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Those with HIV who doubled their vitamin D levels reduced their chance of death by 47 percent – Oct 2013

Twice-higher latest vitamin D almost halves odds of death in EuroSIDA Oct 2013

(from European AIDS treatment Group)

Every doubling of latest vitamin D level cut the odds of all-cause mortality 46% in a study of 250 EuroSIDA cohort members [1]. But neither initial nor latest vitamin D level affected odds of new AIDS or non-AIDS diagnoses.

Vitamin D deficiency and insufficiency are common in people with (and without) HIV, and low D levels are sometimes linked to dire clinical outcomes. A previous analysis of 1985 randomly selected EuroSIDA cohort members found significantly lower adjusted incidence of new AIDS diagnoses and all-cause mortality in people with vitamin D levels in the middle tertile of the study group (12 to 20 ng/mL) or the highest tertile (above 20 ng/mL) compared with the lowest tertile (under 12 ng/mL) [2]. But research in HIV-positive people has not demonstrated convincing clinical gains with vitamin D supplementation [3-5].

To learn more about the impact of vitamin D levels on HIV and non-HIV disease progression and death, the EuroSIDA team conducted a case-control study of people with available baseline and follow-up plasma samples from the previous vitamin D study [2]. Matching for age, gender, region, study entry date, and initial CD4 count and viral load, the researchers created 50 matched pairs of people with or without AIDS progression, 63 pairs of people with or without non-AIDS disease development, and 41 pairs who did or did not die.

The investigators also gauged the impact of vitamin D levels on inflammation by measuring high-sensitivity C-reactive protein (hsCRP), high-sensitivity interleukin 6 (hsIL-6), and soluble CD14 (sCD14) in samples collected at study entry, at the time of the clinical event, and at a midpoint in follow-up (if available). sCD14 has been linked to HIV disease progression markers [6] and impaired neurocognitive function in people with HIV [7].

The analysis included 250 people. Median ages of cases and controls were

  • 39 and 38 in the AIDS progression analysis,
  • 44 and 40 in the non-AIDS analysis, and
  • 42 and 41 in the death analysis.

Respective median CD4 counts were 251 and 270, 321 and 279, and 234 and 293.
Median viral loads ranged from about 500 to 1000 copies.

Proportions of cases and controls with vitamin D levels (measured as 25OHD) below 10 ng/mL were 32% and 18% in the AIDS progression analysis, 25% and 22% in the non-AIDS analysis, and 24% and 21% in the death analysis. Baseline and latest vitamin D levels did not differ significantly between cases and controls, except in the death analysis, in which cases had a significantly lower median vitamin D level (12 versus 19 ng/mL, P = 0.03). Cases had significantly higher hsIL-6 levels than controls in all three case-control groups. Cases had significantly higher hsCRP and sCD14 levels than controls in the AIDS and death case-control groups.

Baseline vitamin D levels were not associated with any outcome. But every 2-fold higher latest vitamin D level was associated with 46% lower odds of death (adjusted odds ratio [aOR] 0.54, 95% confidence interval [CI] 0.98 to 0.30). Every 1-ng/mL gain in average vitamin D level per year was associated with a 6% lower risk of death, but that association was not statistically significant (aOR 0.94, 95% CI 0.84 to 1.05, P = 0.26). Latest vitamin D or yearly change in vitamin D was not associated with development of AIDS or non-AIDS conditions.

Inflammation marker analyses yielded other intriguing associations:
*In people with a current vitamin D level below 10 ng/mL, hsIL-6 rose 4.66% yearly after adjustment for current hsCRP and sCD4 (P = 0.04).
*hsCRP rose 8.35% yearly in people with a current vitamin D level below 10 ng/mL (P = 0.04), but that association was not significant after adjustment for other markers of inflammation.
*sCD14 levels rose yearly at similar rates regardless of vitamin D level.
*CD4 counts rose significantly by 11.14% yearly when vitamin D was above 30 ng/mL (P < 0.01) and by 7.02% yearly when vitamin D was between 10 and 30 ng/mL (P < 0.01), but not when vitamin D was below 10 ng/mL.
*Every 1-unit increase in average absolute change per year in hsCRP raised the risk of death 33% (aOR 1.33, 95% CI 1.03 to 1.72, P = 0.03).

The association between latest vitamin D and all-cause mortality- -but not between baseline vitamin D and mortality- -suggested to the EuroSIDA team that this association diminishes with time. Because current vitamin D below 10 ng/mL was significantly associated with rising inflammatory markers, the researchers proposed that "severe vitamin D deficiency may thus represent a modifiable risk factor for increased inflammation." But they cautioned that this kind of analysis does not establish cause and effect.

By Mark Mascolini

References

  • 1. Viard JP, Shepherd L, Souberbielle JC, et al. Vitamin D level in HIV-infected persons: prognostic value for all-cause death, and association with inflammatory markers, results from the EuroSIDA cohort study. 14th European AIDS Conference. October 16-19, 2013. Brussels. Abstract BPD1/2.
  • 2. Viard, JP, Souberbielle JC, Kirk O, et al. Vitamin D and clinical disease progression in HIV infection: results from the EuroSIDA study. AIDS. 2011;25:1305-1315.
  • 3. Kakalia S, Sochett EB, Stephens D, Assor E, Read SE, Bitnun A. Vitamin D supplementation and CD4 count in children infected with human immunodeficiency virus. J Pediatr. 2011;159:951-957.
  • 4. Cooper C, Thorne A; Canadian HIV Trials Network Influenza Vaccine Research Group. Vitamin D supplementation does not increase immunogenicity of seasonal influenza vaccine in HIV-infected adults. HIV Clin Trials. 2011;12:275-276.
  • 5. Longenecker CT, Hileman CO, Carman TL, et al. Vitamin D supplementation and endothelial function in vitamin D deficient HIV-infected patients: a randomized placebo-controlled trial. Antivir Ther. 2012;17:613-621.
  • 6. Romero-Sánchez M, González-Serna A, Pacheco YM, et al. Different biological significance of sCD14 and LPS in HIV-infection: importance of the immunovirology stage and association with HIV-disease progression markers. J Infect. 2012;65:431-438.
  • 7. Lyons JL, Uno H, Ancuta P, et al. Plasma sCD14 is a biomarker associated with impaired neurocognitive test performance in attention and learning domains in HIV infection. J Acquir Immune Defic Syndr. 2011;57:371-379.

Paper was published later

Prognostic value of vitamin D level for all-cause mortality, and association with inflammatory markers, in HIV-infected persons
Journal of Infectious Diseases 10.1093/infdis/jiu074
Leah Shepherd 1, Jean-Claude Souberbielle 2, Jean-Philippe Bastard 3,4,5, Soraya Fellahi3,4,5, Jaqueline Capeau3,4,5, Joanne Reekie1,6, Peter Reiss7, Anders Blaxhult8, Markus Bickel9, Clifford Leen10,11, Ole Kirk12,13, Jens D. Lundgren12,13, Amanda Mocroft1, Jean-Paul Viard14, On behalf of EuroSIDA in EuroCOORD
1Department of Infection and Population Health, University College London Medical School, NW3 2PF London, UK
2Service d'Explorations Fonctionnelles,Hôpital Necker, F75015 Paris, France
3Department of Biochemistry, Hôpital Tenon, APHP, Paris F75020, France
4INSERM, U938, Faculté de Médecine Saint Antoine, ICAN, Institute of Cardiometabolism and Nutrition, F75012 Paris, France
5UPMC Univ Paris 06, UMR_S 938, F75005 Paris, France
6The Kirby Institute University of New South Wales, Sydney NSW 2010 Australia
7Academic Medical Centre (AMC), University of Amsterdam, NL-1105 AZ Amsterdam, the Netherlands
8Department of Medicine, Division of Infectious Diseases, Karolinska Institute, Stockholm, Sweden
9HIVCENTER Haus 68, 1OG, Theodor Stern Kai 7, 60590 Frankfurt, Germany
10Edinburgh Regional Infectious Diseases Unit, Western General Hospital, EH4 2XU Edinburgh, UK
11Edinburgh Infectious Diseases Edinburgh University, EH9 3JT Edinburgh, United Kingdom
12Copenhagen HIV Programme, University of Copenhagen, DK- 2200 Copenhagen, Denmark
13Centre for Viral Diseases, Department of Infectious Diseases, Rigshospitalet, DK- 2200 Copenhagen, Denmark
14Centre de Diagnostic et de Thérapeutique Hôtel-Dieu, APHP, and EA 3620,Université Paris Descartes, F75181 Paris, France
Corresponding author: Leah Shepherd, leah.shepherd at iinet.net.au, Ph: +44 20 7794 0500 ext 34570
Alternate corresponding author: Jean Paul Viard, jean-paul.viard at htd.aphp.fr, Ph :+33 (0)1 42 34 88 41

Background. Low 25-hydroxyvitamin D (25(OH)D) has been associated with inflammation, HIV disease progression and death. We aimed to identify the prognostic value of 25(OH)D for AIDS, non-AIDS-defining events and death, and its association with immunological/inflammatory markers.

Methods. Prospective 1-1 case–control study nested within the EuroSIDA cohort. Matched cases and controls for AIDS (n=50 matched pairs), non-AIDS-defining (n=63) events and death (n=41), with plasma samples during follow-up were selected. Conditional logistic regression models investigated associations between 25(OH)D levels and annual 25(OH)D change and the probability of events. Mixed models investigated relationships between 25(OH)D levels and immunological/inflammatory markers .

Results. 250 patients were included. Median time between first and last sample and last sample and event was 44.6(IQR:22.7-72.3) and 3.1(IQR:1.4-6.4) months. Odds of death decreased by 46.0%(95%CI:2.0–70.0,P=0.04) for a twofold increase in latest 25(OH)D level. There was no association between 25(OH)D and the occurrence of AIDS or non-AIDS-defining events (P>0.05). In patients with current 25(OH)D <10 ng/mL, hsIL-6 concentration increased by 4.7%(95%CI:0.2,9.4,P=0.04) annually after adjustment for immunological/inflammatory markers, and no change in hsCRP rate was observed (P=0.76).

Conclusions. Low Vitamin D predicts short term mortality in HIV-positive persons. Effectiveness of vitamin D supplementation on inflammation and patient outcomes should be investigated.


Example 10 ng ==> 20 ng

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