Personalized prophylaxis

Authors


P. W. Collins, Arthur Bloom Haemophilia Centre, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK.
Tel.: +44 2920742155; fax: +44 2920745442;
e-mail: peter.collins@.wales.nhs.uk

Abstract

Summary.  Prophylaxis is the recommended treatment for people with severe haemophilia. It is unlikely that a single prophylactic regimen, for example based on weight, would be optimal for all patients and therefore each individual should have a personalized regimen, agreed between themselves and their haemophilia centre. This regimen should take into account the individual’s bleeding pattern, the condition of their musculoskeletal system, level and timing of physical activity and measurement of coagulation factor in their blood. It is important to recognize that prophylactic regimens are likely to need to change with time as the circumstances of an individual change. For example, activity may change with age or with the season and an individual’s factor VIII pharmacokinetics vary with age. Knowledge of a patient’s pharmacokinetics is likely to help personalize prophylaxis when combined with other information. Factor VIII pharmacokinetics are simple to measure in routine clinical practice and can be adequately calculated from 2 to 3 blood samples combined with a simple to use computer program. Prophylaxis is expensive and, in countries with a limited health care budget, ways to improve its cost effectiveness need to be considered to allow increased access to this treatment. For example, increasing the frequency of prophylaxis can dramatically reduce the amount of treatment required to sustain measureable factor levels and hence reduce cost. The introduction of longer-acting coagulation factors may necessitate a change in concepts about prophylaxis because whilst these agents may sustain an apparently adequate trough level with fewer infusions, the length of time a person spends at a low level will be increased and this could increase the risk of bleeding, especially at the time of increased physical activity. There is convincing evidence that prophylaxis is the optimal therapy for severe haemophilia, optimizing treatment for each individual and increasing access to this treatment modality are important goals for the future.

Introduction

It is well established that the natural history of severe haemophilia is characterized by recurrent joint and muscle bleeds leading to severe and progressive musculoskeletal damage and compromised mobility [1]. It is equally well established that if prophylaxis is started early in life, musculoskeletal problems are reduced or prevented [2–6]. It is recommended therefore that prophylaxis should be the treatment of choice for people with severe haemophilia and should be started at least after the first joint bleed [7].

The original concept of prophylaxis was to increase the trough level of factor VIII or IX (FVIII/FIX) above 1 IU dL−1, with the aim of converting the bleeding phenotype from severe to moderate [6,8,9]. This has proven to be a highly successful treatment strategy in long-term follow-up studies, and is usually delivered using a weight-based regimen of 20–40 IU kg−1, 3–4 times a week [1,2,9,10]. Studies support the hypothesis that increased time spent with a FVIII at a low level is associated with more frequent breakthrough bleeding [11].

Although the causes of breakthrough bleeding on prophylaxis have not been extensively studied, it is likely that a number of factors are involved, such as physical activity, the presence of target joints and synovial hypertrophy, the degree of haemophilic arthropathy, the effect FVIII/FIX has on the underlying global haemostatic system, individuals pharmacokinetic response to FVIII/FIX and adherence to the regimen.

The appropriate trough level that should be maintained during prophylaxis is debated and it is recognized that some patients bleed despite having a trough above 1 IU dL−1, whereas others do not bleed despite having an unmeasureable trough level. Although data support the importance of maintaining an adequate trough factor level, there is debate about why this level should vary between people. A possible explanation is that FVIII replacement affects patients’ global blood clotting systems differently [12], and studies that investigate whether tailoring prophylaxis based on thrombin generation or thromboelastography rather than factor level will be of interest. Recent studies suggest that protection from joint bleeds is highly dependent on factor levels between 1 and 4 IU dL−1, but that joint bleeds still occur, although more rarely, until the baseline is above 10–15 IU dL−1 [13]. This supports the view that the factor level required to prevent haemarthroses is likely to vary between patients and that 1 IU dL−1 is not necessarily an appropriate target in all cases. Indeed the concept of raising the trough to just above 1 IU dL−1 may have been more appropriate at a time when people with haemophilia were excluded from many physical activities, whereas now, when participation is encouraged, a higher level may be required.

Based on these principles, the treatment of severe haemophilia could be very simple. If FVIII/FIX is infused in doses that prevents bleeds, irrespective of other considerations, with the aim of maintaining the level above 15 IU dL−1 at all times, then good outcomes could be expected. This strategy is, of course, not feasible because of the cost of concentrate. The high cost of concentrate means that countries using prophylaxis try to minimize the amount used, and more importantly makes prophylaxis impossible for the vast majority of people with haemophilia in the world. It is important to recognize therefore that any debate around appropriate trough levels and personalization of prophylaxis is essentially a balance between what is desirable and affordable.

Given the need to deliver cost-effective prophylaxis, the ability to easily determine an individual’s FVIII/FIX pharmacokinetics and the use of this information to target a desired level would be very useful [14]. Techniques are now available that allow this to be done in routine clinical practice using simple computer programs and population pharmacokinetics [15–17]. A detailed description of the techniques involved is being prepared as a recommendation through the International Society on Thrombosis and Haemostasis.

This study describes potential strategies for individualizing prophylaxis, based both on bleed pattern and individual circumstances combined with pharmacokinetic monitoring. There are two ways to adjust prophylactic regimens, by dose and/or frequency/timing and the relative importance of these depends on the person’s individual circumstances.

Discussion

Standard prophylaxis is usually prescribed on the basis of weight and this has been shown to be a very successful strategy [4]. However, because neither the in vivo recovery nor the half-life of FVIII is directly proportional to weight and both vary between patients, this will result in a wide variation in the trough level achieved. For example, in an adult who has received an infusion of 30 IU kg−1, the FVIII level at 48 h may vary between 2 and 12 IU dL−1 and the time to reach 1 IU dL−1 can vary between 51 and 110 h [14,18] (Fig. 1). The standard regimen of 20–40 IU kg−1 on alternate days is predicted to maintain a trough of above 1 IU dL−1 in almost all young children [18], but in adults, who have substantially longer half-lives [17,19], the median trough at 48 h has been shown to be >6 IU dL−1 [20]. These findings suggest that weigh may not be the best way to prescribe prophylaxis, especially in adults, and good long-term outcomes have been reported using lower dose regimens adjusted on the basis of bleed pattern [10].

Figure 1.

 Variability in the effect of weight-based prophylaxis on FVIII levels. The time for FVIII to reach 1 IU dL−1 after an infusion of 30 IU kg−1 dependent of half-life is shown. The lines depict the 5th and 95th percentile of the normal half-life in a 70 kg man. The difference in the time taken to reach 1 IU dL−1 when comparing the shortest half-life with the longest is 59 h, suggesting that some patients need alternate day treatment, whereas others could be treated every 3 or 4 days. Alternatively, the data can be interpreted in terms of trough level at 48 h which varies between 2 and 12 IU dL−1. This means that if a patient with a long half-life, who is taking 30 IU kg−1 on alternate days, had his dose reduced to 5 IU kg−1, his trough may still be adequate at 1.5 IU dL−1.

Theoretically, prophylaxis should be tailored to minimize joint and significant soft tissue bleeds with the assumption that this will translate into good long-term orthopaedic outcomes [1,2,21]. This adjustment is best done collaboratively between the person with haemophilia (or their family) and their haemophilia centre, and relies heavily on an accurate record of bleeds and treatment. Prophylaxis should be adjusted based on the observed pattern of bleeds, times of expected physical activity and the status of the individual’s musculoskeletal system. These adjustments can be informed, and potentially made more cost-effective, by pharmacokinetic measurements.

For example, if a person on prophylaxis has had no breakthrough bleeds and their trough level is measured at 6 IU dL−1, then their dose of FVIII/FIX could be halved and their trough would still be 3 IU dL−1, if the dose is cut by 66% the trough would be 2 IU dL−1. Although this may not need to be considered in a country with an unlimited supply of concentrate, in countries with limited health care resources, the saved concentrate could allow another one or two people to be started on prophylaxis. If an individual has a target joint, then a period of more intensive prophylaxis that sustains a higher trough can be tried. Once the joint has settled, the regimen can be reduced. If bleeds occur in relation to a specific activity, the timing of the infusions can be adjusted to provide better cover. Regimen may be better adjusted, if pharmacokinetic data are available that give information about the factor level at the time of the break-through bleeds or anticipated activity.

It is common practice to infuse prophylaxis on a Monday, Wednesday and Friday and FIX twice a week. This has the disadvantage of allowing periods with low levels, and potentially increases the risk of break-through bleeds. Giving an increased dose of FVIII on a Friday is a common practice, but to cover the extra day a fourfold increase is required (Fig. 2). A more cost-effective strategy, and one that results in substantially better factor levels, is to give an extra, lower dose, infusion on Saturday or Sunday, depending on when the most activity is anticipated (Fig. 3). Infusing on alternate day avoids this problem and some families find this an easy regimen to follow. The choice of which regimen to use is individual, and often depends on what the patient is used to, in our experience, if alternate prophylaxis is started at a young age, then there are very few problems with adherence.

Figure 2.

 Implications of Monday, Wednesday, Friday dosing. Upper panel depicts the FVIII level of a patient on three times a week prophylaxis, whose FVIII reaches 1 IU dL−1 after 48 h. This means that the FVIII is below 1 IU dL−1 throughout Sunday. The lower panel shows that to sustain FVIII above 1 IU dL−1 throughout Sunday a fourfold increase is required on Friday, assuming a half-life of 12 h. The FVIII scale is arbitrary.

Figure 3.

 Potential prophylactic regimens for active patients. The panels depict a hypothetical patient treated with various prophylactic regimens. The dashed line indicates a time of high physical activity on a Sunday morning, for example playing sport. The upper depicts 1000 IU on Monday and Wednesday, and 1500 IU on Friday. This results in limited cover for activity on Sunday. An alternate day regimen (second panel) could be used and would provide good cover on the first Sunday, but on alternate weeks, a lower level would be achieved (dotted line) and the patient may be vulnerable to break-through bleeds. The same amount of FVIII as used in panel one will give much better cover if an extra dose of 500 IU is given on Sunday (panel 3). Alternatively, by using 500 IU daily a much high trough level can be achieved throughout the week (panel 4). The FVIII scale is arbitrary.

Increasing the frequency of FVIII/FIX infusions can be used to maintain a desired trough level whilst using substantially less FVIII/FIX or to allow a much higher trough to be achieved with the same amount of concentrate (Fig. 3). In haemophilia B, for example, to maintain a trough FIX level above 1 IU dL−1 treating 1–3 times a week, every third day or on alternate days takes an average of 240 000, 137 000 and 108 000 IU year−1 respectively [22]. Similar effects are seen by increasing the frequency of FVIII infusions [23]. An important potential advantage of more frequent dosing is that, by using less concentrate, more people with haemophilia can have access to treatment. For example, in a 70 kg adult with an average FVIII half-life, the baseline FVIII can be maintained above 1 IU, with 100 IU day−1, 36 500 IU year−1 compared with standard weight-based dosing of 110 000 IU year−1 [14].

The frequency of prophylaxis can be tailored to an individual’s circumstances. For example, a very active teenager who wants to play contact sports on a daily basis might decide to take daily prophylaxis at a dose of half his alternate day regimen. This regimen has the advantages of a peak level each day and a much higher trough level whilst not consuming more concentrate (Fig. 3). Short-term daily prophylactic regimens may also be useful for people with target joints or those undergoing intensive physiotherapy.

However, people who started prophylaxis at a young age usually have well preserved joints, those who have received on demand treatment or started prophylaxis later in life often have significant arthropathy and this may be very severe [1–3]. The appropriate trough level in these circumstances is not known and must be established empirically for each patient. Some patients require higher troughs to prevent bleeds, but equally some patients have such compromised mobility that lower troughs are adequate.

Venous access is a further consideration when personalizing prophylaxis. Some centres initiate prophylaxis in young children once weekly and increase the frequency, if bleeds occur. This is a strategy designed to familiarize the child and family with intravenous infusions, and reduce the need for central venous access. The effect of this strategy on long-term orthopaedic outcome, for example by potentially allowing subclinical bleeds to occur, or on the risk of inhibitor development is not known. Some older patients also have poor venous access and, because of their longer FVIII half-lives and less physically demanding lifestyles, may be adequately treated twice a week (Fig. 1), pharmacokinetic studies can be very helpful in these circumstances.

Good adherence to a prophylactic regimen is key to success and any discussion about trough levels is irrelevant if doses are regularly missed because break-through bleeds will increase [11] (Fig. 4). The reasons for lack of adherence need to be discussed openly between the patient and the centre and any problems addressed. A better understanding of how prophylaxis works or changing the regimen to better fit the individual’s lifestyle may help.

Figure 4.

 Effect of non-adherence and hypothetical effect of a long half-life coagulation factor. Panel 1 shows that missing a dose has a very significant effect on the time spent below a hypothetical target level and this is known to be associated with an increased risk of break-through bleeding. The middle panel shows a standard alternate day regimen with the same hypothetical target level. The patient spends a short period of time every second day below this level, but this occurs at night. Panel 3 is a hypothetical long half-life agent. The patient achieves the same trough level, but spends more time below the target level, and this occurs both during the day and at night. The clinical implications of this remain unknown.

An individual’s prophylactic regimen is often considered to be fixed. However, by definition, this inhibits personalization because an individual’s circumstances will inevitably change. Prophylactic regimens are likely to need to change as an individual ages. Young children need cover throughout the day and week because their activity is unpredictable and often constant. Also this age group is probably the most vulnerable to the effects of haemarthroses [5]. Very active teenagers may opt for daily treatment, possible for a short period of time, for example during the part of the year when their sport is played. Young adults may need to continue intensive prophylaxis, but some find that they can stop prophylaxis or use targeted prophylaxis as they gain experience of what causes their bleeds and how to avoid bleeds [1,2,24]. Older adults who undertake very limited activity, either because of their type of work or the effect of musculoskeletal problems, may need only a very low dose or infrequent regimen.

It is our practise to tailor prophylaxis based on all available information and to regularly suggest that patient tries a new regimen. If a regimen is changed, it is very important that a review takes place after 6–8 weeks, to establish whether any undesired events have occurred and also to give the patient confidence that the regimen can be adjusted again if problems have occurred. This review can often be carried out by a haemophilia specialist nurse by telephone or email supported by electronic web-based bleed reporting systems [25,26].

There is much current interest in FVIII/FIX concentrates with prolonged half-lives. These products have an obvious potential for allowing more convenient prophylaxis. It is important to recognize, however, that by prolonging the half-life the patient will spend longer with low factor levels and these will occur during the day and the night. It is possible that higher troughs may need to be maintained. Alternatively, improved adherence may be an advantage of longer half-life products (Fig. 4). Clinical trials are underway to establish the effects of different products and regimens and the results are keenly awaited.

Prophylaxis is the treatment of choice for people with severe haemophilia and the use of personalized regimens is a logical extension to weight-based dosing. Introducing cost-effective low dose frequent regimens will help to make optimal therapy available to more people.

Disclosures

PC has acted as a paid consultant for and received research support from Bayer, Baxter, Novo Nordisk and CSL Behring.

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