Treatment for hemophilia: recombinant versus plasma-derived coagulation factors – controversy and debate forever? An ethical medical challenge?

Hemophilia is an X-linked recessive disorder that results from a shortage of coagulation factor VIII (hemophilia A) or IX (in hemophilia B). Hemophilia, which include hemophilic arthropathy, spontaneous or traumatic hemorrhages, muscle hematomas and hemorrhages in the central nervous system, is a chronic disease and, as such, entails significant hospitalization and pharmaceutical costs. This may be difficult to afford by some of the poorer countries in the world, resulting in higher mortality rates or, at best, in the appearance of disabling clinical conditions. Currently, treatment of hemophilia is based on human plasma-derived products or recombinant products [1–3]. According to current guidelines, both plasma-derived and recombinant products boast high efficacy and safety profiles [4].

With the eradication of infection by HIV and hepatitis C virus (HCV) that were common just a few years ago, the most concerning adverse effect resulting from the use of both recombinant and plasma-derived products is the appearance of antibodies (inhibitors) to perfused exogenous factors [5,6]. The development of inhibitors (30% in hemophilia A and 6% in hemophilia B) undermines the efficacy of current treatment with factor concentrates, leading to higher morbidity and mortality rates; early hemophilic arthropathy and disability; and, inevitably, to a poorer patient quality of life, all of which results in higher treatment costs. A recent study (RODIN study) [7] – although this finding needs to be interpreted with caution – concludes that the risk of developing inhibitors among previously untreated patients was similar in those receiving plasma-derived and recombinant products.

The controversy about whether a recombinant or a plasma-derived product is the most adequate for hemophiliac patients has reached an intensity without precedent in the history of medicine [8]. Recombinant technology has been considered a powerful therapeutic tool given its indisputable benefits, particularly in terms of safety, and numerous recombinant drugs have been used for many decades in the treatment of a large number of clinical conditions. In the case of hemophilia, however, many discrepancies and uncertainties have arisen regarding, for example, whether recipients of recombinant factors may develop more inhibitors than those treated with plasma-derived factors, or whether, given their manufacturing process itself using viral vectors or to their content of trace amounts of murine proteins may trigger another adverse effects. Anyhow, care must be exercised as such arguments are often biased by an economic interest given that the recombinant products are generally more costly than plasma-derived ones, at least in a vast majority of countries.

Deciding what drug to prescribe is, generally speaking, a challenging undertaking, especially in cases where a wide range of products are available, which are equally efficient from the therapeutic point of view and very similar in terms of their security profile and the risk of side effects. But if we also take into account the fact that the price of one of the products is much higher than that of the other and that the world is currently immersed in a serious financial crisis, then we shall soon realize the sheer magnitude of the dilemma facing the medical community. Moreover, this fact may impact on the health care expenditure and on the decisions adopted regarding treatment of patients with hemophilia, including changes from a recombinant to a plasma-derived product or delaying prophylaxis [9].

As regards the treatment of hemophilia, plasma-derived and recombinant products have, as noted above, similar safety profiles, and they have also been shown to be equally effective [4]. In many countries, the problem is that recombinant products are nearly twice as expensive as plasma-derived ones, which makes things particularly complicated in the face of the current economic downturn. Thus, the annualized cost of prophylactic treatment (three-times each week by the Malmö protocol at 25–40 IU/kg per example) is estimated to be $180,000–$300,000 or even higher per year – depending on whether plasma-derived or recombinant factor VIII is infused [10].

Guidelines generally provide information on the products available, on their characteristics and on their advantages and disadvantages. Once in possession of this information, a doctor ideally discusses the different options with the patient and selects a certain therapeutic option. But what criteria are involved in this selection?

Naturally, the decision to select or replace a certain type of concentrate (recombinant or plasma derived in this case) must be based solely on medical and clinical considerations and should be made in as individualized a way as possible. Thus, for example, it would be admissible to justify one’s choice by appeal to a loss of efficacy caused by pharmacokinetic factors or the appearance of inhibitors or other severe adverse effects such as anaphylactic reactions; the unavailability of a similar product can also be invoked. Nonetheless, allegations that prophylactic treatment is too costly, or that there are cheaper products of equal effectiveness and ‘safety’, are not acceptable.

In the midst of an economic crisis, it would nevertheless be rather reckless not to make rational use of drug products in order to save costs. As it was said above, both types of products are equally effective; and moreover, not many retrospective studies have to date shown that recipients of one type of product develop more inhibitors than those receiving the other [11]. Therefore, safety should be the deciding factor. Although the safety profile of both types of products is similar, it certainly cannot be claimed that they are identically safe. Currently available plasma-derived products are safe against lipid-coated viruses (HIV, HCV and many others), but the greatest limitation of using solvents and detergents is their inability to destroy viruses that lack a lipid envelope such as the hepatitis A virus, parvovirus B19 and hepatitis E virus (HEV) [12,13]. They are also unable to inactivate prions, such as those that cause the variant of the Creutzfeldt–Jakob disease (vCJD), which are transmitted through blood and have been detected in a patient with hemophilia [14,15]. Furthermore, neither HEV nor prions can be adequately detected in the donor’s blood. The highest incidence of infection by HEV has been reported in tropical and subtropical regions, although it is also present in developed countries as it is a typical travelers’ disease. Reports, such as those stating that between 1 and 5% of blood donors present with hepatitis E antibodies; that there is currently no effective treatment for all cases; and that the HEV can result in the onset of liver chronic cirrhosis, are the cause of grave concern [13]. On the other hand, recombinant factor concentrates do not contain animal or human proteins, which is highly advantageous as it reduces the risk of transmitting animal or human infectious agents. Moreover, since they were first used in the 1990s, recombinant products have not caused any significant adverse effects.

The foregoing arguments would seem to indicate that deciding which drug to prescribe in an era of budgetary restrictions where so much pressure exists to reduce the health care bill is a difficult endeavor, especially considering the large difference in the cost of the products involved that exists in many countries. This is similar to what happened at the beginning of the HIV/HCV pandemia when predictions regarding the potential for infection were grossly underestimated. The question here would be: Are we prepared for this decision? Another question arising from this one would be whether by taking heed of the voices calling for austerity, we are prepared to potentially condemn many seronegative patients (many of them children) to the torment of emerging infections.

The decision is very difficult and should always be left to the medical profession, even if doctors are sometimes influenced by circumstances unrelated to medical criteria. In order to establish a criterion that can assist us in making the right decision, we must resort to a Hippocratic axiom, which still holds true today, according to which a certain drug may be selected, recommended or replaced only if has shown itself to be efficient for the treatment of the disease affecting the patient and if it is not associated with severe adverse effects.

This is by no means a trivial matter as in the specific case of hemophilia, changing one product for another, even if both are manufactured by the same company, may result – though not necessarily – in the development of inhibitors [16].

Some countries base their decisions on strict and accurate guidelines aimed at achieving the highest safety levels possible, even if the potential risks of using other kinds of products are minimal [4], whereas in other countries, recommendations are laxer and more permissive [17].

It is a well-known fact that hemophilia is a chronic disease whose treatment is associated with a high cost. However, this should in no way lead us to consider criteria that are not of a strictly medical nature when selecting or replacing a certain treatment. Unfortunately, the situation in the different countries of the world is such that medical criteria do not always prevail, either because of a lack of financial resources or because recombinant drugs are unavailable and the only treatment option is a plasma-derived product. Here the question is: can we accept the risk of plasma-derived products, which are used to treat most of the hemophilia population worldwide, on the basis of their affordability and accept the risk of an infectious disease or inhibitor formation?

Most international guidelines do, however, clearly state that both plasma-derived and recombinant products are associated with the same levels of effectiveness and safety – with respect to inactivatable viruses – and an identical incidence of inhibitor formation, although the latter is still subject to a debate that will only be resolved as more data become available.

Therefore, the most pressing questions to answer are: how can we maximize safety in the face of an economic crisis? and is it justifiable to make savings at the expense of accepting ‘minimal’ risks, which may later prove to be more significant than anticipated?

Governments and economic agents need to choose between a reduction in health care costs, which may mean incurring a series of ‘minimal’ risks, and taking drastic measures based upon a set of strict recommendations in return for maximizing patient safety. In both cases, patients need to be provided with precise, rigorous and unbiased information on the advantages and disadvantages of the alternatives available to them.

The debate arises when the decision to use one product rather than another is made on the basis of economic considerations, especially in emerging or developing countries, or even in some Western countries. In countries where the prices of both types of products are kept at par, the question is much less critical. Therefore, a way of resolving the problem may be to follow the example of such countries and equal out the prices of both products at world level.

A way to do this would be to introduce national procurement systems based on tenders aimed at forcing manufacturers to lower the price of recombinant products, maintaining their safety profile intact. This alternative has recently shown itself to be very effective in the UK, Australia and Canada. Moreover, governments should ask manufacturers to provide strict safety guarantees for their products. Currently, available screening tests and pathogen inactivation methods must be used especially for plasma-derived concentrates. Also appropriate selection of blood donors, prion-removing leucodepletion and other effective prion removal methods must be implemented to minimize the potential presence of prions in plasma-derived products obtained from donors with subclinical vCJD [18].

These types of measures could not only put an end to the debate of which product should be used but could also make it possible to address, in a safer and fairer manner, the problem posed by the unequal distribution of the best hemophilia treatments across the world. In this way, many of the patients that make up the 75% of hemophiliacs who do not currently receive appropriate treatment could benefit from the best treatment at a more reasonable cost.

Finally, the fact that economic factors influence medical practice should not be forgotten. In an economic crisis, a responsible behavior forces rational use of drug products in order to save costs. However, it is essential to find a balance between reasonable financial considerations and adequate patient access to the most appropriate treatment. Also, these principles should be applied globally to ensure that patients access the best possible medical care and best distribution of drug products. To achieve these goals, it is essential to also have politicians’ commitment.

Financial & competing interests disclosure

A Liras is Principal Researcher in a preclinical project – not clinical trial – with adipose mesenchymal stem cells and gene/cell therapy protocols for treatment of hemophilia. This project is supported by funding from a grant from the Royal Foundation Victoria Eugenia of Hemophilia. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.