Numerical simulation of oxygen uptake by lipofuscin in paramacular RPE in-vivo during exposure to diffuse sunlight.

<p>Oxygen uptake was calculated based on results from a previous investigation of oxygen uptake by isolated human lipofuscin granules [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0172635#pone.0172635.ref020" target="_blank">20</a>], after correction for factors affecting retinal exposure levels in-vivo (see text). Results were plotted for healthy people of different ages: 20-year old (red), 40-year old (green), and 60-year old (orange). Results for 20-year old patients with STGD1 are also shown (grey).</p

Monte-Carlo simulation of light scattering and absorption in a thick layer of melanosomes.

<p>In this plot generated by MontCarl, the optical paths (blue lines) of 3000 photons are ray-traced through a relatively thick layer of RPE-melanosomes at the concentration in-vivo. Photons are injected by an infinitely thin light beam at X/ Y = 0/ 0. The X- and Z-axes, respectively, indicate the lateral and vertical (depth) location in the sample. Most photons are either absorbed or scattered back at Z = 30 μm. At the assumed maximum in-vivo layer ‘thickness’ of RPE-melanosomes (3 μm), a small proportion of photons are backscattered or absorbed.</p

Light attenuation by RPE-melanin in-vivo varies with age and the presence of Stargardt disease.

<p>We calculated the total optical density (OD) of paramacular RPE-melanin versus wavelength of incident radiation with Eqs <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0172635#pone.0172635.e004" target="_blank">4</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0172635#pone.0172635.e006" target="_blank">6</a> based on results of Monte-Carlo simulations. Colored lines indicate attenuation in healthy people of different ages: 20 (red), 40 (green), and 60 (orange). The same is shown for a 20-year old patient with STGD1 (black).</p

Total rates of oxygen uptake by lipofuscin during light exposure.

<p>Rates of oxygen uptake (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0172635#pone.0172635.g008" target="_blank">Fig 8</a>) were integrated along the wavelength of incident radiation to obtain the total rate of O₂-uptake, as an indication of cellular oxidative stress in-vivo during exposure to diffuse sunlight (white bars) or during SW-AF imaging (grey bars). X-axes: Age of healthy individuals, or patients with STGD1 (age, 20).</p

Relative contributions of light scattering and absorption by RPE-melanin.

<p>(A) Agreement between Monte-Carlo simulation and theory, plotted based on conditions in the paramacular RPE of a healthy 20-year old person. The optical density (OD) was calculated based on the product of the attenuation coefficient and the melanosome layer thickness (<i>l</i>_melanin). Attenuation by absorption (striped line), scattering (dotted line), and total attenuation (straight line) are plotted separately. The MC results are shown in blue (left Y-axis) and the theoretical result is shown in red (right Y-axis). See text for details. (B) Simulations of a thin (3 μm; blue) and thick (52.5 μm; orange) layer of melanosomes. In case of thicker layers, there is a dominance of the absorption coefficient (<i>μ</i>_{<i>a</i>, melanin}, straight lines) over the backscattering coefficient (<i>μ′</i>_{<i>s</i>, melanin}, striped lines) for all tested wavelengths.</p

Retinal exposure from diffuse solar irradiation compared to excitation light of short-wavelength retinal auto-fluorescence.

<p>At <i>λ</i> = 488 nm the peak height is indicated by single colored dots. Exposures were calculated by Eqs (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0172635#pone.0172635.e002" target="_blank">2</a>) and (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0172635#pone.0172635.e003" target="_blank">3</a>), respectively. Exposures in ocular media of different ages are plotted; 20 year-old (red), 40 year-old (green), and 60 year-old (orange).</p

Acceptability curve of the three anti-VEGF treatments.

<p>The acceptability curve shows the probability of a treatment being cost-effective over a range of willingness-to-pay thresholds. The curve shows that bevacizumab is the most likely to be cost-effective until a willingness-to-pay threshold of €407,250 is reached, after which aflibercept is most likely to be cost-effective.</p

Results of meta-analysis.

<p>Results of meta-analysis.</p

The cost-effectiveness of bevacizumab, ranibizumab and aflibercept for the treatment of age-related macular degeneration—A cost-effectiveness analysis from a societal perspective

<div><p>Background</p><p>The discussion on the use of bevacizumab is still ongoing and often doctors are deterred from using bevacizumab due to legal or political issues. Bevacizumab is an effective, safe and inexpensive treatment option for neovascular age-related macular degeneration (AMD), albeit unregistered for the disease. Therefore, in some countries ophthalmologists use the equally effective but expensive drugs ranibizumab and aflibercept. We describe the economic consequences of this dilemma surrounding AMD treatment from a societal perspective.</p><p>Methods</p><p>We modelled cost-effectiveness of treatment with ranibizumab (as-needed), aflibercept (bimonthly) and bevacizumab (as-needed). Effectiveness was estimated by systematic review and meta-analysis. The drug with the most favourable cost-effectiveness profile compared to bevacizumab was used for threshold analyses. First, we determined how much we overspend per injection. Second, we calculated the required effectiveness to justify the current price and the reasonable price for a drug leading to optimal vision. Finally, we estimated how much Europe overspends if bevacizumab is not first choice.</p><p>Results</p><p>Bevacizumab treatment costs €27,087 per year, about €4,000 less than aflibercept and €6,000 less than ranibizumab. With similar effectiveness for all drugs as shown by meta-analysis, bevacizumab was the most cost-effective. Aflibercept was chosen for threshold analyses. Aflibercept costs €943 per injection, but we determined that the maximum price to be cost-effective is €533. Alternatively, at its current price, aflibercept should yield about twice the visual gain. Even when optimal vision can be achieved, the maximum price for any treatment is €37,453 per year. Most importantly, Europe overspends €335 million yearly on AMD treatment when choosing aflibercept over bevacizumab.</p><p>Conclusion</p><p>Bevacizumab is the most cost-effective treatment for AMD, yet is not the standard of care across Europe. The registered drugs ranibizumab and aflibercept lead to large overspending without additional health benefits. Health authorities should consider taking steps to implement bevacizumab into clinical practice as first choice.</p></div

Utility value per visual acuity category.

<p>Utility value per visual acuity category.</p