Figure 2 shows the results of the univariate and multivariate analyses. The lowest 25(OH)D tertile was the reference group for all analyses. After adjustment, persons with 25(OH)D levels in the middle and upper tertiles had a statistically significant lower risk of AIDS, with an incidence rate ratio (IRR) of 0.58 (95% CI 0.39–0.87, P = 0.0086) and 0.61 (95% CI 0.40–0.93, P = 0.020), respectively. Similarly, persons with a 25(OH)D level in the middle tertile had a significantly reduced incidence of death (IRR 0.68, 95% CI 0.47–0.99, P = 0.045), as did those with a 25(OH)D level in the higher tertile (IRR 0.56; 95% CI 0.37–0.83, P = 0.0039). There were no differences between persons with 25(OH)D levels in the middle and higher tertiles. A similar trend was observed for the incidence of non-AIDS events: persons with 25(OH)D levels in the middle and higher tertiles had a nonsignificantly reduced incidence of non-AIDS events (IRR 0.73, 95% CI 0.48–1.12, P = 0.16, and IRR 0.79, 95% CI 0.52–1.20, P = 0.27, respectively). After adjustment, there were no significant differences in the incidence of the most frequent non-AIDS events, cardiovascular events and non-AIDS malignancies, according to 25(OH)D tertile (data not shown).
Deaths were stratified according to cause. Of 188 deaths, 160 were of known cause, of which 48 (30.0%) were judged to be AIDS-related and 112 (70.0%) non-AIDS related. Trends of IRR for both causes of deaths across 25(OH)D strata were consistent with those in Fig. 2, although the lower number of events reduced the power to detect differences. Persons in the middle and higher strata had a nonsignificantly reduced incidence of AIDS-related death (IRR 0.53, 95% CI 0.24–1.15, P = 0.11, and IRR 0.61, 95% CI 0.28–1.32, P = 0.21, respectively). The incidence of non-AIDS-related death was nonsignificantly reduced for persons with 25(OH)D values in the middle tertile (IRR 0.67, 95% CI 0.41–1.09, P = 0.10), but significantly reduced for those with values in the higher tertile (IRR 0.60, 95% CI 0.37–0.98, P = 0.043).
There was no evidence of an interaction between race and 25(OH)D tertile and any of the clinical events (P>0.1), although this analysis had limited power because of the small number of persons of non-white ethnic origin. Furthermore, there was no interaction between 25(OH)D level and HIV RNA viral load or use of cART for the prediction of AIDS, non-AIDS events or death. Further, adjusting for current RNA or CD4 value (i.e. taking account of measurements made during follow-up) did not significantly alter our findings. For example, for death, after additionally adjusting for CD4 and viral load as time-updated covariates, there was a significantly reduced incidence of death in both the middle (IRR 0.65, 95% CI 0.44–0.95, P = 0.025) and higher 25(OH)D tertiles (IRR 0.67, 95% CI 0.45–1.00, P = 0.048). Adjusting for cumulative time on treatment in the 1650 persons on cART at baseline did not significantly impact the analysis (data not shown).
Hemoglobin was measured within 6 months of baseline in 1262 persons. There was very little correlation between 25(OH)D value and hemoglobin (correlation coefficient 0.087, P = 0.0020), across 25(OH)D tertiles. A multivariate model adjusting additionally for baseline or current anemia status showed consistent results to those in Fig. 2 (data not shown). In addition, serum creatinine values within 6 months of baseline were available for 355 persons. There was no correlation between estimated glomerular filtration rate (eGFR) and 25(OH)D (correlation coefficient -0.091, P = 0.086), and no patient had chronic kidney disease (two consecutive eGFR <60 ml/min/1.73 m2) at or before 25(OH)D evaluation.
Body mass index (BMI) was available for 1518 persons within 6 months of baseline, and there was no correlation with 25(OH)D levels (correlation coefficient 0.016, P = 0.53). After adjustment, compared to those with medium BMI, persons with a low BMI (≤18) had marginally increased odds of having a 25(OH)D level in the lowest tertile (aOR 1.71; 95% CI 0.92–3.17, P = 0.091), and persons with a high BMI (>25) had similar odds of having a 25(OH)D level in the lowest tertile (aOR 1.02; 95% CI 0.79–1.32, P = 0.88).
The study examined 25(OH)D levels in a large population of well characterized HIV-infected persons. The objectives were to describe the prevalence and correlates of vitamin D deficiency, and to determine whether a 25(OH)D level was associated with subsequent all-cause death, AIDS-defining or non-AIDS events.
The present results confirm [15–19] that vitamin D insufficiency or deficiency is frequent in HIV-infected persons. Studies across Europe have found highly variable 25(OH)D levels in the general population, with levels below 10 ng/ml in 2–30% of adults . In the US, 25(OH)D levels below 30 ng/ml and below 20 ng/ml were similarly prevalent in the SUN cohort of HIV-infected persons vs. in the general population (NHANES study), after adjustment for age, sex and race: 70.3 vs. 79.1% and 29.7 vs. 38.8%, respectively . Therefore, vitamin D deficiency might not be more frequent in people living with HIV than in the general population. Unsurprisingly, the season of sampling was associated with 25(OH)D levels, and persons with less, or benefiting less from, sun exposure (living outside Southern Europe and Argentina, or of black ethnic origin) were more likely to have very low 25(OH)D levels. Nonhomosexual route of HIV-1 transmission was also associated with lower 25(OH)D levels. This is in agreement with an earlier study suggesting that intravenous drug use is a risk factor for low 25(OH)D . Of note, the association with heterosexual transmission remained after adjustment for ethnicity. These differences across transmission groups may reflect other factors we were not able to adjust for, such as nutrition and sun exposure. As in the general population, increasing age was also associated with lower 25(OH)D levels. Exposure to cART  and the use of efavirenz [17,18,28,29] have been associated with lower 25(OH)D levels, but we were unable to reproduce this finding in the present study. Neither the use of NRTIs or protease inhibitors was associated with lower levels of 25(OH)D. The finding that protease inhibitor use was associated with higher 25(OH)D levels, as also shown in the SUN cohort , is of unclear biological relevance.
Having a 25(OH)D level in the lowest tertile (<12 ng/ml) was strongly associated with the occurrence of AIDS events and all-cause mortality over a median follow-up of 5 years, after adjusting for a large number of variables, including season, ethnic and geographic origin, CD4 cell count and viral load (at baseline and time-adjusted), and there was no interaction between these variables and 25(OH)D levels for the association with events. Thus, a very low 25(OH)D level was associated with events, even in the case of virologically controlled HIV infection and immune restoration. The prognostic value of vitamin D deficiency was also independent of anemia, another prognostic factor of HIV infection , that has been associated with low 25(OH)D levels in untreated HIV-infected African women . In addition, although we only had information on a subgroup of persons, low 25(OH)D levels were not correlated with low eGFR, an indicator of cardiovascular risk in the general and HIV-infected populations , associated with all-cause and cardiovascular mortality .
We thus found a strong association between the lowest 25(OH)D tertile (<12 ng/ml) and the two main endpoints of all-cause death and AIDS events, but no differences between the medium and high 25(OH)D tertiles. Vitamin D deficiency therefore represents a new, independent, unfavorable prognostic marker in HIV infection, but without further research this cannot translate into clinical recommendations.
The association of low 25(OH)D with clinical progression in HIV infection echoes the multiple functions now attributed to vitamin D, which, like other steroid hormones, can regulate gene activity in numerous cell types [2,5,6]. Vitamin D deficiency has been associated with cancer risk [1,2,5], with a large study suggesting that vitamin D supplementation could lower the risk of malignancies . Studies have also associated vitamin D insufficiency with hypertension, insulin resistance and high BMI, thus establishing a link with cardiovascular risk , clinical cardiovascular disease [34,35], and cardiovascular and all-cause death [10,14]. Vitamin D regulates endothelial function , down-regulates the renin gene activity , and a placebo-controlled trial has shown that vitamin D administration lowers blood pressure in hypertensive persons . Vitamin D has regulatory effects on immune functions : the vitamin D receptor is expressed on adaptive and innate immune cells; vitamin D plays a role in innate immunity, particularly in the defence against mycobacteria, and in T-cell activation, with vitamin D insufficiency leading to altered T-cell proliferation . Vitamin D deficiency has also been associated with inflammation . In a study of patients referred for a coronary angiography, vitamin D deficiency was associated with all-cause and cardiovascular mortality, and correlated with high levels of markers of cell adhesion, oxidative stress and inflammation [C-reactive protein (CRP) and interleukin 6 (IL-6)] . In a placebo-controlled study, vitamin D supplementation lowered the level of the inflammatory cytokine TNF-α and increased the level of the anti-inflammatory cytokine IL-10, in patients with congestive heart failure . In a large cohort, low vitamin D levels have also been associated with increased levels of the coagulation activation markers tissue plasminogen activator and D-dimer .
Taken together, these results are of particular relevance to our findings, because of the well described increased vascular risk in HIV-infected persons, and because markers of inflammation (CRP and IL-6) and coagulation activation (D-dimers) have been associated with mortality and opportunistic diseases in HIV-infected persons [44,45]. In the present study, whereas non-AIDS events were not significantly associated with low 25(OH)D (possibly due to a lack of power), non-AIDS deaths were: this could reflect an aggravating effect of vitamin D deficiency, possibly linked with immune dysfunction or increased inflammation, on different conditions.
The study has several limitations. The study population may not be representative of the whole cohort, with excluded persons being older and having been sampled during spring less often: however, this would only attenuate the effect of 25(OH)D level on events. There were also a relatively low number of non-AIDS events: the impact of vitamin D on these events should therefore be addressed in larger studies. Information on vitamin D supplementation is not collected in EuroSIDA, but it is unlikely that HIV-infected persons sampled around 2001 were widely receiving vitamin D supplementation, and persons who were included earlier in the cohort had higher 25(OH)D levels, as observed in the general population . This study was based on a single 25(OH)D measurement, at entry into the cohort, which leaves open the questions whether the length of exposure to low 25(OH)D, or its level at a given time point, is the key factor, and whether 25(OD) level has a short or mid-term, rather than long-term, prognostic value. Lastly, this is an observational study, from which causal relations cannot be drawn. However, the association between vitamin D deficiency and immune dysfunction, inflammation and coagulation activation may suggest a coherent, testable, pathogenic link between low 25(OH)D levels and events in HIV-infected persons.
These results provide strong evidence that vitamin D deficiency is an important cofactor in HIV disease progression, even in the setting of widespread, efficient cART. Whether the relationship between vitamin D deficiency and events is causal must now be addressed, because of potential public health consequences.
Primary support for EuroSIDA is provided by the European Commission BIOMED 1 (CT94-1637), BIOMED 2 (CT97-2713), the 5th Framework (QLK2-2000-00773) and the 6th Framework (LSHP-CT-2006-018632) programs. Current support also includes unrestricted grants by Gilead, Pfizer, and Merck and Co. The participation of centers from Switzerland was supported by The Swiss National Science Foundation (Grant 108787). 25-hydroxyitamin D measurements were funded by SIDACTION.
Authors acknowledge the technical expertise of Mélanie Ducarteron who performed all 25-hydroxyvitamin D determinations.
J.-P.V., J.-C.S., O.K., J.D.L., and A.M. designed the study, planned the analyses and wrote the first draft of the manuscript. They had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. J.-C.S. supervised vitamin D measurements. A.M. and J.R. performed the statistical analyses. B.K., M.L., J.G., C.P., J.R.B. contributed major suggestions for analysis and participated in the writing of the manuscript. All clinicians enrolled persons in the study and collected data.
Funding sources were not involved at any step of the present work (design and conduct of the study, collection, management, analysis, or interpretation of data; preparation, review or approval of the manuscript).
The EuroSIDA study group (national coordinators): Argentina: (M. Losso), C. Elias, Hospital JM Ramos Mejia, Buenos Aires. Austria: (N. Vetter) Pulmologisches Zentrum der Stadt Wien, Vienna; (R. Zangerle) Medical University Innsbruck, Innsbruck. Belarus: (I. Karpov), A. Vassilenko, Belarus State Medical University, Minsk, V.M. Mitsura, Gomel State Medical University, Gomel; O. Suetnov, Regional AIDS Centre, Svetlogorsk. Belgium: (N. Clumeck) S. De Wit, B. Poll, Saint-Pierre Hospital, Brussels; R. Colebunders, Institute of Tropical Medicine, Antwerp; (L. Vandekerckhove) University Ziekenhuis Gent, Gent. Bosnia: (V. Hadziosmanovic) Klinicki Centar Univerziteta Sarajevo, Sarajevo. Bulgaria: K. Kostov, Infectious Diseases Hospital, Sofia. Croatia: J. Begovac, University Hospital of Infectious Diseases, Zagreb. Czech Republic: (L. Machala) H. Rozsypal, Faculty Hospital Bulovka, Prague; D. Sedlacek, Charles University Hospital, Plzen. Denmark: (J. Nielsen) G. Kronborg, T. Benfield, M. Larsen, Hvidovre Hospital, Copenhagen; J. Gerstoft, T. Katzenstein, A.-B.E. Hansen, P. Skinhøj, Rigshospitalet, Copenhagen; C. Pedersen, Odense University Hospital, Odense, L. Oestergaard, Skejby Hospital, Aarhus. Estonia: (K. Zilmer) West-Tallinn Central Hospital, Tallinn, Jelena Smidt, Nakkusosakond Siseklinik, Kohtla-Järve. Finland: (M. Ristola), Helsinki University Central Hospital, Helsinki. France: (C. Katlama) Hôpital de la Pitié-Salpétière, Paris; J.-P. Viard, Hôtel-Dieu, Paris; P.-M. Girard, Hospital Saint-Antoine, Paris; J.M. Livrozet, Hôpital Edouard Herriot, Lyon; P. Vanhems, University Claude Bernard, Lyon; C. Pradier, Hôpital de l'Archet, Nice; F. Dabis, D. Neau, Unité INSERM, Bordeaux. Germany: (J. Rockstroh) Universitäts Klinik Bonn; R. Schmidt, Medizinische Hochschule Hannover; J. van Lunzen, O. Degen, University Medical Center Hamburg-Eppendorf, Infectious Diseases Unit, Hamburg; H.J. Stellbrink, IPM Study Center, Hamburg; S. Staszewski, J.W. Goethe University Hospital, Frankfurt; J. Bogner, Medizinische Poliklinik, Munich; G. Fätkenheuer, Universität Köln, Cologne. Greece: (J. Kosmidis) P. Gargalianos, G. Xylomenos, J. Perdios, Athens General Hospital; G. Panos, A. Filandras, E. Karabatsaki, 1st IKA Hospital; H. Sambatakou, Ippokration Genereal Hospital, Athens. Hungary: (D. Banhegyi) Szent Lásló Hospital, Budapest. Ireland: (F. Mulcahy) St. James's Hospital, Dublin. Israel: (I. Yust) D. Turner, M. Burke, Ichilov Hospital, Tel Aviv; S. Pollack, G. Hassoun, Rambam Medical Center, Haifa; S. Maayan, Hadassah University Hospital, Jerusalem. Italy: (A. Chiesi) Istituto Superiore di Sanità, Rome; R. Esposito, I. Mazeu, C. Mussini, Università Modena, Modena; C. Arici, Ospedale Riuniti, Bergamo; R. Pristera, Ospedale Generale Regionale, Bolzano; F. Mazzotta, A. Gabbuti, Ospedale S Maria Annunziata, Firenze; V. Vullo, M. Lichtner, University di Roma la Sapienza, Rome; A. Chirianni, E. Montesarchio, M. Gargiulo, Presidio Ospedaliero AD Cotugno, Monaldi Hospital, Napoli; G. Antonucci, F. Iacomi, P. Narciso, C. Vlassi, M. Zaccarelli, Istituto Nazionale Malattie Infettive Lazzaro Spallanzani, Rome; A. Lazzarin, R. Finazzi, Ospedale San Raffaele, Milan; M. Galli, A. Ridolfo, Osp. L. Sacco, Milan; A. d'Arminio Monforte, Istituto Di Clinica Malattie Infettive e Tropicale, Milan. Latvia: (B. Rozentale) P. Aldins, Infectology Centre of Latvia, Riga. Lithuania: (S. Chaplinskas) Lithuanian AIDS Centre, Vilnius. Luxembourg: (R. Hemmer), T. Staub, Centre Hospitalier, Luxembourg. Netherlands: (P. Reiss) Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam. Norway: (J. Bruun) A. Maeland, V. Ormaasen, Ullevål Hospital, Oslo. Poland: (B. Knysz) J. Gasiorowski, Medical University, Wroclaw; A. Horban, E. Bakowska, Centrum Diagnostyki i Terapii AIDS, Warsaw; D. Prokopowicz, R. Flisiak, Medical University, Bialystok; A. Boron-Kaczmarska, M. Pynka, Medical Univesity, Szczecin; M. Beniowski, E. Mularska, Osrodek Diagnostyki i Terapii AIDS, Chorzow; H. Trocha, Medical University, Gdansk; (E. Jablonowska) E. Malolepsza, K. Wojcik, Wojewodzki Szpital Specjalistyczny, Lodz. Portugal: (F. Antunes) E. Valadas, Hospital Santa Maria, Lisbon; K. Mansinho, Hospital de Egas Moniz, Lisbon; F. Maltez, Hospital Curry Cabral, Lisbon. Romania: (D. Duiculescu) Spitalul de Boli Infectioase si Tropicale: Dr Victor Babes, Bucarest. Russia: (A. Rakhmanova), Medical Academy Botkin Hospital, St Petersburg; E Vinogradova, St Petersburg AIDS Centre, St Peterburg; S. Buzunova, Novgorod Centre for AIDS, Novgorod. Serbia: (D. Jevtovic), The Institute for Infectious and Tropical Diseases, Belgrade. Slovakia: (M. Mokráš) D. Staneková, Dérer Hospital, Bratislava. Slovenia: (J. Tomazic) University Clinical Centre Ljubljana, Ljubljana. Spain: (J. González-Lahoz) V. Soriano, L. Martin-Carbonero, P. Labarga, Hospital Carlos III, Madrid; S. Moreno, Hospital Ramon y Cajal, Madrid; B. Clotet, A. Jou, R. Paredes, C. Tural, J. Puig, I. Bravo, Hospital Germans Trias i Pujol, Badalona; J.M. Gatell, J.M. Miró, Hospital Clinic i Provincial, Barcelona; P. Domingo, M. Gutierrez, G. Mateo, M.A. Sambeat, Hospital Sant Pau, Barcelona. Sweden: (A. Karlsson), Karolinska University Hospital, Stockholm; P.O. Persson, Karolinska University Hospital, Huddinge; L. Flamholc, Malmö University Hospital, Malmö. Switzerland: (B. Ledergerber) R. Weber, University Hospital, Zürich; P. Francioli, M. Cavassini, Centre Hospitalier Universitaire Vaudois, Lausanne; B. Hirschel, E. Boffi, Hospital Cantonal Universitaire de Geneve, Geneve; H. Furrer, Inselspital Bern, Bern; M. Battegay, L. Elzi, University Hospital Basel. Ukraine: (E. Kravchenko) N. Chentsova, Kiev Centre for AIDS, Kiev; (G. Kutsyna) Luhansk AIDS Center, Luhansk; S. Servitskiy, Odessa Region AIDS Center, Odessa; (S. Antoniak) Kiev; (M. Krasnov) Kharkov State Medical University, Kharkov. United Kingdom: (S. Barton) St. Stephen's Clinic, Chelsea and Westminster Hospital, London; A.M. Johnson, D. Mercey, Royal Free and University College London Medical School, London (University College Campus); A. Phillips, M.A. Johnson, A. Mocroft, Royal Free and University College Medical School, London (Royal Free Campus); M. Murphy, Medical College of Saint Bartholomew's Hospital, London; J. Weber, G. Scullard, Imperial College School of Medicine at St. Mary's, London; M. Fisher, Royal Sussex County Hospital, Brighton; C. Leen, Western General Hospital, Edinburgh. Virology group: B. Clotet, R. Paredes (Central Coordinators) plus ad hoc virologists from participating sites in the EuroSIDA Study. Steering Committee: F. Antunes, B. Clotet, D. Duiculescu, J. Gatell, B. Gazzard, A. Horban, A. Karlsson, C. Katlama, B. Ledergerber (Chair), A. D'Arminio Montforte, A. Phillips, A. Rakhmanova, P. Reiss (Vice-Chair), J. Rockstroh. Coordinating Centre Staff: J. Lundgren (project leader), O. Kirk, A. Mocroft, N. Friis-Møller, A. Cozzi-Lepri, W. Bannister, M. Ellefson, A. Borch, D. Podlekareva, J. Kjær, L. Peters, J. Reekie, J. Kowalska.
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Keywords:© 2011 Lippincott Williams & Wilkins, Inc.
AIDS-defining events; all-cause mortality; HIV infection; vitamin D