Correction: Optimization of prophylaxis for hemophilia A

<p>Correction: Optimization of prophylaxis for hemophilia A</p

Optimization of prophylaxis for hemophilia A

<div><p>Background & aims</p><p>Prophylactic injections of factor VIII reduce the incidence of bleeds and slow the development of joint damage in people with hemophilia. The aim of this study was to identify optimal person-specific prophylaxis regimens for children with hemophilia A.</p><p>Methods</p><p>Analytic and numerical methods were used to identify prophylaxis regimens which maximize the time for which plasma factor VIII concentrations exceed a threshold, maximize the lowest plasma factor VIII concentrations, and minimize risk of bleeds.</p><p>Results</p><p>It was demonstrated analytically that, for any injection schedule, the regimen that maximizes the lowest factor VIII concentration involves sharing doses between injections so that all of the trough concentrations in a prophylaxis cycle are equal. Numerical methods were used to identify optimal prophylaxis schedules and explore the trade-offs between efficacy and acceptability of different prophylaxis regimens. The prophylaxis regimen which minimizes risk of bleeds depends on the person’s pattern of physical activity and may differ greatly from prophylaxis regimens that optimize pharmacokinetic parameters. Prophylaxis regimens which minimize risk of bleeds also differ from prophylaxis regimens that are typically prescribed. Predictions about which regimen is optimal are sensitive to estimates of the effects on risk of bleeds of factor VIII concentration and physical activity.</p><p>Conclusion</p><p>The methods described here can be used to identify optimal, person-specific prophylaxis regimens for children with hemophilia A.</p></div

Optimal prophylaxis regimens identified using Broderick’s model.

<p>A, a ‘very active’ child, B, an ‘inactive’ child, and C, a ‘weekend active’ child. In each panel, the 100 prophylaxis regimens that best minimize bleeds incidence are shown. Each prophylaxis regimen is shown by a horizontal line joining three circles. The horizontal location of the symbols indicates the timing of the injections for each prophylaxis regimen and the vertical location indicates the incidence rate ratio associated with the prophylaxis regimen (lower values indicate lower incidence of bleeds). Time is expressed as hour of the week, starting at midnight on Sunday night. Patterns of physical activity are shown as bars in the lower part of each panel. Blue bars are periods of category 2 activity. Red bars are periods of category 3 activity. Unfilled bars are periods of sleep. The size and colour of the circles indicates the dose (small green circles 15 IU/kg, intermediate black circles 30 IU/kg, large pink circles 45 IU/kg).</p

Effect of timing and dose of injections on the lowest factor VIII concentration.

<p>Panels A and B show the effect of timing of injections when the dose of injections is fixed. Panels C and D show the effect of dose of injections when the timing of injections is fixed. In panels A and C, the dose of all three injections is equal (<i>D</i>_<i>1</i> = <i>D</i>_<i>2</i> = <i>D</i>_<i>3</i> = 30 IU/kg). In panels B and D, the dose of injections is unequal (<i>D</i>_<i>1</i> = <i>D</i>_<i>2</i> = 15 IU/kg; <i>D</i>_<i>3</i> = 30 IU/kg).</p

Optimal prophylaxis regimens identified using the modified Broderick’s model.

<p>A, a ‘very active’ child, B, an ‘inactive’ child, and C, a ‘weekend active’ child. The figure is the same as <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0192783#pone.0192783.g003" target="_blank">Fig 3</a> except that the effect of factor VIII concentration has been increased (<i>ln(a) =</i> 0.870).</p

Effect of factor VIII half-life on optimal prophylaxis regimens identified using Broderick’s model for the ‘very active’ child.

<p>A, half-life = 10.7 hours (This panel is the same as <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0192783#pone.0192783.g003" target="_blank">Fig 3A</a>), B, half-life = 8 hours, and C, half-life = 15 hours.</p

Effect of timing and dose of injections on time (in hours per week) above a threshold of 1 IU/dL.

<p>Panels A and B show the effect of timing of injections when the dose of injections is fixed. Panels C and D show the effect of dose of injections when the timing of injections is fixed. In panels A and C, the dose of all three injections is equal (<i>D</i>_<i>1</i> = <i>D</i>_<i>2</i> = <i>D</i>_<i>3</i> = 30 IU/kg). In panels B and D, the dose of injections is unequal (<i>D</i>_<i>1</i> = <i>D</i>_<i>2</i> = 15 IU/kg; <i>D</i>_<i>3</i> = 60 IU/kg). The threshold is 1 IU/dL. In this and subsequent figures, three injections of a total of 90 IU/kg are given in a weekly cycle to a person with <i>E =</i> 0 IU/dL, IVR = 2 kg/dL, and a half-life of 10.7 hours.</p