Advertisement

Infection

pp 1–7 | Cite as

Vitamin D deficiency is associated with neurocognitive impairment in HIV-infected subjects

  • Alessandra Vergori
  • Carmela PinnettiEmail author
  • Patrizia Lorenzini
  • AnnaClelia Brita
  • Raffaella Libertone
  • Ilaria Mastrorosa
  • Stefania Cicalini
  • Andrea Antinori
  • Adriana Ammassari
Original Paper
  • 50 Downloads

Abstract

Purpose

Low vitamin D levels are associated with higher odds of cognitive dysfunction in the older population, and in subjects with mental disorders or with chronic neurologic diseases. With combination antiretroviral therapy (cART), incidence of HIV-associated dementia has reduced, while the prevalence of milder forms of neurocognitive impairment (NCI) persisted stable over time. Hypovitaminosis D is often found in HIV infection but its association with NCI has not been investigated yet. The aim was to explore this association in a clinic-based HIV-positive population.

Methods

A retrospective, cross-sectional analysis of an existing monocenter dataset obtained from patients undergoing neuropsychological assessment in routine clinical care between January, 2011 and December, 2016 was carried out. NCI was assessed through a standardized battery of 13 tests on 5 different cognitive domains and HIV-associated neurocognitive deficit (HAND) was classified according to Frascati’s criteria. Vitamin D deficiency was defined by 25 hydroxy-vitamin D 25(OH)D levels < 10 ng/mL. Logistic regression was adjusted for main associated covariates and seasonality.

Results

542 patients were included: 96.7% were receiving cART, median CD4 count was 611/mmc (IQR, 421–809), HIV RNA was < 40 cp/mL in 85.8%. Median 25(OH)D was 23.2 ng/mL (IQR, 15.6–29.2), with vitamin D insufficiency 67.7% and deficiency in 9.4%. Overall, NCI was found in 37.1% and HAND in 22.7%. Compared to patients with higher vitamin D levels, subjects with vitamin D deficiency had increased proportions of NCI (52.9% versus 35.4%; p = 0.014) or of HAND (42.9% versus 24.9%; p = 0.012). Median NPZ-8 scores were significantly different based on vitamin D levels (p = 0.021). At multivariable analyses, vitamin D deficiency was the only risk factor of NCI (OR 2.05; 95% CI 1.04–4.05; p = 0.038) or of HAND (OR 2.12; 95% CI 0.99–4.54; p = 0.052).

Conclusions

In HIV-positive persons, severe hypovitaminosis D was independently associated with a higher risk of neurocognitive impairment in general, and of HIV-associated neurocognitive disorders in particular. Future studies are needed to elucidate causal relationship and whether vitamin D supplementation may reverse this risk.

Keywords

Neurocognitive impairment HAD Vitamin D HIV 

Notes

Acknowledgements

The authors thank Dr Pietro Balestra and Dr Martina Ricottini as well as psychologists, physicians, nurses, laboratory staff of the National Institute for Infectious Diseases, L. Spallanzani, IRCCS and laboratory staff of the San Camillo- Forlanini Hospital for valuable collaboration.

Author contributions

Each author participated sufficiently in the work giving substantial contributions to realization; AAm, AAn, CP, SC and AV made contributions to the study conception and design, interpretation of data, drafting and revising the manuscript; ACB performed the neurocognitive assessment, RL, IM and ACB contributed to the acquisition of data, PL carried out the statistical analysis. All authors contributed to the intellectual content and gave their final approval to the submitted manuscript.

Funding

The study was supported by the INMI “Lazzaro Spallanzani” Ricerca Corrente grants (line 3d) from the Italian Ministry of Health 2016 and Gilead Fellowship 2017, awarded by Alessandra Vergori, MD.

Compliance with ethical standards

Conflict of interest

Adriana Ammassari (AAm) received speaker’s fees from AbbVie, BMS, Gilead, Janssen Cilag, Merck, ViiV and participated in Advisory Boards for Merck and Janssen; Andrea Antinori (AAn) received personal fees for consultancy and lectures from AbbVie, Bristol Myers Squibb, Gilead, Janssen, Merck, ViiV and research institutional grants from Bristol Myers Squibb, Gilead, Janssen, ViiV. Carmela Pinnetti (CP) participated in Advisory Boards for Janssen and received speaker’s fees from Gilead. For the remaining authors, none were declared.

References

  1. 1.
    Deeks SG, Lewin SR. Bekker LG (2017) The end of HIV: still a very long way to go, but progress continues. PLoS Med. 2017;14:e1002466.  https://doi.org/10.1371/journal.pmed.1002466.eCollection.CrossRefGoogle Scholar
  2. 2.
    Haddow LJ, Laverick R, Daskalopoulou M, Cognitive impairment in people with HIV in the European Region (CIPHER) Study Group, et al. Multicenter European prevalence study of neurocognitive impairment and associated factors in HIV positive patients. AIDS Behav. 2017.  https://doi.org/10.1007/s10461-017-1683-z.Google Scholar
  3. 3.
    Heaton RK, Franklin DR Jr, Deutsch R, et al. Neurocognitive change in the era of HIV combination antiretroviral therapy: the longitudinal CHARTER study. Clin Infect Dis. 2015;60:473–80.  https://doi.org/10.1093/cid/ciu862 (Epub 2014 Oct 31).CrossRefGoogle Scholar
  4. 4.
    Cross S, Önen N, Gase A, Overton ET, Ances BM. Identifying risk factors for HIV-associated neurocognitive disorders using the international HIV dementia scale. J Neuroimmune Pharmacol. 2013;8:1114–22.  https://doi.org/10.1007/s11481-013-9505-1 (Epub 2013 Oct 10).CrossRefGoogle Scholar
  5. 5.
    Attonito JM, Dévieux JG, Lerner BD, Hospital MM, Rosenberg R. Exploring substance use and HIV treatment factors associated with neurocognitive impairment among people living with HIV/AIDS. Front Public Health. 2014;2:105.  https://doi.org/10.3389/fpubh.2014.00105 (eCollection 2014).CrossRefGoogle Scholar
  6. 6.
    Heaton RK, Clifford DB, Franklin DR Jr, et al. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology. 2010;75:2087–96.  https://doi.org/10.1212/WNL.0b013e318200d727.CrossRefGoogle Scholar
  7. 7.
    Giancola ML, Balestra P, Ammassari A, et al. Prevalence and associated factors of neurocognitive impairment in HIV-positive patients on effective efavirenz/emtricitabine/tenofovir disoproxil fumarate treatment. AIDS Res Hum Retroviruses. 2018;23:654.  https://doi.org/10.1089/aid.2018.0074 (Epub ahead of print).Google Scholar
  8. 8.
    Heaton RK, Franklin DR, Ellis RJ, et al. HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neurovirol. 2011;17:3–16.  https://doi.org/10.1007/s13365-010-0006-1 (Epub 2010 Dec 21).CrossRefGoogle Scholar
  9. 9.
    Brew BJ. Has HIV-associated neurocognitive disorders now transformed into vascular cognitive impairment? AIDS. 2016;30:2379–80.  https://doi.org/10.1097/QAD.0000000000001225.CrossRefGoogle Scholar
  10. 10.
    Schlögl M, Holick MF. Vitamin D and neurocognitive function. Clin Interv Aging. 2014;9:559–68.  https://doi.org/10.2147/cia.s51785 (eCollection 2014).Google Scholar
  11. 11.
    Etgen T, Sander D, Bickel H, Sander K, Förstl H. Vitamin D deficiency cognitive impairment and dementia: a systematic review and meta-analysis. Dement Geriatr Cogn Disord. 2012;33:297–305.  https://doi.org/10.1159/000339702 (Epub 2012 Jul 2. Review).CrossRefGoogle Scholar
  12. 12.
    Balion C, Griffith LE, Strifler L, et al. Vitamin D, cognition and dementia: a systematic review and metanalysis. Neurology. 2012;79:1397–405.CrossRefGoogle Scholar
  13. 13.
    Llewellyn DJ, Lang IA, Langa KM, Melzer D. Vitamin D and cognitive impairment in the elderly US population. J Gerontol A Biol Sci Med Sci. 2011;66:59–65.  https://doi.org/10.1093/gerona/glq185 (Epub 2010 Nov 1).CrossRefGoogle Scholar
  14. 14.
    Buell JS, Dawson-Hughes B, Scott TM, et al. 25hydroxyvitamin D, dementia and cerebrovascular pathology in elders receiving home services. Neurology. 2010;74:18–26.  https://doi.org/10.1212/WNL.0b013e3181beecb7 (Epub 2009 Nov 25).CrossRefGoogle Scholar
  15. 15.
    Feart C, Helmer C, Merle B, et al. Associations of lower vitamin D concentrations with cognitive decline and long-term risk of dementia and Alzheimer’s disease in older adults. Alzheimers Dement. 2017;13:1207–16.  https://doi.org/10.1016/j.jalz.2017.03.003 (Epub 2017 May 16).CrossRefGoogle Scholar
  16. 16.
    Annweiler C, Dursun E, Féron F, et al. Vitamin D and cognition in older adults: international consensus guidelines. Geriatr Psychol Neuropsychiatr Vieil. 2016;14:265–73.  https://doi.org/10.1684/pnv.2016.0613.Google Scholar
  17. 17.
    Benguella L, Arbault A, Fillion A, et al. Vitamin D supplementation, bone turnover, and inflammation in HIV-infected patients. Med Mal Infect. 2018;48:449–56.  https://doi.org/10.1016/j.medmal.2018.02.011 (Epub ahead of print).CrossRefGoogle Scholar
  18. 18.
    Huff H, Merchant AT, Lonn E, Pullenayegum E, Smaill F, Smieja M. Vitamin D and progression of carotid intima-media thickness in HIV-positive Canadians. HIV Med. 2018;19:143–51.  https://doi.org/10.1111/hiv.12563 (Epub 2017 Nov 6).CrossRefGoogle Scholar
  19. 19.
    Tin A, Zhang L, Estrella MM, et al. Vitamin D status and kidney function decline in HIV-infected men: a longitudinal study in the multicenter AIDS cohort study. AIDS Res Hum Retroviruses. 2017;33:1140–8.  https://doi.org/10.1089/AID.2017.0009 (Epub 2017).CrossRefGoogle Scholar
  20. 20.
    Noe S, Oldenbuettel C, Heldwein S, et al. Secondary hyperparathyroidism in HIV-infected patients in Central Europe. Horm Metab Res. 2018;50:317–24.  https://doi.org/10.1055/s-0043-125073 (Epub 2018 Jan 23).CrossRefGoogle Scholar
  21. 21.
    Dadabhai AS, Saberi B, Lobner K, Shinohara RT, Mullin GE. Influence of vitamin D on liver fibrosis in chronic hepatitis C: a systematic review and meta-analysis of the pooled clinical trials data. World J Hepatol. 2017;9:278–87.  https://doi.org/10.4254/wjh.v9.i5.278.CrossRefGoogle Scholar
  22. 22.
    Jao J, Freimanis L, Mussi-Pinhata MM, NISDI LILAC Protocol, et al. Severe vitamin D deficiency in human immunodeficiency virus-Infected pregnant women is associated with preterm birth. Am J Perinatol. 2017;34:486–92.  https://doi.org/10.1055/s-0036-1593536 (Epub 2016 Oct 7).Google Scholar
  23. 23.
    Jiménez-Sousa MÁ, Martínez I, Medrano LM, Fernández-Rodríguez A, Resino S. Vitamin D in human immunodeficiency virus infection: influence on immunity and disease. Front Immunol. 2018;9:458.  https://doi.org/10.3389/fimmu.2018.00458 (eCollection 2018).CrossRefGoogle Scholar
  24. 24.
    Gois PHF, Ferreira D, Olenski S, Seguro AC. Vitamin D and infectious diseases: simple bystander or contributing factor? Nutrients. 2017;9:651.  https://doi.org/10.3390/nu9070651.CrossRefGoogle Scholar
  25. 25.
    Coelho L, Cardoso SW, Luz PM, et al. Vitamin D3 supplementation in HIV infection: effectiveness and associations with antiretroviral therapy. Nutr J. 2015;14:81.CrossRefGoogle Scholar
  26. 26.
    Ross AC, Manson JE, Abrams SA, et al. The 2011 report on dietary reference intakes for calcium and vitamin from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011;96:53–8.  https://doi.org/10.1210/jc-2010-2704.CrossRefGoogle Scholar
  27. 27.
    Holick MF, Binkley NC, Bischoff-Ferrari HA, Endocrine Society, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96:1911–30.  https://doi.org/10.1210/jc.2011-0385.CrossRefGoogle Scholar
  28. 28.
    Antinori A, Arendt G, Becker JT, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology. 2007;69:1789–99 (Epub 2007 Oct 3).CrossRefGoogle Scholar
  29. 29.
    Liu X, Baylin A, Levy PD. Vitamin D deficiency and insufficiency among US adults: prevalence, predictors and clinical implications. Br J Nutr. 2018;119:928–36.  https://doi.org/10.1017/S0007114518000491.CrossRefGoogle Scholar
  30. 30.
    Klassen KM, Fairley CK, Kimlin MG, Hocking J, Kelsall L, Ebeling PR. Vitamin D deficiency is common in HIV-infected southern Australian adults. Antivir Ther. 2016;21:117–25.  https://doi.org/10.3851/IMP2983 (Epub 2015 Aug 11).CrossRefGoogle Scholar
  31. 31.
    Adeyemi OM, Agniel D, French AL, et al. Vitamin D deficiency in HIV-infected and HIV-uninfected women in the United States. J Acquir Immune Defic Syndr. 2011;57:197–204.  https://doi.org/10.1097/QAI.0b013e31821ae418.CrossRefGoogle Scholar
  32. 32.
    Yu J, Gattoni-Celli M, Zhu H, et al. Vitamin D3-enriched diet correlates with a decrease of amyloid plaques in the brain of AβPP transgenic mice. J Alzheimers Dis. 2011;25:295–307.  https://doi.org/10.3233/JAD-2011-101986.CrossRefGoogle Scholar
  33. 33.
    Morello M, Landel V, Lacassagne E, et al. Vitamin D improves neurogenesis and cognition in a mouse model of Alzheimer’s disease. Mol Neurobiol. 2018;55:6463–79.  https://doi.org/10.1007/s12035-017-0839-1 (Epub 2018 Jan 9).CrossRefGoogle Scholar
  34. 34.
    Caccamo D, Ricca S, Currò M, Ientile R. Health risks of hypovitaminosis D: a review of new molecular insights. Int J Mol Sci. 2018;19:E892.  https://doi.org/10.3390/ijms19030892.CrossRefGoogle Scholar
  35. 35.
    Garcion E, Wion-Barbot N, Montero-Menei CN, Berger F, Wion D. New clues about vitamin D functions in the nervous system. Trends Endocrinol Metab. 2002;13:100–5.CrossRefGoogle Scholar
  36. 36.
    Vaidya A, Williams JS. The relationship between vitamin D and the renin-angiotensin system in the pathophysiology of hypertension, kidney disease and diabetes. Metabolism. 2012;61:450–8.  https://doi.org/10.1016/j.metabol.2011.09.007 (Epub 2011 Nov 9).CrossRefGoogle Scholar
  37. 37.
    Choi AI, Lo JC, Mulligan K, et al. Association of vitamin D insufficiency with carotid intima-media thickness in HIV infected persons. Clin Infect Dis. 2011;52:941–4.CrossRefGoogle Scholar
  38. 38.
    McCutchan JA, Marquie-Beck JA, Fitzsimons CA, CHARTER group, et al. Role of obesity, metabolic variables, and diabetes in HIV-associated neurocognitive disorder. Neurology. 2012;78:485–92.CrossRefGoogle Scholar
  39. 39.
    Dufouil C, Richert L, Thiébaut R, ANRS CO3 Aquitaine Study Group, et al. Diabetes and cognitive decline in a French cohort of patients infected with HIV-1. Neurology. 2015;85:1065–73.CrossRefGoogle Scholar
  40. 40.
    Sempos CT, Heijboer AC, Bikle DD. Vitamin D assays and the definition of hypovitaminosis D: results from the 1st international conference on controversies in vitamin D. Br J Clin Pharmacol. 2018;84:2194–207.  https://doi.org/10.1111/bcp.13652 (Epub ahead of print).CrossRefGoogle Scholar
  41. 41.
    Hsieh E, Yin MT. Continued interest and controversy: vitamin D in HIV. Curr HIV/AIDS Rep. 2018;15:199–211.  https://doi.org/10.1007/s11904-018-0401-4.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Alessandra Vergori
    • 1
  • Carmela Pinnetti
    • 1
    Email author
  • Patrizia Lorenzini
    • 1
  • AnnaClelia Brita
    • 1
  • Raffaella Libertone
    • 1
  • Ilaria Mastrorosa
    • 1
  • Stefania Cicalini
    • 1
  • Andrea Antinori
    • 1
  • Adriana Ammassari
    • 1
  1. 1.HIV/AIDS DepartmentNational Institute for Infectious Diseases, IRCCS, Lazzaro SpallanzaniRomeItaly

Personalised recommendations