Abstract
BackgroundAbout 20–30% of persons with HIV infection, especially those living in countries with limited resources, experience an immune reconstitution inflammatory syndrome (IRIS) after starting antiretroviral treatment. The active form of vitamin D, 1,25-dihydroxyvitamin D, is a key player in the clearance of pathogens and influences the level of inflammation and macrophage activation.Presentation of the hypothesisWe hypothesize that low availability of 1,25-dihydroxyvitamin D, either due to vitamin D deficiency or due to polymorphisms in the vitamin D receptor or in its activating/inactivating enzymes, contributes to the appearance of IRIS. Furthermore, drug interactions with the enzymatic pathways of vitamin D could favour the development of IRIS.Testing the hypothesisOur hypothesis could be explored by a case-control study to assess the prevalence of vitamin D deficiency in HIV-infected patients on antiretroviral treatment who develop and do not develop IRIS.Implications of the hypothesisIf the role of vitamin D in IRIS is confirmed, we would be able to screen patients at risk for IRIS by screening for vitamin D deficiency. After confirmation by means of a clinical trial, vitamin D supplementation could be a cheap and safe way to reduce the incidence of IRIS.
Highlights
About 20–30% of persons with human immunodeficiency virus (HIV) infection, especially those living in countries with limited resources, experience an immune reconstitution inflammatory syndrome (IRIS) after starting antiretroviral treatment
Active anti-retroviral therapy (HAART) decreases the mortality and improves the quality of life of persons living with human immunodeficiency virus (HIV) infection [1]
17–32% of HIV infected persons living in countries with limited resources experience a temporary worsening of their clinical status after starting Highly active anti-retroviral therapy (HAART) despite immunological improvement [2,3]
Summary
Active anti-retroviral therapy (HAART) decreases the mortality and improves the quality of life of persons living with human immunodeficiency virus (HIV) infection [1]. In case of low 25-(OH)D levels prior to HAART, we hypothesize that a defective clearing of pathogens and a delayed negative feedback on macrophage activation due to low 1,25-(OH)2D production, can lead to excessive granuloma formation and an exacerbated inflammatory response described as IRIS. Vitamin D decreases immune stimulation [38], but if vitamin D is given when granulomas are already flourishing, the 1α-hydroxylase in activated macrophages can produce high amounts of 1,25-(OH)2D with systemic spillover [34] resulting in hypercalcemia [38] as described in Mtb-IRIS [39,40,41] and cryptococcus-IRIS [42]. We propose to perform functional testing of vitamin D enzymes to find out if an increase of the vitamin D catabolism or a decrease of its production could contribute to low 1,25-(OH)2D concentrations at the site of inflammation, possibly leading to IRIS. If the role of vitamin D in IRIS is confirmed, vitamin D supplementation could be a cheap and safe way to prevent IRIS
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