Unrestricted access to CFC
Most developed countries have had relatively unrestricted access to CFCs for over two decades. Yet, early prophylaxis is not universal in many of these countries for several reasons. Apart from healthcare system-related access issues, there is also the lack of motivation of the families, difficulties with venous access, other logistic difficulties and fear of inhibitors [11-13]. Even with nearly a third of patients developing inhibitors [14, 15], significant data on the epidemiology of inhibitor development and the contribution of environmental factors to it have mostly come from one group [16, 17]. The total quantity of CFC used in the developed countries has nearly doubled over the last decade with addition of new patients, better survival of older PWH, increasing intensity of doses and prophylaxis extending to adults as well as immune tolerance induction for those with inhibitors (Fig 1). However, this has not been matched with proper data on outcomes to show its full benefits.
Figure 1. Use of clotting factor concentrates and numbers of patients in different parts of the world over the last decade. Source: WFH Annual Global Survey.
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While observational data with prophylaxis collected over several decades at two centres (Malmo, Sweden and Utrecht, the Netherlands) has established its role in reducing bleeding and maintaining near normal musculoskeletal status, it is important to recognize that the two worked with different philosophies – the former aiming to maintain >1% circulating factor level at all times and the latter targeting the clinical avoidance of bleeding. This resulted in the total doses at Malmo being nearly double those at Utrecht [3, 18]. Both centres have increased their total annual doses, with greater availability of CFC and evolving philosophy of intensified replacement therapy, but the proportions remain similar. Recently performed randomized controlled studies have confirmed the obvious superiority of prophylaxis over episodic treatment in preventing bleeds and therefore improving long-term outcomes [19, 20]. While all these approaches used fairly fixed dose protocols, investigators in Canada attempted to individualize requirements with escalating doses based on individual bleeding patterns . Such approaches, however, need to be carefully designed so as not to allow too many joint bleeds before escalating replacement. No major study has been attempted to prospectively compare different prophylaxis protocols.
In the absence of data comparing different doses for prophylaxis, varying doses are used, based on individual experiences or conviction of what is best. There is therefore great heterogeneity in replacement therapy protocols with regard to time for initiation as well as the dose and frequency of administration, even within the same healthcare environment . The irony of these practices is perhaps most obvious in Western Europe, a zone with relative socioeconomic parity in healthcare and where considerable efforts have been made to standardize care . Data collected by the annual global survey of the WFH and a European Hemophilia Consortium survey have shown for some years now that the CFC use in these countries varied from less than 3 IU per capita to more than 7 IU per capita . There is hardly an example of another disease where there is such variation in doses of a drug used for its treatment. National registries and databases, such as the one in the UK, that have included data on CFC use, have shown that even within the same country, there can be >twofold differences between regions or centres . As these practices have not been combined with any systematic data on outcomes, it has not been possible to judge the relative merits of the different protocols .
This lack of prospective comparative data is often attributed to the relative rarity of haemophilia and the small number of patients at most centres. This is perhaps only partly true because two centres from countries with relatively small populations have collected basic outcome data such as the annual bleeding rates (ABR) and joint scores (clinical and radiological) systematically over a period of decades and taught much to the world. Certainly this could have been done elsewhere as well. We continue to learn from their experiences. A recent comparison of these data have shown that with prophylaxis starting in Sweden at about 1 year of age and an average annual dose of ~4000 IU kg−1 year−1, there were about 2.5 joint bleeds over 5 years compared with prophylaxis starting at about 4.5 years in Netherlands with an average annual dose of ~2000 IU kg−1 year−1 but nearly 10 joint bleeds per PWH . At 24 years of age, this resulted in slightly worse joint scores for patients in the Netherlands but no difference in activities. However, the total annual cost was 66% higher in Sweden. Extrapolated, this meant an extra US $91 000 for every bleed avoided. These are very important conclusions because it allows informed choices to be made. We must also recognize their limitations. The most striking issue is the age of starting prophylaxis which is a well-recognized predictor of long-term outcome . If prophylaxis had been started earlier by about 2 years of age, would the outcome on the lower dose protocol have been the same? It is indeed possible that the differences may have been even less significant. If more centres had collected similar data, there would have been much more data on the correlation between different doses and outcomes. Better informed choices could have been made then regarding treatment options within the dose range used at these centres – about 1500–5000 IU kg−1 year−1.
Therefore, the art of replacement therapy, even after 50 years of practicing it, is far from optimal. This needs to be addressed. It is obvious that the studies most needed are prospective comparisons between different prophylaxis protocols balancing as many variables as possible. While this is unlikely to find commercial sponsorship, why this has not being done with support from healthcare funds defies logic given the fact that >90% of the cost of care is for CFC. Healthcare providers as well as patients should support such studies so that the quality of care is more strongly grounded and therefore better protected. This is important not only for the developed countries in how they would practice prophylaxis but even more so for those developing countries that are now beginning to initiate prophylaxis programmes.
Restricted access to CFC
Where access to CFC continues to be restricted, there are many more difficult issues to be addressed with regard to replacement therapy. Many of these countries have only identified 25–50% of the expected number of PWH in their populations. Identifying the rest and accurately diagnosing them is a major task . With regard to the treatment of those already identified, while support from governments is increasing in many countries, there are challenges related to regular procurement and distribution of CFCs so as to allow access to those who need it [28, 29]. Introduction of the concepts of prophylaxis and making that acceptable to PWH and their families is also a big task. While many of these issues need to be addressed at the bureaucratic, social and educational levels, there is an urgent need to develop suitable models of replacement therapy that are practical and effective in those circumstances .
Until about 5 years ago, CFC replacement in most developing countries was episodic only. Much of this was done not at home but in hospitals, usually only after large bleeds. Given the wide socioeconomic diversity in the region of the developing world, the doses used varied between <100 IU kg−1 year−1 to about 1500 IU kg−1 yr−1, depending on availability. Data on long-term outcome were limited and showed generally poor results [31, 32]. This has been confirmed in a recent prospective observational study  which showed that ABR and joint damage did not improve over a wide range of doses from 100–2000 IU kg−1 year−1 given as episodic replacement. These data therefore showed that episodic CFC replacement over a wide range of doses do not meaningfully alter the bleeding profile and joint damage in severe haemophilia. Good long-term outcome therefore cannot be expected from such treatment protocols.
How should healthcare providers in these countries decide how much CFC to provide in their health budgets for haemophilia? More importantly, what outcomes can they expect with what they will provide? This becomes increasingly relevant in countries that have access to about 1000–2000 IU kg−1 year−1 but think that they cannot implement prophylaxis as per current models? This would include many developing countries as is evident from the WFH annual global survey  including some of the larger ones such as Russia, Brazil and South Africa [34, 35].
The important question therefore is whether these countries should continue to practice episodic treatment or move to the best form of prophylaxis that is practical at the quantities available to them. Prophylactic CFC replacement therapy aims at reducing the number of days a PWH is at risk of spontaneous haemorrhage. In a PWH with severe disease, the ‘time at risk’ of bleeding can be considered 100% without any replacement therapy. Now if his factor level is raised to >1%, taken as a marker of successful replacement therapy, then even at 10 IU kg−1 dose−1 given twice a week, a severe PWH reduces this ‘time at risk’ by ~33% (taking a t½ of ~8 h for FVIII). As clinical efficacy often lasts beyond levels being maintained above 1%, it is likely that this reduction in risk time may be even greater. If this is enhanced to 10 IU kg−1 three times per week, this will then start reaching reductions in the ‘time at risk’ of ~60%. If paradigms could be changed completely and find practical and convenient ways found to administer CFC once a day then even with doses as low 5 IU kg−1 day−1 one could maintain >1% at all times with an annual dose well below 2000 IU kg−1. All the evidence suggests that any prophylaxis that reduces ABR should help improve long-term outcomes. After all, even in Western countries, prophylaxis had started with lower doses and they had already noted improvements in their patients before reaching current doses. There are also limited recent data that CFC doses as low as 10 IU kg−1 two to three times/week reduce joint bleeding in patients who previously received episodic replacement . Such prophylaxis programmes need to be systematically initiated in different countries .