AIDS Res Hum Retroviruses. 2013 Mar;29(3):528-34. doi: 10.1089/AID.2012.0120. Epub 2012 Oct 31.
Serum 25-hydroxyvitamin D levels and C-reactive protein in persons with human immunodeficiency virus infection.
Waseda Institute for Advanced Study, Waseda University, Tokyo, Japan.
Human immunodeficiency virus (HIV) infection has frequently been associated with vitamin D deficiency as well as chronic inflammatory response. We tested the hypothesis of an independent relationship between serum concentrations of 25-hydroxyvitamin D [25(OH)D] and high-sensitivity C-reactive protein (CRP) in a cohort of HIV-positive people. A cross-sectional survey was conducted among 316 HIV-positive people (181 men and 135 women) aged 16 to 60 years residing in the Kathmandu Valley, Nepal. Serum high-sensitivity CRP concentrations and serum 25(OH)D levels were measured by the latex agglutination nephelometry method and the competitive protein-binding assay, respectively. The relationship between serum CRP concentrations and 25(OH)D serum level was assessed using multiple logistic regression analysis with adjustment of potential cardiovascular and HIV-related factors. The proportions of participants with 25(OH)D serum levels <20 ng/ml, 20-30 ng/ml, and ≥30 ng/ml were 83.2%, 15.5%, and 1.3%, respectively. The mean 25(OH)D serum levels in men and women were 15.3 ng/ml and 14.4 ng/ml, respectively. Participants with a 25(OH)D serum level of <20 ng/ml had a 3.2-fold higher odds of high CRP (>3 mg/liter) compared to those with a 25(OH)D serum level of ≥20 ng/ml (p=0.005). Men and women with a 25(OH)D serum level of <20 ng/ml had 3.2- and 2.7-fold higher odds of high CRP (>3 mg/liter), respectively, compared to those with a 25(OH)D serum level of ≥20 ng/ml. The relationships remained significant only in men (p =0.02) but not in women (p=0.28). The risk of having a high level of inflammation (CRP>3 mg/liter) may be high among HIV-positive men and women with a 25(OH)D serum level of <20 ng/ml.
This is the first study exploring the association between serum concentrations of 25-hydroxyvitamin D (25[OH]D) and high-sensitivity C-reactive protein (CRP) in a cohort of persons infected with Human Immunodeficiency Virus (HIV). This study provided special focus on vitamin D among micronutrients as emerging studies suggest high prevalence of vitamin D deficiency together with its potential health benefits in HIV-infected persons. For example, low vitamin D levels are associated with evidence of subclinical arterial dysfunction,1 carotid intima-media-thickness,2 higher serum insulin,3 disease progression,4 mortality,5 and wasting and opportunistic illness.6
This study discussed that a risk of having high level of inflammation (CRP >3 mg/L) may be high among HIV-positive men and women with 25(OH)D serum level of <20 ng/mL. The protective effect of 25(OH)D serum level of >20 ng/mL against inflammation did not change in further analysis after excluding participants with any history of disease in past 12-month including minor illnesses or participants without a history of anti-retroviral medication. The exposure to anti-retroviral therapy such as nevirapine, efavirenz, tenofovir and nucleoside reverse transcriptase inhibitor was not significantly associated with 25(OH)D serum level of <20 ng/mL/ >20 ng/mL. In stratified analysis, the multivariate-adjusted odds ratios (95% confidence intervals) of having high CRP for HIV-positive participants with 25(OH)D serum levels of < 10 ng/ml and 10-19.99 ng/mL as compared to HIV-positive participants with 25(OH)D serum levels of > 20 ng/mL were 4.00 (1.52-10.55) and 2.99 (1.29-6.94), respectively (P for trend = 0.007). The multiple linear regression analysis also showed an inverse relationship between serum CRP concentrations and 25(OH)D serum level (β = -0.03; P = 0.06).
The present study findings supporting a protective role of 25(OH)D serum level of >20 ng/mL against inflammation can be explained through immunomodulating effects of vitamin D referring to mechanistic study.7Vitamin D may act as an immune modulator and interfere with systemic inflammation through the expression of nuclear vitamin D receptors in most cells of the immune system, including activated CD4 and CD8 T lymphocytes, as well as macrophages.8 For example, some experimental studies have suggested that vitamin D can exert regulatory effects on the cytokine production of human peripheral blood lymphocytes8,9 and can also down-regulate the activation of nuclear factor-kB, an important regulator of genes encoding for several inflammatory cytokines.10
This study finding is in line with those studies previously highlighting an inverse association between vitamin D and inflammatory markers in populations other than HIV-positive persons. For example, in a European cohort of obese subjects, 25(OH)D serum concentrations were inversely related to significant levels of high CRP, regardless of the total quantity of fat mass.11 In another study among patients with early inflammatory polyarthritis, each 10 ng/mL increase in 25[OH]D serum level was associated with a 25% decrease in serum CRP.12 In addition, a clinical trial has suggested that vitamin D supplementation markedly reduces serum levels of CRP and several other inflammation markers in patients with congestive heart failure.13
Thus, this study result is a critical first step that provides the foundation for a further supplementation and intervention program to improve the survival of persons infected with HIV in Nepal and other resource limited countries. Results from this study may lead to clinical trials of vitamin D supplementation as a simple low-cost intervention to improve the health, lifespan, and the quality of life for HIV-positive persons in the resource-poor settings.
- Shikuma CM, Seto T, Liang CY, Bennett K, DeGruttola V, Gerschenson M, Stein JH, Budoff M, Hodis HN, Delaney JA, Ogata-Arakaki D, Pramyothin P, Chow D. Vitamin D levels and markers of arterial dysfunction in HIV. AIDS Res Hum Retroviruses. 2012;28(8):793-7. doi: 10.1089/AID.2011.0086.
- Choi AI, Lo JC, Mulligan K, Schnell A, Kalapus SC, Li Y, Hunt PW, Martin JN, Deeks SG, Hsue PY. Association of vitamin D insufficiency with carotid intima-media thickness in HIV-infected persons. Clin Infect Dis. 2011;52:941-4.
- Hammond E, McKinnon E, Glendenning P, Williams R, Mallal S, Phillips E. Association between 25-OH vitamin D and insulin is independent of lipoatrophy in HIV. Clin Endocrinol 2012;76:201-6.
- Lau B, Sharrett R, Kingsley LA, et al. C-reactive protein is a marker for human immunodeficiency virus disease progression. Arch Intern Med. 2006;166:64–70.
- Feldman JG, Goldwasser P, Holman S, et al. C-reactive protein is an independent predictor of mortality in women with HIV-1 infection. JAIDS. 2003;32:210–214.
- Mehta S, Mugusi FM, Bosch RJ, Aboud S, Chatterjee A, Finkelstein JL, Fataki M, Kisenge R, Fawzi WW. A randomized trial of multivitamin supplementation in children with tuberculosis in Tanzania. NutrJ. 2011 ;10:120. doi: 10.1186/1475-2891-10-120.
- Guillot X, Semerano L, Saidenberg-Kermanach N, et al. Vitamin D and inflammation. Joint Bone Spine. 2010;77:552–557.
- Gysemans CA, Cardozo AK, Callewaert H et al. 1,25-dihydroxyvitamin D3 modulates expression of chemokines and cytokines in pancreatic islets: implications for prevention of diabetes in nonobese diabetic mice. Endocrinology. 2005;146:1956–1964.
- Willheim M, Thien R, Schrattbauer K et al. Regulatory effects of 1alpha, 25-dihydroxyvitamin D3 on the cytokine production of human peripheral blood lymphocyte. J Clin Endocrinol Metab. 1999;84:3739–3744.
- D’ Ambrosio D, Cippitelli M, Cocciolo MG, et al. Inhibition of IL-12 production by 1, 25-dihyoxyvitamin D3. Involvement of NF-kBdownregulation in transcriptional repression of the p40 gene. J Clin Invest. 1998;101:252–262.
- Bellia A, Garcovich C, D’Adamo M, et al. Serum 25-hydroxyvitamin D levels are inversely associated with systemic inflammation in severe obese subjects. Intern Emerg Med. 2011 DOI 10.1007/s11739-011-0559-x.
- Patel S, Farragher T, Berry J, et al. Association between serum vitamin D metabolites levels and disease activity in patients with early inflammatory polyarthritis. Arthritis Rheum. 2007;56:2143–2149.
- Schleithoff SS, Zittermann A, Tenderich G et al. Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure a double-blind, randomized, placebo controlled trial. Am J Clin Nutr. 2006;83:754–759.
This study is supported by the Grant-in-Aid for Young Scientists (B) (22790581), Japan Society for the Promotion of Science, The Ministry of Education, Culture, Sports, Science and Technology, Japan and by the Grant for Research on Global Health and Medicine (No. 21A-2) from the Ministry of Health, Labour, and Welfare, Japan. This study was based on the baseline data of the Healthy Living Intervention Study (HLIS) – a prospective study of HIV-positive persons overseen by Dr. Krishna C Poudel, Associate Professor, Department of Public Health, School of Public Health and Health Sciences, University of Massachusetts, Amherst (Krishna@schoolph.umass.edu).
Kalpana Poudel-Tandukar, PhD, MPH, MPHC
Waseda Institute for Advanced Study (WIAS), Waseda University
1-6-1 Nishi-waseda, Shinjuku-ku, Tokyo 169-8050, Japan.
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