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Factor VIII products

give more side effects than episodic treatment (on demand), and modern plasma-derived and recombinant FVIII concentrates do not differ with regard to safety, including risk of inhibitor development. The issue of inhibitors and type of concentrate and dosing are especially controversial. Avoiding so-called danger signals and using low doses during the start of prophylaxis have indicated less risk for inhibitor development17

and third generation of

recombinant products has reported to elicit more inhibitors when starting treatment.18

been confirmed and other studies contrast to these results.

Starting prophylaxis

Due to difficulties in easily obtaining venous access in the young boy, it can be recommended to start prophylaxis using an infrequent schedule, that is, once weekly around the age of one year,7


starting early seems more important than exact dosing in the first years of life.8 Intervals are then rapidly shortened until a dose frequency of every second day is obtained. Such a schedule will virtually prevent all bleeds and the child can lead a virtually normal life and grow up without joint disease impacting his quality of life.9,10

If venous access is problematic, a port is needed to facilitate infusions during the first years.

Dosing schedules

The high cost of prophylaxis has prompted development of different dosing schedules. Traditionally, the Swedish programme aimed at keeping trough levels above 1% of normal,4

intense schedule11

the Dutch programme used a less and, in the Canadian

programme, a dose escalation schedule has been used.12

Although no head-to-head

studies have compared these schedules, the publications so far indicate a better long-term outcome using the more intense Swedish schedule. In recent years, tailoring prophylaxis according to the individual need has come to attention, as this may have a better medical effect and a potential to lower the cost of prophylaxis.

Dose tailoring using pharmacokinetics

Already during the 1970s it was shown that dosing using shorter intervals gave a considerably better effect on bleeding frequency than did using the same total dose at a longer interval.13

During the 6 1990s, pharmacokinetic dose tailoring

indicated the possibility of increasing cost efficacy of prophylaxis.14

In a recent

prospective, randomised cross-over study, daily dosing was compared to standard dosing, that is, dosing every second day in ten patients.15

The goal was

to keep at least the same trough level during daily dosing as with standard dose. Concentrate consumption was reduced by one-third, whereas the majority of the patients remained at their usual annual bleeding rate. However, two patients had to increase the dose, and the quality of life was somewhat more impaired during daily dosing. More studies are needed until patients can be switched to more economic schedules as indicated, by using computer modelling of their dosing. The daily dosing study seems to tell us that trough levels alone cannot be the only parameter to determine dose schedule. As there is a broad phenotypic variability among individuals with severe haemophilia, dosing needs to be tailored according to bleeding phenotype, individual pharmacokinetics and according to the recourses that are available in the healthcare setting the patient lives in. Ideally, the missing factor, in this case, should be normalised or at least kept at a level where the patient can live a physically active life without the risk of getting bleeds. Prophylaxis using relatively intense schedules has been shown to emerge in a beneficial outcome in terms of joint disease, bone mineralisation and quality of life.10,16

Factor VIII products and prophylaxis Factor VIII products licenced for use in haemophilia are today safe and convenient to use. According to current knowledge, prophylaxis as such does not

Stopping prophylaxis Prophylaxis during childhood and adolescence is a huge investment in time, cost and endurance. Much experience, as cited above, tells us that one should never stop prophylaxis and jeopardise the investment. Adult prophylaxis has gained attention and the trend today is to start and continue prophylaxis with the intention of delivering a life-long therapy.

Future perspectives

Due to economic constraints even in wealthy countries, prophylaxis will become more tailored to the individual. There are patients who probably can use lower total doses. In countries with fewer resources, the situation is, of course, very different, but the possibility of using very low but frequent doses is being explored. Increased awareness of disease, predictions of bleeding phenotype and improved possibilities to determine individual pharmacokinetics using Bayesian analysis and computer modelling have opened up new possibilities in prophylaxis. An obvious obstacle for implementing prophylaxis on an even more global scale and with more beneficial schedules is the issue of venous access, which is still a problem in the young child. The advent of FVIII products with prolonged half-life will probably to some extent overcome this problem, but not entirely. Better devices for venous access are on the wish list but this seems to be a difficult technical challenge to solve. Gene therapy has the potential to more or less cure haemophilia and introduce the ultimate mode of prophylaxis. However, this option is still a long way down the road, even if recent progress has been obtained.

These indications have not

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