Open Access

Is vitamin D deficiency involved in the immune reconstitution inflammatory syndrome?

  • Anali Conesa-Botella1, 3Email author,
  • Chantal Mathieu2,
  • Robert Colebunders1, 3,
  • Rodrigo Moreno-Reyes4,
  • Evelyne van Etten2,
  • Lut Lynen1 and
  • Luc Kestens5
AIDS Research and Therapy20096:4

https://doi.org/10.1186/1742-6405-6-4

Received: 13 February 2009

Accepted: 21 April 2009

Published: 21 April 2009

Abstract

Background

About 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 hypothesis

We 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 hypothesis

Our 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 hypothesis

If 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.

Background

Highly active anti-retroviral therapy (HAART) decreases the mortality and improves the quality of life of persons living with human immunodeficiency virus (HIV) infection [1]. Nevertheless, 17–32% of HIV infected persons living in countries with limited resources experience a temporary worsening of their clinical status after starting HAART despite immunological improvement [2, 3]. This paradoxical reaction occurs most frequently during the first 3 months after initiation of HAART and is known as immune reconstitution inflammatory syndrome (IRIS) or immune restoration disease (IRD) [4]. To date, more than 20 different pathogens have been associated with IRIS [2, 3, 5, 6]. However, IRIS has also been described in association with autoimmune diseases, cancer, and some non-infectious granulomatous diseases such as sarcoidosis and Crohn's disease [7].

In countries with limited resources, Mycobacteria sp. are by far the most common pathogens involved [5].

There is now evidence that vitamin D plays a role in improving anti-tuberculosis immunity as well as in the regulation of immune responses [811], both of which are crucial steps in the development of IRIS. A double blind randomized controlled trial showed that a single dose of vitamin D significantly enhanced immunity to Mycobacteria tuberculosis (Mtb) among contacts of tuberculosis (TB)-infected patients [12]. Liu et al showed later that vitamin D acts by increasing the level of the antimicrobial peptide cathelicidin produced by monocytes and macrophages [13, 14].

Low levels of vitamin D levels have been observed in African populations [15] as well as in HIV-infected persons (reviewed by Villamor [16]). A recent study in a cohort of HIV-positive patients in the Netherlands (73% white, 20% black) showed a prevalence of vitamin D deficiency of 29% in the total population, and 62% in black patients. Low levels of active vitamin D have been associated with low CD4 counts and AIDS progression [17].

TB treatment is also known to interfere with vitamin D metabolism and to cause osteomalacia [18]. Vitamin D deficiency may be influenced by deficient substrate, but also by polymorphisms in its receptor or in the enzymes controlling the activation of this steroid.

Presentation of the hypothesis

Low levels of vitamin D could predispose HIV infected patients with a current or undiagnosed opportunistic infection (OI) to IRIS. Indeed, the active form of vitamin D, 1,25-(OH)2D, has anti-inflammatory activity [19] and there is now accumulating evidence for its role in the regulation of human T-cell and antigen-presenting cell (APC) functions [20, 21]. Furthermore, drug interactions with the enzymatic pathways of vitamin D [22] could favour the development of IRIS.

Pathogenesis of IRIS

HIV causes progressive depletion of CD4+ T-cells and impairs the immune system [2, 5]. In HIV/Mtb patients with severe immunodeficiency, impaired T-cell function impedes granuloma formation [23]. When HAART is started, T-cell function is restored and granuloma formation is re-established, mainly in the lungs and lymph nodes, through activation of Mtb-infected macrophages by interferon-γ (IFN-γ) producing T-cells [23]. Unfortunately, rapid or unbalanced restoration of the immune system against living or death organisms [7, 24] may also lead to uncontrolled antigen-specific responses [2] with reappearance of clinical symptoms [5] and development of IRIS.

Known risk factors for the development of IRIS include a low CD4 T-cell count when starting HAART, advanced OI with high OI antigen load, and a short time interval between OI treatment and the start of HAART [2, 2528]. Other risk factors such as younger age, male gender, a higher CD8 T-cell percentage, a high viral load at baseline, a fast increase in CD4 T-cell count and fast decrease in viral load after the start of HAART, and a protease inhibitor (PI) based HAART regimen, were reported in some studies but not in others [29].

Vitamin D and the immune system

The main source of vitamin D stems from sun exposure: pre-vitamin D is converted by solar ultraviolet B radiation in the skin into vitamin D. Skin pigmentation is a known risk factor for hypovitaminosis D since melanin, responsible for the skin pigmentation, filters UV radiation [3032].

Food uptake is limited to vitamin D supplementation or consumption of oily fish [31]. Vitamin D is transported into the blood by the vitamin D-binding protein (VDBP) is converted in the liver by 25-hydroxylases (CYP34A, CYP27A1, CYP2R1, ...) into 25-hydroxyvitamin D (25-(OH)D). 25-(OH)D is considered the best indicator of vitamin D status [31, 33] with normal levels between 30 and 50 ng/ml [34]. Vitamin D deficiency is defined as 25-(OH)D below 20 ng/ml [31]. The cytochrome CYP3A4, present in liver, intestine, kidney and leukocytes [35] is also a key enzyme in P450 cytochrome-mediated drug metabolism such as anti-retrovirals (non nucleoside reverse transcriptase inhibitor and PI) as well as certain anti-tuberculous drugs (rifampicin and isoniazid) [18, 33, 35]. The inactive form of vitamin D, 25-(OH)D, is converted in kidney cells into its circulating active form 1,25-(OH)2D by the enzyme 1-α-hydroxylase (CYP27B1). Other cells such as macrophages also express CYP27B1 [33]. In the late phase of macrophage activation, macrophage-CYP27B1 produces 1,25-(OH)2D which presumably has a local rather than a systemic effect on immune cells [20]. Although the macrophage-CYP27B1 is identical to the renal CYP27B1, its expression is not down-regulated by the parathyroid hormone nor the active vitamin D and is mainly up-regulated by inflammatory cytokines such as IFN-γ and by lipopolysaccharides (LPS) [20, 33]. Figure 1 illustrates the complex action of active vitamin D on regulatory and effector T-cells and on APC, which results in a negative feedback on macrophage activation to prevent their overstimulation [20, 36].
Figure 1

Role of vitamin D locally at the inflammation site – example based on Mtb infection. 1,25-(OH)2D, the active form of vitamin D produced by macrophage-CYP27B1 at the inflammation site, has many local actions leading to a negative feedback loop avoiding macrophage overstimulation. 1,25-(OH)2D reduces T helper (Th1) lymphocyte-mediated macrophage activation, (a) by activating regulatory T-cells (Treg) which inhibit the activation of Th1 lymphocytes by antigen-presenting cells (APC) [36], (b) by directly inhibiting activation of Th1 lymphocytes and thus their interferon-γ (IFN-γ) production, and (c) by preventing antigen presentation by APC to Th1 lymphocytes [34]. 1,25-(OH)2D acts also directly on macrophages (d) by reducing expression of Toll-like receptor (TLR) to Mycobacterium tuberculosis (Mtb) [34], and (e) by inducing intracellular Mtb destruction via the cathelicidin-mediated system. If macrophages are overstimulated, high local level of 1,25-(OH)2D could lead to systemic spill over and thus hypercalcemia, as has been described in Mtb-IRIS [39], since no systemic negative feedback by the parathyroid axis exists on macrophage-1,25-hydroxylase (CYP27B1) [15].

To exert its actions, 1,25-(OH)2D binds to the vitamin D receptor (VDR) expressed in normal, malignant and immune cells [34]. At least 36 tissues possess VDR and more than 10 tissues are able to produce 1,25-(OH)2D in a paracrine fashion [8]. By the wide expression of VDR [8], 1,25-(OH)2D can regulate calcium homeostasis and bone metabolism as well as play an essential role in cell proliferation, differentiation and the above described regulation of the immune response [31, 33]. The variability in patients' susceptibility to immune dysfunction and thus IRIS could be explained by the polymorphisms of the VDR gene known to influence immune cell function [37], or by polymorphisms of hydroxylases regulating the production or the degradation of the bioactive vitamin D.

Vitamin D, HAART and IRIS

During HAART and immune reconstitution, pathogen-derived antigens are de novo recognized by APC, processed and presented to CD4+ T-cells leading to T-cell activation and secretion of macrophage-activating interferon-γ. Vitamin D inhibits this IFN-γ production [34].

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.

To avoid macrophage-overstimulation, vitamin D should be given before their massive activation, i.e. before the initiation of the inflammation. Indeed 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 [3941] and cryptococcus-IRIS [42]. At that moment vitamin D supplementation could worsen the clinical status of the patient.

Protease inhibitors (PI) are known to interfere with vitamin D metabolism (Figure 2) reducing 1,25-(OH)2D levels [22]. Low 1,25-(OH)2D levels and bone loss has been described to be most frequent in PI-treated patients compared to other HAART regimens [43, 44]. Brown et al. concluded that odds of having osteoporosis was 1.6 times higher if patients where PI-treated [45]. We suggest that the interaction between PI and vitamin D metabolism could result in an increased risk of IRIS in patients treated with a PI-based regimen [29].
Figure 2

Vitamin D production in macrophages and PI interaction. The 25-hydrolylase CYP3A4 converts vitamin D into 25-(OH)D, its inactive form. To be active, the circulating 25-(OH)D is 1-α-hydroxylated by the renal or the extrarenal P450 cytochrome (CYP27B1) into 1,25-(OH)2D. Both 25-(OH)D and 1,25-(OH)2D can also be catabolized by 24-hydroxylation (CYP24A1) into 24,25-(OH)2D and 1α,24,25-(OH)2D respectively [33]. Activated macrophages possess both CYP27B1 and CYP24A1 and are able to produce 1,25-(OH)2D locally at the site of inflammation. Protease inhibitors (PI) inhibit the function of the hepatic-CYP3A4 and the macrophage-CYP27B1 which are critical for active vitamin D synthesis, and exert a milder inhibition on the activity of the 24-hydroxylase (arrows). The net effect is a reduced production of 1,25-(OH)2D [22] that could influence immunity.

Testing the hypothesis

Our hypothesis could be explored by a case-control study to assess the prevalence of vitamin D deficiency in HIV infected patients on HAART who develop and do not develop IRIS. In cohort studies of patients initiated on HAART, the incidence of IRIS should be compared in patients with low, normal and high baseline vitamin D levels.

Moreover, polymorphisms of the VDR, the VDBP and the enzymes involved in vitamin D production should be investigated. We also 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. Finally remains the issue whether the levels of vitamin D that are currently accepted as 'sufficient' for bone health apply to 'global health' and in particular anti-bacterial and anti-inflammatory properties of vitamin D [46].

Implication of the hypothesis

There is an inter-relationship between vitamin D metabolism, HAART therapy and immunity. Impaired vitamin D metabolism in macrophages, whether caused by vitamin D deficiency or by HAART therapy, might be a determinant of IRIS in HIV-positive individuals. The potential role of vitamin D status in the pathogenesis of IRIS should be investigated. Indeed, if the role of vitamin D in IRIS is confirmed, vitamin D supplementation could be a cheap and safe way to prevent IRIS.

Declarations

Authors’ Affiliations

(1)
Institute of Tropical Medicine, Department of Clinical Sciences
(2)
Katholieke Universiteit Leuven, Laboratory of Experimental Medicine and, Endocrinology
(3)
University of Antwerp, Faculty of Medicine
(4)
Department of Nuclear Medicine, Université Libre de Bruxelles
(5)
Institute of Tropical Medicine, Department of Immunology

References

  1. Egger M, May M, Chene G, Phillips AN, Ledergerber B, Dabis F: Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet. 2002, 360: 119-129. 10.1016/S0140-6736(02)09411-4View ArticlePubMedGoogle Scholar
  2. Dhasmana DJ, Dheda K, Ravn P, Wilkinson RJ, Meintjes G: Immune reconstitution inflammatory syndrome in HIV-infected patients receiving antiretroviral therapy: pathogenesis, clinical manifestations and management. Drugs. 2008, 68: 191-208. 10.2165/00003495-200868020-00004View ArticlePubMedGoogle Scholar
  3. Murdoch DM, Venter WD, Feldman C, Van RA: Incidence and risk factors for the immune reconstitution inflammatory syndrome in HIV patients in South Africa: a prospective study. AIDS. 2008, 22: 601-610. 10.1097/QAD.0b013e3282f4a607View ArticlePubMedGoogle Scholar
  4. Meintjes G, Lawn SD, Scano F, Maartens G, French MA, Worodria W: Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis. 2008, 8: 516-523. 10.1016/S1473-3099(08)70184-1PubMed CentralView ArticlePubMedGoogle Scholar
  5. Colebunders R, John L, Huyst V, Kambugu A, Scano F, Lynen L: Tuberculosis immune reconstitution inflammatory syndrome in countries with limited resources. Int J Tuberc Lung Dis. 2006, 10: 946-953.PubMedGoogle Scholar
  6. Lawn SD, Bekker LG, Miller RF: Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis. 2005, 5: 361-373. 10.1016/S1473-3099(05)70140-7View ArticlePubMedGoogle Scholar
  7. French MA: Disorders of immune reconstitution in patients with HIV infection responding to antiretroviral therapy. Curr HIV/AIDS Rep. 2007, 4: 16-21. 10.1007/s11904-007-0003-zView ArticlePubMedGoogle Scholar
  8. Norman AW: From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health. Am J Clin Nutr. 2008, 88: 491S-499S.10.View ArticlePubMedGoogle Scholar
  9. Tsoukas CD, Provvedini DM, Manolagas SC: 1, 25-dihydroxyvitamin D3: a novel immunoregulatory hormone. Science. 1984, 224: 1438-1440. 10.1126/science.6427926View ArticlePubMedGoogle Scholar
  10. Kankova M, Luini W, Pedrazzoni M, Riganti F, Sironi M, Bottazzi B: Impairment of cytokine production in mice fed a vitamin D3-deficient diet. Immunology. 1991, 73: 466-471.PubMed CentralPubMedGoogle Scholar
  11. Yang S, Smith C, Prahl JM, Luo X, DeLuca HF: Vitamin D deficiency suppresses cell-mediated immunity in vivo. Arch Biochem Biophys. 1993, 303: 98-106. 10.1006/abbi.1993.1260View ArticlePubMedGoogle Scholar
  12. Martineau AR, Wilkinson RJ, Wilkinson KA, Newton SM, Kampmann B, Hall BM: A single dose of vitamin D enhances immunity to mycobacteria. Am J Respir Crit Care Med. 2007, 176: 208-213. 10.1164/rccm.200701-007OCView ArticlePubMedGoogle Scholar
  13. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR: Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006, 311: 1770-1773. 10.1126/science.1123933View ArticlePubMedGoogle Scholar
  14. Liu PT, Stenger S, Tang DH, Modlin RL: Cutting edge: vitamin D-mediated human antimicrobial activity against Mycobacterium tuberculosis is dependent on the induction of cathelicidin. J Immunol. 2007, 179: 2060-2063.View ArticlePubMedGoogle Scholar
  15. Wejse C, Olesen R, Rabna P, Kaestel P, Gustafson P, Aaby P: Serum 25-hydroxyvitamin D in a West African population of tuberculosis patients and unmatched healthy controls. Am J Clin Nutr. 2007, 86: 1376-1383.PubMedGoogle Scholar
  16. Villamor E: A potential role for vitamin D on HIV infection?. Nutr Rev. 2006, 64: 226-233. 10.1111/j.1753-4887.2006.tb00205.xView ArticlePubMedGoogle Scholar
  17. Bout-Van Den Beukel Van Den CJ, Fievez L, Michels M, Sweep FC, Hermus AR, Bosch ME: Vitamin D deficiency among HIV type 1-infected individuals in the Netherlands: effects of antiretroviral therapy. AIDS Res Hum Retroviruses. 2008, 24: 1375-1382. 10.1089/aid.2008.0058View ArticleGoogle Scholar
  18. Zhou C, Assem M, Tay JC, Watkins PB, Blumberg B, Schuetz EG: Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia. J Clin Invest. 2006, 116: 1703-1712. 10.1172/JCI27793PubMed CentralView ArticlePubMedGoogle Scholar
  19. Tsoukas CD, Provvedini DM, Manolagas SC: 1, 25-dihydroxyvitamin D3: a novel immunoregulatory hormone. Science. 1984, 224: 1438-1440. 10.1126/science.6427926View ArticlePubMedGoogle Scholar
  20. van Etten E, Mathieu C: Immunoregulation by 1, 25-dihydroxyvitamin D3: basic concepts. J Steroid Biochem Mol Biol. 2005, 97: 93-101. 10.1016/j.jsbmb.2005.06.002View ArticlePubMedGoogle Scholar
  21. Mathieu C, Adorini L: The coming of age of 1, 25-dihydroxyvitamin D(3) analogs as immunomodulatory agents. Trends Mol Med. 2002, 8: 174-179. 10.1016/S1471-4914(02)02294-3View ArticlePubMedGoogle Scholar
  22. Cozzolino M, Vidal M, Arcidiacono MV, Tebas P, Yarasheski KE, Dusso AS: HIV-protease inhibitors impair vitamin D bioactivation to 1, 25-dihydroxyvitamin D. AIDS. 2003, 17: 513-520. 10.1097/00002030-200303070-00006View ArticlePubMedGoogle Scholar
  23. Saunders BM, Britton WJ: Life and death in the granuloma: immunopathology of tuberculosis. Immunol Cell Biol. 2007, 85: 103-111. 10.1038/sj.icb.7100027View ArticlePubMedGoogle Scholar
  24. Kestens L, Seddiki N, Bohjanen PR: Immunopathogenesis of immune reconstitution disease in HIV patients responding to antiretroviral therapy. Current Opinion in HIV and AIDS. 2009, 3: 419-424. 10.1097/COH.0b013e328302ebbb.View ArticleGoogle Scholar
  25. Burman W, Weis S, Vernon A, Khan A, Benator D, Jones B: Frequency, severity and duration of immune reconstitution events in HIV-related tuberculosis. Int J Tuberc Lung Dis. 2007, 11: 1282-1289.PubMedGoogle Scholar
  26. Lawn SD, Myer L, Bekker LG, Wood R: Tuberculosis-associated immune reconstitution disease: incidence, risk factors and impact in an antiretroviral treatment service in South Africa. AIDS. 2007, 21: 335-341.View ArticlePubMedGoogle Scholar
  27. Navas E, Martin-Davila P, Moreno L, Pintado V, Casado JL, Fortun J: Paradoxical reactions of tuberculosis in patients with the acquired immunodeficiency syndrome who are treated with highly active antiretroviral therapy. Arch Intern Med. 2002, 162: 97-99. 10.1001/archinte.162.1.97View ArticlePubMedGoogle Scholar
  28. Shelburne SA, Visnegarwala F, Darcourt J, Graviss EA, Giordano TP, White AC: Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS. 2005, 19: 399-406. 10.1097/01.aids.0000161769.06158.8aView ArticlePubMedGoogle Scholar
  29. Manabe YC, Campbell JD, Sydnor E, Moore RD: Immune reconstitution inflammatory syndrome: risk factors and treatment implications. J Acquir Immune Defic Syndr. 2007, 46: 456-462. 10.1097/QAI.0b013e3181594c8cView ArticlePubMedGoogle Scholar
  30. Lips P: Vitamin D physiology. Prog Biophys Mol Biol. 2006, 92: 4-8. 10.1016/j.pbiomolbio.2006.02.016View ArticlePubMedGoogle Scholar
  31. Holick MF: Vitamin D deficiency. N Engl J Med. 2007, 357: 266-281. 10.1056/NEJMra070553View ArticlePubMedGoogle Scholar
  32. Loomis WF: Skin-pigment regulation of vitamin-D biosynthesis in man. Science. 1967, 157: 501-506. 10.1126/science.157.3788.501View ArticlePubMedGoogle Scholar
  33. Prosser DE, Jones G: Enzymes involved in the activation and inactivation of vitamin D. Trends Biochem Sci. 2004, 29: 664-673. 10.1016/j.tibs.2004.10.005View ArticlePubMedGoogle Scholar
  34. Baeke F, Etten EV, Overbergh L, Mathieu C: Vitamin D3 and the immune system: maintaining the balance in health and disease. Nutr Res Rev. 2007, 20: 106-118. 10.1017/S0954422407742713View ArticlePubMedGoogle Scholar
  35. Gupta RP, He YA, Patrick KS, Halpert JR, Bell NH: CYP3A4 is a vitamin D-24- and 25-hydroxylase: analysis of structure function by site-directed mutagenesis. J Clin Endocrinol Metab. 2005, 90: 1210-1219. 10.1210/jc.2004-0966View ArticlePubMedGoogle Scholar
  36. Helming L, Bose J, Ehrchen J, Schiebe S, Frahm T, Geffers R: 1alpha, 25-Dihydroxyvitamin D3 is a potent suppressor of interferon gamma-mediated macrophage activation. Blood. 2005, 106: 4351-4358. 10.1182/blood-2005-03-1029View ArticlePubMedGoogle Scholar
  37. Colin EM, Weel AE, Uitterlinden AG, Buurman CJ, Birkenhager JC, Pols HA: Consequences of vitamin D receptor gene polymorphisms for growth inhibition of cultured human peripheral blood mononuclear cells by 1, 25-dihydroxyvitamin D3. Clin Endocrinol (Oxf). 2000, 52: 211-216. 10.1046/j.1365-2265.2000.00909.xView ArticleGoogle Scholar
  38. Overbergh L, Decallonne B, Valckx D, Verstuyf A, Depovere J, Laureys J: Identification and immune regulation of 25-hydroxyvitamin D-1-alphahydroxylase in murine macrophages. Clin Exp Immunol. 2000, 120: 139-146. 10.1046/j.1365-2249.2000.01204.xPubMed CentralView ArticlePubMedGoogle Scholar
  39. Lawn SD, Macallan DC: Hypercalcemia: a manifestation of immune reconstitution complicating tuberculosis in an HIV-infected person. Clin Infect Dis. 2004, 38: 154-155. 10.1086/380451View ArticlePubMedGoogle Scholar
  40. Ferrand RA, Elgalib A, Newsholme W, Childerhouse A, Edwards SG, Miller RF: Hypercalcaemia complicating immune reconstitution in an HIV-infected patient with disseminated tuberculosis. Int J STD AIDS. 2006, 17: 349-350. 10.1258/095646206776790169View ArticlePubMedGoogle Scholar
  41. Shelburne SA, Hamill RJ, Rodriguez-Barradas MC, Greenberg SB, Atmar RL, Musher DW: Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy. Medicine (Baltimore). 2002, 81: 213-227. 10.1097/00005792-200205000-00005View ArticleGoogle Scholar
  42. Jenny-Avital ER, Abadi M: Immune reconstitution cryptococcosis after initiation of successful highly active antiretroviral therapy. Clin Infect Dis. 2002, 35: e128-e133. 10.1086/344467View ArticlePubMedGoogle Scholar
  43. Madeddu G, Spanu A, Solinas P, Calia GM, Lovigu C, Chessa F: Bone mass loss and vitamin D metabolism impairment in HIV patients receiving highly active antiretroviral therapy. Q J Nucl Med Mol Imaging. 2004, 48: 39-48.PubMedGoogle Scholar
  44. Rivas P, Gorgolas M, Garcia-Delgado R, az-Curiel M, Goyenechea A, Fernandez-Guerrero ML: Evolution of bone mineral density in AIDS patients on treatment with zidovudine/lamivudine plus abacavir or lopinavir/ritonavir. HIV Med. 2008, 9: 89-95. 10.1111/j.1468-1293.2007.00525.xView ArticlePubMedGoogle Scholar
  45. Brown TT, Qaqish RB: Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS. 2006, 20: 2165-2174. 10.1097/QAD.0b013e32801022ebView ArticlePubMedGoogle Scholar
  46. Holick MF: Vitamin D status: measurement, interpretation, and clinical application. Ann Epidemiol. 2009, 19: 73-78. 10.1016/j.annepidem.2007.12.001PubMed CentralView ArticlePubMedGoogle Scholar

Copyright

© Conesa-Botella et al; licensee BioMed Central Ltd. 2009

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.