18 18 20

Abstract The introduction of clotting factor concentrates led to major advances in hemophilia care. Rather than simply providing an alternative to plasma-derived concentrates, the introduction in the 1990s of recombinant concentrates added value to replacement therapy particularly with respect to prophylaxis and immune-tolerance induction. While the safety of plasma-derived concentrates has improved considerably, these concentrates may still pose an infectious risk through as-yet unknown pathogens and poor impurity constituent characterization. Recombinant concentrates are increasingly used because of their benefits in pathogen safety, convenience and the potential for unfettered supply. Yet worldwide they remain accessible only to a limited number of patients due to fear of the potential for inhibitor development, overestimation

∗

Corresponding author. Tel.: +32 2 764 1785; fax: +32 2 764 8959. E-mail address: [email protected] (C. Hermans).

1040-8428/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2011.08.001

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of their costs and underestimation of their benefits. This article reviews the characteristics and properties of recombinant FVIII concentrates to help physicians and patient representatives promote the right of access of patients to the safest products. © 2011 Elsevier Ireland Ltd. All rights reserved. Keywords: Recombinant factor VIII; Prophylaxis; Hemophilia A; Safety; Inhibitor

1. Introduction Widespread use of factor VIII concentrates by patients with severe hemophilia has been one of the outstanding success stories of medical history. Such treatment today enables patients to reverse the negative effects of, and even prevent, bleeds that once would have left them crippled, leading to improvements in quality of life for affected patients. Indeed, the modern management of hemophilia has been so successful that it is easy to forget that as recently as in 1960, the average life expectancy of a boy affected by severe hemophilia was <20 years [1]. At that time, treatment of bleeding episodes was based on the infusion of fresh frozen plasma, which was severely limited by the volume of plasma required, and which frequently made elective surgery unfeasible [2]. The discovery in the mid-1960s that factor VIII was concentrated in plasma cryoprecipitate led to the production of more specific and effective replacement therapy [3]. Initially, cryoprecipitate harvested from single units of plasma was used directly or as crude lyophilized concentrates. These preparations had relatively low specific activities, being primarily composed of other plasma proteins. Processing of pooled cryoprecipitate with chromatography and precipitation led to the production of concentrates of intermediate-purity and later to high-purity concentrates obtained by chromatographic separation, including immunoaffinity purification with monoclonal antibodies to factor VIII or von Willebrand factor. While immunoaffinity-purified concentrates can be purified to very near the theoretical maximal specific activity, pure factor VIII is unstable at this concentration and albumin or other chemicals are needed as a stabilizer. The development of such concentrates was achieved by a large, worldwide plasma-fractionation industry, with concentrates prepared from pooled plasma obtained from as many as 200,000 donors, and manufactured in large quantities. Donors were generally paid in order to obtain sufficient plasma to meet national and international needs. Unfortunately, such plasma donations were sometimes affected by then-unknown viruses such as HIV and hepatitis C (HCV, originally termed “non-A non-B hepatitis”). As is well known, the epidemic of HIV infection that afflicted the hemophilia community in the 1980s was largely the result of US-derived commercial concentrates [4]. In the UK, 1246 of 7250 patients with hemophilia were infected with HIV, halting the improvement in life expectancy among people with hemophilia. Fig. 1 shows the mortality rate among patients infected with HIV compared with those who remained HIV negative, and illustrates how deaths from HIV were reduced following the

Fig. 1. Change in the annual death rate among people with hemophilia infected with HIV compared with those not infected (Darby et al. [5]).

availability of highly active retroviral therapy in the early 1990s [5]. Efforts to inactivate viruses present in coagulation factor VIII concentrates began in response to the recognition of Hepatitis B and HCV in patients with hemophilia who had received transfusions, and were intensified as it was found that most hemophilia patients infected with HIV were coinfected [6,7] In addition, the transmission of viruses by plasma-derived products spurred efforts to produce factor VIII by recombinant DNA technology, which became possible when the factor VIII gene was cloned and expressed in tissue culture [8,9]. By the early 1990s, recombinant factor VIII products were manufactured and licensed. While early recombinant factor VIII products were stabilized with pasteurized human albumin, by the end of the decade they were stabilized with sucrose, thereby eliminating human protein from the last stages of formulation. These enhanced purity products are now widely used and, unlike earlier plasmaderived products, have been meticulously studied in clinical trials characterizing their pharmacokinetics, suitability for home treatment, surgery and use in previously untreated patients (PUPs), mostly children [4]. The availability of recombinant concentrates has resulted in a steady increase in demand for and consumption of factor VIII concentrates: worldwide demand increased from 1.3 billion units in 1984 to 5.5 billion units in 2008 [10]. In many industrialized countries, patients have increasingly been switched to recombinant factor VIII concentrates, which now represent around 42% of factor available to patients worldwide. Most of this (88%) is sold in North America and Europe. In addition, the focus of treatment has progressively shifted as prophylaxis and immune tolerance have become widely accepted.

C. Hermans et al. / Critical Reviews in Oncology/Hematology 83 (2012) 11–20

Production of plasma-derived factor VIII has increased in the past 18 years from 1.3 to 2.1 billion units due to increasing fractionation throughput. However, it has become increasingly difficult to extract a higher quantity of factor VIII from source plasma as the yield is affected by the fractionation process. Consequently, the yield remains low at 5–10%, which could have important consequences for the future.

2. Current concerns with factor concentrates 2.1. Pathogen safety Over recent decades, major advances have been made in relation to the safety of the plasma-derived FVIII concentrate supply, with an increasing array of techniques available for the removal of infectious agents, including: • Plasma fractionation to reduce the concentration of viral contaminants through physical separation and removal of viral particles from the desired factor proteins. • Filtration methods to concentrate plasma products. Methods include depth filtration, diafiltration, ultrafiltration, and nanofiltration, a validated removal method for both enveloped and non-enveloped viruses. Plasma fractions are passed through a membrane that retains molecules that are greater than 1 kDa. • Chromatographic methods to separate molecules based on differences in charge (ion exchange), size (gel filtration), or affinity for specific antibodies (immunoaffinity). With respect to pathogen inactivation, processes frequently employed include: • Pasteurization, or heat processing to kill pathogens. • Solvent/detergent treatment to destroy the envelope structure of lipid-enveloped viruses. • High-salt incubation, a chemical treatment used to reduce a range of viruses. • Heat treatment to disrupt the infectivity of viral structures by thermal denaturation. These procedures have reduced the theoretical risk of transmission of blood–borne viruses, particularly HIV and hepatitis viruses B and C [11]. However, not all of these techniques are used for every product. Most products are subjected to two or three different methods only, which may have an impact on product safety. Furthermore, despite these measures, sporadic cases of infection of unknown pathological impact continue to occur, caused by both known and newly emergent pathogens [12]. The modern world is characterized by globalization and low-cost travel, with goods and people regularly and rapidly crossing countries and continents. Infectious diseases that once would have remained confined to their ecological niche can now potentially spread rapidly to every corner of the earth before preventive measures can be implemented as

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recent experience with SARS and “swine flu” has shown. Furthermore, plasma products derived and purified in one part of the world can easily be transported to and used in other parts of the world. Throughout the past 40 years, new infectious pathogens have continually emerged, affecting the blood supply and people with hemophilia. Even after the well publicized cases of transmission of hepatitis B, HIV and HCV, transfusion-transmitted viruses (TTV) including parvovirus and circovirus were found to be transmissible through blood transfusion in the 1990s and parvovirus B19 was reported in hemophilia patients who received early recombinant factor VIII concentrates. Even within the last decade, the blood supply has been susceptible to the transmission of variant Creutzfeldt–Jakob disease (vCJD) through blood transfusion, while transfusion-associated infections with West Nile virus have been reported [13,14]. The hemophilia community has been affected by many of these agents. It would be complacent to assume that new pathogens will not continue to emerge. Viral transmission by blood products prompted the implementation of donor and plasma pool screening; however, screening cannot guarantee safety from transmission of infectious pathogens. The screening of blood donors and plasma pools may miss contamination from infectious but not yet seropositive donors. In addition, among donors there may also be people who are low level chronic carriers: these people can remain undetected and contribute to the plasma pool. Furthermore, the possibility of laboratory error remains. In addition, some viral mutants may escape screening. But perhaps most important is the fact that it is only possible to screen for known pathogens – there can be no donor or supply screening for the moving target posed by emerging pathogens [12,13,15]. 2.1.1. The parvovirus experience Some viruses such as parvovirus B19 appear to be resistant to currently available inactivation techniques. Human parvovirus B19 has frequently been detected in plasma-derived coagulation factor concentrates. A recent study analyzed samples from 13 currently available products and 8 products available until the early 1980s, which had not been treated by viral inactivation procedures [16]. It identified parvovirus DNA in 42.5% of currently administered products and 81% of previously used products. In a French cohort study, the prevalence of IgG antibodies to B19 (anti-B19) was studied in 193 children with hemophilia aged 1–6 years who had previously been treated with albumin-stabilized recombinant factor VIII only (n = 104) or with solvent/detergent high-purity non-immunopurified and non-nanofiltered factor VIII or IX concentrates (n = 89) [17]. A higher prevalence of anti-B19 was found in children previously treated with solvent/detergent high-purity non-immunopurified and nonnanofiltered factor VIII or IX concentrates than in children treated with albumin-stabilized recombinant factor VIII only

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(OR: 22.3; CI: 7.9–62.8), independently of the other factors studied.

Table 1 Incidence of inhibitor development noted in studies of recombinant factor VIII products conducted in PUPs with severe hemophilia A [27,28,47–49].

2.1.2. The variant Creutzfeldt–Jakob disease experience There is strong evidence that prions can be transmitted via blood transfusion and there is currently no method for screening of blood products. To date there have been more than 184 cases reported worldwide but only one case in a hemophilia patient, a 74-year-old patient who died from unrelated causes in whom vCJD was found in the spleen at autopsy [14]. The patient had displayed no neurological symptoms before death but it is known that in 1996 he had been infused with a UK-produced factor VIII concentrate extracted from the plasma of a donor who subsequently developed vCJD. Plasma-derived factor VIII concentrate exposure is accepted as the likely source of prion transmission. Overall, a major reduction in the infective potential of fractionated plasma products has been achieved through major multi-step improvements in the fractionation process. The result is that no transmission of HBV, HCV or HIV attributable to manufactured plasma derivatives licensed for use in the US has been reported since 1985. While this is clearly reassuring, plasma-derived factor VIII concentrates might in theory still contain and transmit as yet unidentified infectious agents.

Concentrate (manufacturer)

Inhibitor incidence (%)

Reference

rFVIII-FS (Bayer) rFVIII-FS (Bayer) rFVIII (Bayer) BDD-rFVIII (Pfizer) rFVIII (Baxter) rFVIII (Baxter) BDD-rFVIII-AF (Pfizer) rFVIII-AF (Baxter)

8 15 29.2 31.7 28 31.9 No data available Only interim data available

Musso et al. [49] Kreuz et al. [28] Lusher et al. [27] Lusher et al. [48] Rothschild et al. [47] Gruppo et al. [54] N/A N/A

2.1.3. Presence of impurities Besides infectious safety, there is also a concern that both plasma-derived and recombinant factor VIII may contain impurities that may have adverse consequences for the patients. In recent studies proteins from several recombinant and plasma-derived concentrates have been separated and characterized. One recent study used proteomic techniques and identified inter-alpha inhibitor proteins, fibrinogen, fibronectin and clotting factor II (prothrombin) in two of three commercial plasma-derived von Willebrand containing factor VIII concentrates [18]. While recombinant products may contain minimal traces of impurities such as host cell proteins or cleavage products, the risk that they contain infectious contaminants from animal or cell sources is minimal due to low likelihood of infectious agents entering the cell culture process. 2.2. Neutralizing inhibitors There are structural differences between recombinant products for instance in the degree of glycosylation and sulfation, which may affect stability and efficacy. However, the major adverse consequence of using factor VIII concentrates is the development of neutralizing inhibitors. About 25% of children with severe hemophilia A develop alloantibodies against infused factor VIII concentrates [19]. Patients with high titer inhibitors are at increased risk of severe and potentially life threatening bleeds such as intracranial hemorrhage. Quality of life is severely affected, while the presence of

the inhibitor impairs the response to replacement therapy. Overall, treatment becomes more complex and costly [20]. It is often suggested that there is less inhibitor development in PUPs treated with plasma derived factor VIII concentrates than with recombinant products [21]. Cohort studies conducted in the UK and France have indicated that inhibitors develop more frequently in those patients treated with recombinant products compared with plasma-derived products [22,23]. However, some studies have contradicted this view. A Swedish study found no significant increase (P = 0.65) in incidence of inhibitors (n = 10/48, total incidence 21%) in the 1990s, when patients with hemophilia A were treated mainly with recombinant products, as compared to the 1980s (n = 9/52, 17%), when they received intermediate/high-purity plasma-derived concentrates [24]. The incidence of inhibitors is now routinely studied in clinical trials of new recombinant products. In individual studies, a cumulative incidence up to 30% has been reported in PUPs with severe hemophilia A treated with early recombinant factor VIII concentrates [25–27] and second-generation recombinant factor VIII concentrates [28]. Table 1 summarizes the incidence of inhibitor development noted in studies of recombinant factor VIII products conducted in previously untreated or minimally treated patients with severe hemophilia A. Recent data from the prospective PUP study conducted by the German, Swiss, and Austrian Society of Thrombosis and Hemostasis Research suggests that inhibitor incidence in hemophilia A is 17.3% (22.2% in severe hemophilia A), with severe hemophilia A, on demand treatment, and intensive treatment moments associated with a significantly higher risk of developing inhibitors compared to moderate/mild hemophilia A and prophylaxis [29]. The hazard ratio for inhibitor development was 1.59, comparing subjects treated with recombinant factor VIII with those treated with plasmaderived factor VIII (P = 0.09). While the incidence of inhibitors appears to vary among users of different factor VIII concentrates, to date there is no evidence to support the concern that switching from one product to another is itself a risk factor for inhibitor formation, independent of the factor VIII product. Following the conversion of most Canadian hemophilia A patients

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from plasma-derived products to an early human albumin stabilized recombinant product, inhibitor formation was monitored for 1–2 years and showed no increased incidence of inhibitors [30]. More recently, the Association of Hemophilia Clinic Directors of Canada prospectively followed the Canadian hemophilia A population for 2 years following the switch from albumin-stabilized recombinant factor VIII to a recombinant product stabilized with sucrose [31]. Again, this surveillance study suggests that the altered formulation was not associated with an increased incidence of inhibitor formation. 2.2.1. Interpretation of clinical studies Much of the confusion around the seemingly contradictory data on inhibitor development stems from inappropriate comparisons between trials, particularly with respect to trial design, the inhibitor assay used, the frequency of inhibitor testing and the characteristics of the patient populations studied. With respect to trial design, it is important to understand that prevalence studies (such as the early plasma-derived factor VIII product trials) tend to underreport inhibitors because they do not include full data on transient inhibitors and those inhibitors that are eradicated by ITI. In addition, it is important to differentiate between prospective and retrospective studies. In general, retrospective studies tend to underreport events. Most plasma-derived factor VIII product trials in the literature are retrospective while most trials of recombinant products have taken a prospective design. The inhibitor assay used and frequency of testing will also affect the determination of inhibitors. The Bethesda assay is the most commonly used method to detect inhibitors, yet the Nijmegen modification, which allowed better discrimination between positive and negative samples and improved the reliability of the assay was introduced only in the mid 1990s [32]. Most plasma-derived factor VIII studies were conducted prior to this, and are likely to underreport inhibitors. Furthermore, prospective trials for recombinant factor VIII products test for inhibitor formation after few exposures to factor VIII; by contrast, older trials of plasma-derived factor VIII products only tested for inhibitors annually or when a patient demonstrated reduced recovery, thus under-reporting incidence. A further clinically relevant consideration is the proportion of low titer versus high titer inhibitors, and the number of transient versus persistent inhibitors. The characteristics of the patient population under study also need to be considered. Most inhibitors develop early during a patient’s exposure to factor VIII, usually within the first 50 exposure days (EDs). Therefore, trials should ideally separate out the incidence in PUPs and minimally treated patients (MTPs) from that in previously treated patients (PTPs). In addition, certain patients groups are at higher risk for inhibitors. These will include patients of African or Latino descent and those with severe hemophilia A, family history of inhibitors and large mutations. Many older plasma-derived

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factor VIII trials provide no detail on patient characteristics, making direct comparison between trials difficult. 2.2.2. Results from pooled analyses A recent systematic review by Iorio and colleagues pooled data on 2094 patients from 24 retrospective and prospective studies, in which 420 patients developed inhibitors [21]. The pooled incidence inhibitor rate was 14.3% for plasmaderived FVIII concentrates and 27.4% for recombinant FVIII products (P < 0.001), although the difference lost statistical significance in multivariate analysis. Similar results were observed when the analysis was restricted to the 19 prospective studies (9.1% for plasma-derived FVIII concentrates and 23.7% for recombinant FVIII products, P < 0.001). By contrast, in a more recent systematic review of data from 800 PUPs with severe hemophilia A enrolled in 25 prospective studies, Franchini et al. found no statistically significant difference [33]. The weighted mean inhibitor rates in recipients of plasma-derived and recombinant FVIII concentrates were 21% (95% CI 14–30) and 27% (95% CI 21–33), respectively. Similarly, high titer inhibitors did not differ significantly between patients treated with plasma-derived (weighted means: 14%; 95% CI 8–25) or recombinant FVIII concentrates (weighted means: 16%; 95% CI 13–20). It seems likely that discussion on the impact of type of factor concentrate on inhibitor development will remain a topic of debate among academics until it is settled in the ongoing prospective randomized Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET). Until then, data from well conducted contemporary studies such as CANAL should help to guide clinical practice. 2.2.3. Evidence from the CANAL study The Concerted Action on Neutralizing Antibodies in severe hemophilia A (CANAL) study was a retrospective, multicenter cohort study designed to describe the relationship between treatment characteristics and inhibitor development in 366 PUPs with severe hemophilia (residual factor VIII activity < 2%) born between 1990 and 2000 [34]. This was the largest retrospective study conducted to date, and was carefully designed to capture all clinically relevant inhibitors. The study assessed the occurrence of at least two positive inhibitor titers combined with a decreased recovery inhibitor and provided a unique opportunity to compare the difference in incidence of inhibitor development between recombinant and plasma derived concentrates [35]. In all, 87 patients (24%) developed clinically relevant inhibitors, of whom 69 (19%) had high-titer inhibitors and 18 (5%) had low-titer inhibitors. Patients developed inhibitors after a median of 14 exposure days at a median age of 15 months. The median duration between the first exposure to factor VIII and inhibitor development was 5 months. Importantly, the risk of inhibitor development was not clearly lower in plasma-derived compared with recombinant factor VIII products (relative risk, 0.8; 95% confidence interval [CI], 0.5–1.3). Among hightiter inhibitors, the possible reduction in risk was even less

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pronounced (RR, 0.9; CI, 0.5–1.5). Compared to recombinant factor VIII products, the inhibitor risk was similar in patients on plasma-derived products containing considerable quantities of von Willebrand factor (RR, 1.0; CI, 0.6–1.6), and it was 70% decreased in patients receiving plasma-derived products containing small quantities of von Willebrand factor (RR, 0.3; CI, 0.1–1.1). These findings did not change after adjustment for potentially confounding factors. The study found no significantly higher risk of developing inhibitors when switching from one product to another. 2.2.4. Impact of treatment modality on inhibitor development As treatment modalities (indication, dosage, intensity and duration) all play a role in determining the risk of inhibitor development, such risk can be minimized in daily clinical practice by modifying approaches to treatment: • Using the appropriate treatment – initiating prophylaxis early and individualizing treatment after the first exposure to factor VIII. • Avoiding peak treatment in children <1 year; where this is unavoidable, limiting treatment to <2 days and following it with low-dose prophylaxis.

result in an increased incidence of inhibitor development. In 1990, a pasteurized factor VIII (CPS-P) was licensed and distributed in the Netherlands and Belgium. Shortly afterwards researchers noted an enhanced incidence of inhibitors in PTPs. This was then repeated in Belgium in 1995, following the introduction of Bisinact® , a solvent-detergent-treated and pasteurized factor VIII concentrate [37–39]. Both products, because of the manufacturing process, had a high immunogenicity and were consequently withdrawn from the market. It is noteworthy that these would have gone undetected in the absence of careful epidemiological studies.

3. Factors that may influence product choice While efficacy and safety are clearly the key issues in selecting a product, many other features will play into the decision, including guideline recommendations, cost, the degree of scientific validation and practical issues, as well as the security of the blood supply. 3.1. Guideline recommendations on choice of concentrate

Current regimens for primary prophylaxis involve administration of factor VIII 3 times/week up to 50 IU/kg, started with or after the first joint bleed using a Port-A Cath as needed. While this offers optimal protection against joint disease, the use of such high dose factor VIII might not be optimal for avoidance of inhibitors, and the use of a Port-ACath introduces potential for surgery, bleeds and infection. The greatest risk for developing inhibitors is during the first 20 exposure days (EDs). Recent evidence suggests that modifying the prophylaxis regimen for the first 20–50 EDs and avoiding immunological “danger signals” (surgery within the first 20 EDs, vaccination on a factor VIII treatment day, and giving the first factor VIII treatment into a bleed or during an infection) may help to induce tolerance to the administered factor VIII, resulting in a subsequent low level of risk [36]. In a pilot study, the cumulative inhibitor incidence in the 26 consecutive PUPs with severe hemophilia A given this early low dose prophylaxis regimen was reduced by 95% (OR 0.048) as compared to the standard prophylaxis regimen given to a historical control group of 30 PUPs (P = 0.0003, 95% CI: 0.001–0.372).

The guidelines of the World Federation of Hemophilia do not express a preference for one type of factor VIII concentrate over another, wisely accepting that the eventual choice between these classes of product will be made according to local criteria. However, most guidelines recognize that the major safety issues are transmission of infectious agents and risk of inhibitor formation. The UK Hemophilia Center Doctors’ Organization guidelines recommend recombinant products for those patients with congenital hemophilia, particularly if they have never been exposed to plasma products [40]. The guidelines of the Australian Hemophilia Centre Directors Organization (AHCDO) go further and state that recombinant factor VIII is the treatment of choice for bleeding episodes in all patients with hemophilia A, adding that inhibitor development is equally likely with recombinant factor VIII treatment or prophylaxis, as with plasma-derived factor VIII [41]. In many countries, such as Italy and the Netherlands guidelines leave physicians, patients and parents free to choose between plasma-derived and recombinant products but advise that young children (<5 years) should be treated with recombinant factor VIII (Table 2).

2.3. Increased immunogenicity related to manufacture of plasma-derived factor VIII

3.2. Cost considerations

Overall, there is no objective reason to consider that plasma-derived factor VIII concentrate used according to the same modalities as currently available recombinant concentrates will provide protection against the development of inhibitor. However, there is evidence that even subtle changes in the manufacturing process of plasma-derived factor VIII can affect the immunogenicity of the factor VIII protein and

Clearly, in some countries, product availability is determined by price. In many countries, recombinant products have a higher price than plasma-derived products. Historically, it is unarguable that pathogen transmission with plasma-derived concentrates increased morbidity and mortality, and was associated with costs with respect to treatment, litigation and compensation. While recombinant products reduce the risk of pathogen transmission they are complex

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Table 2 Major guidelines favour recombinant FVIII over plasma-derived concentrates. Country

Recommendations

UK [40]

Advise recombinant products as treatment of choice, with plasma derived products when these are not available To reduce risk of viral infection, suggest selecting a recombinant concentrate manufactured with the least human or animal protein Recognise recombinant FVIII as the most technologically advanced product, but consider plasma-derived concentrates adequate as efficacy is equal and viral safety has reached a high degree PUPs must be, and HCV and HIV−ve patients should be, treated with recombinant products. Prophylaxis is the optimal therapeutic strategy No specific product recommendation but advocate replacement in form of prophylaxis; primary prophylaxis for severe hemophiliacs; PUPs usually start on recombinant FVIII In general, rFVIII concentrate, which carries a substantially reduced risk of human viral transmission, is recommended for the management of hemophilia Patients or parents are free to choose their product; but suggest that young children (<5 years) should be treated with recombinant FVIII Advocate rFVIII as treatment of choice for all patients Recombinant FVIII is treatment of choice; all efforts should be made to eliminate human and bovine proteins from the manufacturing process of recombinant products

Italy [46]

Sweden [50] Canada [51] Netherlands [52] Australia [41] MASAC [53]

and costly to produce. Therefore, it is inappropriate to compare the cost of a modern recombinant factor VIII product with that of a low-purity plasma-derived factor VIII. Furthermore, it is important to note that the price of plasma-derived concentrates is likely to rise in the future due to the cost of donor screening, more costly manufacturing processes and the ever lower production yield from each liter of plasma. Indeed, in some markets, state-of-the art plasma-derived concentrates that include nanofiltration in the manufacturing process are already priced at a similar level to recombinant products. 3.3. Scientific validation A further important issue to consider is the extent of scientific validation to support different types of concentrate. Most recombinant concentrates have been extensively validated in large prospective multicenter studies conducted in relevant clinical settings. A simple PubMed search of clinical trial reports published in peer-reviewed publications by factor concentrate name indicates that recombinant factor VIII concentrates are supported by considerably more evidence compared with plasma-derived factor VIII concentrates. Furthermore, most recombinant concentrates are subject to ongoing post-marketing studies in many different countries, providing extensive real life experience as well as further information on safety and efficacy [42]. By contrast, many plasma-derived concentrates are produced by national companies and some are used only nationally, resulting in much less experience globally. 3.4. Practical features In practical terms, many recombinant and plasma-derived concentrates currently on the market offer several practical advantages for patients in terms of needle-free reconstitution devices, room temperature stability (which allows the patient to store the concentrate at home and to travel with

fewer problems), a prolonged shelf life and additional vial size. Importantly, the lower infusion volumes required with recombinant products offers a major practical advantage in the treatment of small children, while the faster reconstitution time offers an advantage with respect to treatment compliance. Recombinant technology will undoubtedly play a major role in future product development and availability. Studies are currently ongoing with clotting factor proteins that have been fused with the Fc component of human immunoglobulin G. This protects the factor VIII against catabolism and extends its half-life, potentially reducing the dosing frequency required to maintain prophylaxis. In addition, in the future, it is hoped that recombinant technology will offer the ability to modify the factor VIII molecule and perhaps reduce its antigenicity and improve its pharmacokinetics [43,44]. 3.5. Pressures on the blood supply An important issue to consider is the security of the blood supply. The increasingly global environment has meant that the plasma industry has undergone major consolidation. Mergers and acquisitions have led to the closure of a number of small plants in Europe. As a result, few countries have a national fractionator. Some 15 countries have now contracted plasma fractionation programs to ensure plasmaproduct supply. An additional factor is that immunoglobulin G has clearly replaced factor VIII and albumin as the main driver of plasma fractionation and is now the leading plasma product. In consequence, many countries are no longer selfsufficient in factor VIII production. This could prove a fault line in the future: as patients and populations age, there is a growing requirement for blood products. A recent study based on data from the Finnish transfusion registry demonstrates a marked increase in red blood cell consumption with increasing age among recipients, beginning at around 50 years of age [45]. Thus, there may be problems in the future

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with respect to supply of plasma derived factor VIII concentrates, a situation less likely with recombinant factor VIII products.

4. Conclusion This article has set out some of the factors that physicians should consider when selecting between recombinant and plasma-derived factor VIII concentrates. Both products exhibit the same hemostatic properties and the same ability to correct factor VIII deficiency, and there is no evidence of any difference in terms of efficacy. With respect to safety, while there is no difference between recombinant and plasma derived concentrates in inhibitor incidence there may be differences in infectious potential and other adverse events. But other factors should also play a role into the selection decision, such as the consistency and reliability of supply, the degree of scientific validation, patient convenience and patient preference. Cost will also be a factor for many. Where a price premium is the result of enhanced safety, for any factor VIII concentrate, there is a strong case for considering this as representing the cost of insuring patients against pathogen transmission in the future. While plasma-derived products are undoubtedly becoming safer, recombinant products are widely perceived as being safer in the developed world. While some countries, such as Canada, Sweden, Norway, the UK and Ireland, have chosen to switch all hemophilia patients to recombinant products, the USA and many countries within Europe have adopted a more gradual approach. For some countries, however, considerations of cost remain important and plasma-derived products continue to dominate the hemophilia treatment market. Some countries have managed the introduction of recombinant factor VIII by targeting use first to specific “priority” patient groups [46]. Where there is the opportunity to introduce recombinant products, it may be appropriate to target treatment in the following way: • First priority: PUPs, particularly children, as recombinant products are associated with smaller infusion volumes and the lowest risk of viral transmission. • Second priority: HCV and HIV negative patients, who have been treated in the past with virus-inactivated concentrates only, with the aim of minimizing the residual risk of infection. • Third priority: HIV-infected patients, as the choice of recombinant products will prevent the transmission of other viral infections such as parvovirus B19. • Fourth priority: All remaining patients. Such managed introduction is advantageous from a clinical and cost–benefit point of view in ensuring that treatment is directed first at those in whom benefit has been robustly proven and in whom prior viral infection is unlikely.

Conflict of interest statement Dr. Hermans has received consultancy honorarium and grants from Baxter Bioscience, Bayer Schering, CSL Behring, Novo Nordisk, Wyeth-Pfizer, LFB, Octapharma. Dr. Brackmann received a grant from Bayer. Dr Schinco has received grants from Baxter, Bayer, NovoNordisk, Wyeth-Pfizer and Kedrion. Dr. Auerswald has received funding from CSL Behring, Baxter, Bayer, Biotest, Novonordisk and Pfizer, and research grants from Bayer, Baxter, Novonordisk and CSL Behring.

Reviewer Dr. Robert Klamroth, M.D., Vivantes Klinikum im Friedrichshain, Klinik für Innere Medizin, Angiologie Haemostaseologie, und Pneumologie, Berlin, Germany.

Acknowledgements The authors acknowledge the contribution of Michael Holland of Driftwood Publishing Ltd. for literature searching and editorial assistance. The development of this paper was supported by a scientific grant from Bayer Healthcare.

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Biographies Professor Dr Cedric Hermans has completed his medical training and specialization in General Internal Medicine at the Saint-Luc University Hospital, part of the Catholic University of Louvain, Belgium. He obtained his PhD in Biomedical Sciences, specializing in Toxicology, in 1999. In 2000 Dr Hermans took up a one-year fellowship in the Haemophilia Centre & Haemostasis Unit of the Royal Free Hospital, London. He was appointed Associate Professor at the Medical School of the Catholic University of Louvain in 2003 and Clinical Professor in 2009. He currently heads the Division of Haematology, and the Haemostasis and Thrombosis Unit, of the Saint-Luc University Hospital. Hans-Hermann Brackmann is Academic Director of the Hemophilia Center at the Institute for Experimental Hematology and Transfusion Medicine at the University of Bonn. After gaining his MD from the University of Bonn in 1970, Dr Brackmann became responsible for the Hemophilia Department at the same institute in 1971. Between 1973 and 1976 Dr Brackmann worked on the development of a prophylactic treatment program for hemophiliacs and the immune tolerance treatment (the Bonn protocol) for hemophiliacs with inhibitors. In 1980 he was awarded the “Alexander Schmidt Prize” for his successful work with immune tolerance treatment in hemophilia patients with inhibitors. A recipient of numerous research awards, Dr Brackmann has studied the “Psychological aspects in HIV-infected patients with hemophilia and their relatives” on behalf of the German Ministry of Health, and also undertaken research work on the “Analyses of Factor VIII gene defects in hemophilia A patients” through a grant from the DFG

(German Community for Research) and on the “Genotype/Phenotype correlation in hemophilia A” for the German Human Genome Project. Together with Prof. G. Mariani from Italy he created the International Immune Study Group and organized 4 international workshops on “Immune Tolerance in Hemophilia and the Treatment of Hemophiliacs with an Inhibitor”. Between 1976 and 2000 Dr Brackmann was responsible for 21 clinical trials in hemophilia. In 2005 Dr Brackmann was awarded the Wolfgang Paul Medal by the University of Bonn for the organization and development of the Hemophilia Center and for extraordinary scientific achievement in the development of successful treatment concepts for patients with hemophilia. Piercarla Schinco after gaining her Medical Degree, Dr Schinco specialized in Internal Medicine at the Turin University Medical School, and, later, in Hematology at the Rome University Medical School. In Turin, she worked as a Research and Clinical Assistant at the Hemostasis Unit/Hemophilia Center, which she helped to set up at the Molinette University Hospital. Dr Schinco has been a Lecturer in Hemostasis at the Turin University Medical School since 1998 and Director of the Hemostasis Unit/Hemophilia Center since 2006. Since 2009 she has been serving as Contract Professor at the Turin University Medical School. Günter Auerswald is Senior Physician and Head of the Comprehensive Care Centre for Hemophilia and Thrombosis at the Professor Hess Children’s Hospital in Bremen, Germany. He was also Head of the Blood Clotting Laboratory in the Department of Pediatrics at the Medical University of Lübeck. Dr Auerswald’s special research interests include von Willebrand’s disease, rare coagulation disorders (e.g. congenital factor VII and factor X deficiencies), and treatment protocols for hemophilia patients with inhibitors to factor VIII as well as for treatment protocols to decrease inhibitor development in severe hemophilia A. He has published extensively on these subjects.