Severe hypovitaminosis D correlates with increased inflammatory markers in HIV infected patients.

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by  Ansemant, Thiphaine

Ansemantetal.BMCInfectiousDiseases2013,13:7
http://www.biomedcentral.com/1471-2334/13/7
RESEARCH ARTICLE Open Access
Severe hypovitaminosis D correlates with
increased inflammatory markers in HIV infected
patients
Thiphaine Ansemant1,2, Sophie Mahy1, Christine Piroth2, Paul Ornetti2,5, Stephanie Ewing3, Jean-Claude Guilland3,
Delphine Croisier1, Laurence Duvillard3, Pascal Chavanet1,4, Jean-Francis Maillefert2,4,5 and Lionel Piroth1,4*
Abstract
Background: Even though it has been suggested that antiretroviral therapyhas an impact onsevere
hypovitaminosis D (SHD) inHIV infected patients, it could be speculatedthatthedifferent levels ofresidual
inflammation onHAART (Highly Active Anti Retroviral Therapy) could contribute to SHD and aggravate bone
catabolism in thesepatients.
Methods: A cross-sectional study was carried out inan unselected cohort of 263 HIVinfected outpatients
consulting during Spring 2010. Clinical examinations were performed and medical history, food habits, sun
exposure and addictions were collected. Fasting blood samples were taken for immunological, virological,
inflammation, endocrine and bone markers evaluations.
Results: Ninety-five (36%)patientshad SHD. In univariate analysis, a significant and positive association was found
between SHD and IL6 (p =0.001),hsCRP (p = 0.04), increased serum C-Telopeptides X(CTX)(p = 0.005)and
Parathyroid Hormon (PTH) (p< 0.0001) levels. Inmultivariate analysis, SHD deficiency correlated significantly with
increased IL-6, highserum CTX levels, lower mean daily exposureto the sun, current or past smoking, hepatitisC,
and functional status (falls), but not with thetime spent onthecurrent HAART (by specific drug or overall).
Conclusions: SHD is frequent and correlates with inflammation inHIVinfectedpatients. Since SHD is also
associated with fallsand increased bonecatabolism,it may be of interest to take into account not only thetypeof
antiretroviral therapy butalso theresidual inflammation onHAART inorder to assess functional and bone risks. This
finding also suggests that vitamin D supplementation maybe beneficial inthese HIV-infected patients.
Keywords: Antiretroviral therapy, Bone metabolism, HIV, Inflammation, 25-hydroxyvitamin D
Background diseases and mortality, particularly in HIV-infected
There is growing evidence that 25 OH vitamin D3 defi- patients [6]. The risk factors of hypovitaminosis D in
ciency is highly prevalent in HIV-infected patients, and HIV infected patients are: a precarious social situation,
induces a number of clinical consequences [1-4]. Low high alcohol intake, coinfection with viral hepatitis, and/
serum 25-OHD3 concentrations induce bone disorders or a renal hydroxylation defect [7]. The impact of anti-
like osteomalacia, are associated with increased bone re- retroviral therapy (ARV) has also been raised, but the
sorption due to secondary hyperparathyroidism, and in- role of antiretroviral therapy on bone catabolism
crease the risks of falls and vertebral and hip fractures remains controversial[8-11].
[5]. Vitamin D deficiency is also associated with an While there is growing evidence that certain antiretro-
increased risk of cardio metabolic disorders, infectious viral drugs affect vitamin D metabolism by increasing 25
OH vitamin D3 catabolism for efavirenz, or inhibiting
renal hydroxylation of vitamin D for protease inhibitors
*Correspondence:[email protected]
1InfectiousDiseasesDepartment,CHU,Dijon21079,France (PIs), for example, all the potential mechanisms and
4UniversityofBurgundy,DijonF-21079,France their relevance remains unclear. On the other hand, it
Fulllistofauthorinformationisavailableattheendofthearticle
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CreativeCommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,
distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
Ansemantetal.BMCInfectiousDiseases2013,13:7 Page2of7
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has been shown that inflammation markers (such as level below 10 ng/ml [25 nmol/l], by contrast with mod-
interleukin-6 (IL6) and highly-sensitive C-Reactive Pro- erate deficiency (between 10 and 30 ng/ml) and normal
tein (hsCRP)) correlated significantly with morbidity in levels (above 30 ng/ml – 75 nmol/l). Ionized calcium
patientsonARV[12,13].Itcouldthusbespeculatedthat was measured on an ABL 800 analyzer (Radiometer,
the different levels of residual inflammation on ARV Bronshoj, Denmark). Serum PTH (Parathyroid hormon)
could contribute to hypovitaminosis D and aggravate was quantified on an Immulite 2500 analyzer (Siemens
bone catabolisminHIVinfectedpatients. Healthcare Diagnostics, Erlangern, Germany) with dedi-
cated reagents. Serum C-telopeptides X (CTX) were
Methods quantified using an ELISA kit (IDS Immunodiagnostic
Since no direct studies have been conducted yet, we car- systems, France). The normal serum CTX value was
ried out a cross-sectional study in an unselected cohort defined according to sex and age (normal range in men:
of 263 HIV infected outpatients consulting during 0.115 -0.748 ng/ml, in pre-menopausal women: 0.112-
Spring (March-June) 2010. Thisresearch was carried out 0.738 ng/ml, and in menopausal women: 0.142 - 1.351
in compliance with the Declaration of Helsinki. All of ng/ml). Inflammation was assessed by the measurement
the patients included provided written informed consent of hsCRP (immunonephelemetry on a VISTA analyzer,
to specifically participate to this study. According to Siemens Healthcare Diagnostics, Erlangen, Germany)
current French research guidelines, no additional and and IL6 (using the ultra sensitive ELISA kit, R&D Sys-
specific ethical approval was needed since blood sam- tem, Minneapolis,Minn,US).
pling was performed as part of the usual care in a single Patients with severe deficiency were compared with
center without additional visit or sampling. All of the those with moderate deficiency and those with normal
patients underwent a clinical examination, in particular levels. Categorical variables were compared using Fish-
to determine body mass index, Karnofsky’s index and to er’s exact and chi-square tests, and continuous variables
screen for lipodystrophy, and data on their medical his- using the analysis of variance or the Mann–Whitney test
tory, food habits, sun exposure and addictions were col- when appropriate. Correlations between 25-OHD3 vita-
lected. In particular, the immunological and virological min D levels and bone and inflammation markers were
efficacy and the type of past and present antiretroviral also analyzed by linear regression. In the second step,
therapy were collected. In addition, the following data the patients with severe deficiency were compared with
were systematically collected for each patient via a stan- the others. A backward step-by-step logistic regression
dardized questionnaire: present or past addiction, was then conducted for multivariate analysis of the fac-
present and past personal and family history of bone tors associated with severe 25 OH vitamin D3 deficiency
fractures,endocrinedisorders,chronicinflammatorydis- (dependent variables), including all of the factors asso-
eases (enterocolopathy, inflammatory arthritis, cirrhosis, ciated in univariate analysis with a p value of less than
asthma and chronic obstructive pulmonary disease), 0.20. All of the tests were two-sided and a final p-value
treatments (in particular systemic glucocorticoids, and of less than 0.05 was considered statistically significant.
W
hormone therapy), functional status (history of falls dur- All statistical analyses were performed using StatView
ing the previous year), age at menopause and amenor- version 5.0.
rhea for women, and orchidectomy for men. Sun
exposure (expressed as minutes per day) was evaluated Results
by the patients themselves. The daily intake of calcium The median age of the patients included was 47.7 years
was assessed using the questionnaire recommended by (range 20–72 years), and 188 (71.5%) were male. BMI
the French Research and Information Group on Osteo- was lower than 19 kg/m2 in 27 patients (10.2%) and
porosis (GRIO) [14]. Daily intake of alcohol was consid- higher than 25 kg/m2 in 83 patients (31.4%). Among the
ered “excessive” when above 20 g per day in women and 75 women included, 33 (44%) were post-menopausal,
30gperdayinmen. and four were not menopausal, but suffering from
Fastingbloodsamplesweretakenfrompatientsaspart amenorrhea. Twenty patients (7.6%) had a family history
of standard care for immunological, virological, inflam- of hip fracture and 104 (39.5%) patients had a personal
mation, endocrine and bone markers evaluations. Serum historyoffracture:15 had fragility fracture(s) (6.5%), and
25 OH vitamin D3 levels were measured by High Per- 82 had traumatic fracture(s) (35.7%) (undetermined in 7
formance Liquid Chromatography (HPLC) coupled with patients). Long-term corticosteroid treatment was on-
fluorometry. Plasma total calcium, phosphorus, albumin going in 22 (8%) patients. Fifty-three patients were suf-
and thyroid stimulating hormone (TSH) were quantified fering from a chronic disease, including two cases of
on a Vista analyzer (Siemens Healthcare Diagnostics, inflammatory rheumatic diseases, two cases of enteroco-
Erlangen, Germany) with dedicated reagents. A severe lopathy, 23 cases of liver cirrhosis, and 24 cases of
deficiency in 25 OH vitamin D3 was defined as a blood chronic bronchitis. Mean daily calcium intake was 760
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(+/− 356) mg per day, and 149 (57%) patients had cal- increased serum C-Telopeptides X (CTX) (p = 0.05) and
cium intakes below 800 mg per day. Excessive alcohol PTH(p<0.0001)levels(Table3).Inunivariatelinearre-
consumptionwasreported in86(32%) cases. gression analysis, 25 OH vitamin D levels were found to
The main current and past characteristics of HIV in- correlate negatively with IL-6 levels (r = 0.14, p = 0.02,
fection and antiretroviral therapy are presented in Figure 1A) and also tended to correlate negatively with
Table 1. The time since the HIV diagnosis was 13 years serum CTX (r = 0.1, p = 0.10, Figure 1B), but not with
(+/− 8 years). Patients had very often been followed for hsCRP.
several years and nearly one third of them (33.1%) had In multivariate analysis (Table 4), SHD deficiency
experienced AIDS defining illness. Most of them (91.6%) remained significantly correlated with increased IL-6,
were on antiretroviral therapy, with a significant im- but also with serum CTX levels above the normal value,
mune response, since the mean CD4 level at inclusion lower mean daily exposure to the sun, current or past
was 551 +/− 271/mm3, with a mean CD4 nadir of 198 smoking, hepatitis C coinfection, and functional status.
+/− 190/mm3, and 207 (78.7%) patients had an un- CTX levels expressed as quantitative values did not
detectable viralload (<50 copies/ml). modify these results and remained significantly asso-
Ninety-five (36%) patients had SHD (Table 2). In uni- ciated with SHD (OR +1 ng/ml, 1.96, 95% CI: 1.10-3.50,
variate analysis, age, ethnicity, functional status (Kar- p=0.02).
nofsky’s index and history of falls), daily sun exposure,
tobacco use and hepatitis C coinfection were associated Discussion
with SHD. The estimated duration of the HIV infection In keeping with previous studies [1], vitamin D defi-
was also associated with hypovitaminosis D (p=0.0008), ciency was highly prevalent in HIV-infected patients
whereas the HIV CDC stage, current and nadir CD4, (close to 90% in our study cohort), with a prevalence of
HIV viral load, and time spent on the current ARV (by SHD ranging between 10 and 50% according to the
specific drug or overall), andtheduration with undetect- places and the seasons [1,8,15-17]. However, the associ-
ableHIVviralload were not. ation with antiretroviral therapy appeared limited in our
A significant and positive association was also found study, despite a significant number of patients on efavir-
between SHD and IL6 (p = 0.002), hsCRP (p = 0.12), enz, PIs and/or tenofovir. The first explanation could be
Table1HIV-relatedcharacteristicsofthe263patientsincluded
TimeelapsedsinceHIVdiagnosis(years),mean+/−SD 13+/−8
CDCstageA,n(%) 101(38.4)
CDCstageB,n(%) 75(28.5)
CDCstageC,n(%) 87(33.1)
Karnofsky’sindex%,mean+/−SD 92+/−14
TimespentonNRTI(months),mean+/−SD 95+/−71
Timespentontenofovir(months),mean+/−SD 25+/−27
TimespentonNNRTI(months),mean+/−SD 40+/−47
TimespentonPI(months),mean+/−SD 44+/−47
Withoutcurrentantiretroviraltherapy,n(%) 22(8.4)
OnHAARTincludingNTI,n(%) 210(80.5)
OnHAARTincludingtenofovir,n(%) 164(62.8)
OnHAARTincludingNNTI,n(%) 92(35.4)
OnHAARTincludingPI,n(%) 151(57.9)
OnHAARTincludingII,n(%) 21(8.0)
CD4nadir(/mm3),mean+/−SD 198+/−190
TimespentwithundetectableHIVviralload(months),mean+/−SD 58+/−45
CurrentCD4(/mm3),mean+/−SD 551+/−271
CurrentCD8(/mm3),mean+/−SD 810+/−420
CurrentCD4/CD8ratio,mean+/−SD 0.80+/−0.49
CurrentundetectableHIVviralload,n(%) 207(78.7%)
CurrentHIVviralload(whendetectable),log copies/ml+/−SD 3.1+/−1.2
10
SD:standarddeviation;HAART:HighlyActiveAntiRetroviralTherapy;NRTI:nucleosidereversetransciptaseinhibitor;NNRTI:nonnucleosidereversetransciptase
inhibitor;PI:proteaseinhibitor;II:integraseinhibitor.
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Taraeblseho2wAnssionctiahtiisotnasbbleetweenvitaminDstatusandclinicalandtherapeuticcharacteristics(univariateanalysis)–onlyassociatedfactorswithapvalue<0.20 l.com tious
Allpatients Sevdeerfeici2e5n-c(OyH(<)1v0itnagm/minl)D3 Moddeefircaiteen2cy5-((1O0H–)3v0itnagm/minl)D3 25-(OH)VitaminD3>30ng/ml pvalue /1471-23 Diseases
N=263 N=95(36%) N=135(51%) N=33(13%) 3420
Sex M,n(%) 188(72%) 75(79%) 89(66%) 24(69%) 0.10 /13/713,13
F,n(%) 75(28%) 20(21%) 46(34%) 9(31%) :7
Age(years)mean+/−SD 48+/−10 49+/−9 46+/−10 51+/−12 0.03
Ethnicity non-Africanorigin,n(%) 230(87%) 87(92%) 112(83%) 31(94%) 0.07
Africanorigin,n(%) 33(13%) 8(8%) 23(17%) 2(6%)
Pasthistoryoffalls,n(%) 120(46%) 53(57%) 55(41%) 12(36%) 0.03
Co-infections PositiveHBsantigenemia 14(5.3%) 8(8%) 6(4%) 0(0%) 0.14
PositiveHCVserology,n(%) 57(22%) 33(35%) 18(14%) 6(18%) 0.12
Pastsmokers,n(%) 52(20%) 20(21%) 25(19%) 7(21%) 0.003
Activesmokers,n(%) 120(46%) 55(59%) 50(37%) 14(45%) 0.003
Sunexposure(min),mean+/−SD 106+/−114 93+/−108 102+/−111 157+/−132 0.02
LengthofHIVinfection(yrs),mean+/−SD 13+/−8 16+/−8 12+/−7 12+/−8 0.0008
NRTIexposure(months),mean+/−SD 95+/−71 108+/−70 89+/−69 84+/−73 0.08
Lipodystrophy,n(%) 65(25%) 29(31%) 31(23%) 5(15%) 0.005
Karnofsky’sIndex(%),mean+/−SD 92+/−14 89+/−17 92+/−17 97+/−7 0.008
M:male,F:female,NRTI:nucleosidereversetransciptaseinhibitor,HBV:hepatitisBinfection,HCV:hepatitisCinfection.
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Table3AssociationsbetweenvitaminDstatusandboneandinflammationbiomarkers(univariateanalysis)
All Severe25-(OH)vitamin moderate25-(OH)vitamin 25-(OH)Vitamin pvalue
patients D3deficiency(<10ng/ml) D3deficiency(10–30ng/ml) D3>30ng/ml
N=263 N=95(36%) N=135(51%) N=33(13%)
Bone Ionizedcalcium<1.12 9(3%) 3(3%) 3(2%) 3(9%) 0.001
metabolism mmols/l,n(%)
parameters
CTX(ng/mL),median 0.45 0.49(0.31-0.92) 0.45(0.31-0.70) 0.33(0.22-0.60) 0.05
(interquartilerange) (0.30-
0.77)
HighserumCTX,n(%) 56(21%) 29(32%) 24(18%) 3(9%) 0.01
Serumintactparathyroid 62(24%) 31(34%) 29(21%) 2(6%) <0.0001
hormone>65ng/l,n(%)
inflammation hsCRP(mg/l),median 1.7(0.7- 2.3(1.2-5.3) 1.5(0.9-2.7) 1.4(0.8-4.2) 0.12
parameters (interquartilerange) 4.0)
IL6(pg/ml),median 1.8(1.0- 2.0(0.7-6.3) 1.7(0.6-3.6) 1.6(1.0-3.8) 0.002
(interquartilerange) 3.6)
hsCRP:highly-sensitiveC-ReactiveProtein;IL6:Interleukin6;HighserumCTX=CTelopeptideX>0.748ng/ml(men),0.738ng/ml(pre-menopausalwomen),and
1.351ng/ml(menopausalwomen).
that, by contrast with most previous studies, we also haveanambiguousimpactonvitaminDlevels.Byreducing
adjusted for the season (since blood samples were exclu- HIV viral replication and inflammation, ARV is likely to
sively collected inspring 2010, at a time when vitamin D have a positive impact on vitamin D levels, which is coun-
is synthesized). Sun exposure was found to correlate terbalanced by the potential direct negative effect of some
positively with vitamin D levels, and each additional one drugs. We did not observe a statistically significant direct
hour per day of exposure was associated with a signifi- correlation between HIV viral load and inflammation bio-
cant reduction in the OR of SHD (0.84), which is con- markers(datanot shown).Thisassociationwithinflamma-
sistentwith previousdata innon-HIV individuals. tion, which has also been recently observed in non HIV
Anotherexplanationissuggestedbythehighlysignificant infected patients [18-20], could also partly explain the
association between vitamin D levels and inflammation increasedriskofcardio-metabolicdisordersassociatedwith
parameters we observed, which to date has never been hypovitaminosis D, since hsCRP and IL6 have also been
reported. It can thus be suggested that HIV therapy could shown to be predictors of cardio-vascular and HIV disease
progressionandmortality[12,13,16].
Another result of interest is the association between
A vitamin D levels, inflammation and bone catabolism (in
80 particular bone turnover markers CTX and PTH). CTX
70
corresponds to the serum fraction of collagen called C
mL) 5600 r = 0.14, p = 0.02 telopeptid X, which is associated with osteoclast bone
g/
p 40 resorption. By contrast with the results from other study
L-6 ( 2300 in HIV-infected patients, in our study, ionized calcium
I
10 in the serum stayed within the normal range despite the
0 vitamin D deficiency, suggesting an adaptive response to
0 20 40 60 80 100
parathyroidhormone [1].Eventhoughwefound astatis-
25 OH vitD3 (ng/mL)
tically significant association between SHD and inflam-
B mation and between SHD and increased bone
5 catabolism, but not between inflammation and bone ca-
4 tabolism, the respective weights of hypovitaminosis D
g/mL) 3 r = 0.1, p = 0.10 and inflammation in the increase in bone catabolism
n cannotbedefinitelyandclearly established.
X ( 2
T In addition, an association between SHD and a history
C 1
of falls, which has never been reported in HIV-infected
0 patients, was also observed in the present study. This
0 20 40 60 80 100
proportion of patients with a history of falls is quite
25 OH vitD3 (ng/mL)
high, considering the median age of our study popula-
Figure1AandB:correlationsbetween25OHvitaminD3levels
tion. It may be partially due to the other characteristics
andIL-6(1A)orC-telopeptideX(1B).
of the patients included, all of whom were followed in a
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Table4FactorsassociatedwithseverehypovitaminosisD(<10ng/L)inmultivariateanalysis(finalmodel-logistic
regression)
Odds-ratio 95%ConfidenceInterval pvalue
Sunexposure(/+1hour) 0.84 0.74-0.94 0.03
Pasthistoryoffalls(yesvs.no) 1.80 1.00-3.27 0.05
Pastsmokers(yesvs.no) 2.74 1.17-6.43 0.02
Activesmokers(yesvs.no) 2.63 1.27-5.45 0.009
Co-infections PositiveHCVserology(positivevs.negative) 1.87 0.92-3.85 0.09
Positiveanti-HBcandnegativeanti-HBs(yesvs.no) 2.76 1.17-6.54 0.005
Biologicalmarkers IL-6(+1pg/mL) 1.13 1.02-1.25 0.02
HighserumCTX(yesvs.no) 2.44 1.23-4.81 0.01
HCV:HepatitisCVirus;HBVHepatitisBVirus;hsCRP:highly-sensitiveC-ReactiveProtein;IL6:Interleukin6;HighserumCTX=CTelopeptideX>0.748ng/ml(men),
0.738ng/ml(pre-menopausalwomen),and1.351ng/ml(menopausalwomen).
day-care hospital unit, had been infected for several on the one hand, and with a history of falls and
years and had often experienced disease progression. increased bone catabolism on the other, the results of
Nevertheless, hypovitaminosis D has been shown to be our study may have three main implications. First, we
associated with impaired muscle function in elderly believe that vitamin D levels have to be systematically
people [21], and vitamin D supplementation led to and regularly assessed in HIV infected patients. Second,
improved muscle function and a decreased risk of falls it may be of interest to take into account not only the
inthispopulation. type of antiretroviral therapy but also the residual in-
Last, we also observed a positive association between flammation onHAARTinorder to assess functional and
SHD and a history of viral hepatitis (positive HCVserology fracture risks of HIV infected patients. Third, it is likely
and “non-cured” HBV infection - i.e. positive HBc without that there is an interest in supplementing hypovitamino-
anti-HBsantibodies),butwedidnotobserveanassociation sis D, at least because it is associated with falls and
with HCV RNA or HBV DNA. The association with HCV increased bone catabolism (as we observed) and thus
seropositivitywaspreviouslyreportedinarecentstudy[15]. fractures (as previously reported). However, whether
These HCVand HBVserological profiles can reflect a wide increased bone catabolism is a process mainly driven by
rangeofdifferentrealities.However,consideringthenumber hypovitaminosis D rather than by residual inflammation
of our patients with known cirrhosis and/or with past or isyetto beestablished, as isthe best strategy for hypovi-
presentchronichepatitisviralreplication,itcouldbeargued taminosis D screening and supplementation. It is now
thatthisrelationshipmaybepartiallyrelatedtodisordersin necessary to conduct longitudinal studies to assess not
thehepatichydroxylationof vitaminDassociatedwithliver only the relationship between vitamin D levels and in-
fibrosis[22].VitaminDdeficiencywasalsofoundtobesig- flammation parameters, but also their potential clinical
nificantly associated with active or past smoking, as previ- consequences, as well as the potential benefit of vitamin
ouslyobserved[23]. Dsupplementation.
However, this study may suffer from several limita-
tions, in part due to its cross-sectional design, since no Competinginterests
Alltheauthorsreadandapprovedthefinalmanuscriptandhavenoconflict
repetitive measurements of vitamin D levels and inflam-
ofinterestwithregardtothepresentarticle.
mation parameters were performed, and thus no causal
relationships can be determined. There was also no con- Authors’contributions
TA,CP,JFM,andLPconceivedthestudy,andparticipatedinitsdesignand
trol group without HIV in order to compare the preva-
coordinationandhelpedtodraftthemanuscript.SM,PO,PCenrolledthe
lence of hypovitaminosis D. In addition, the patients patientsandhelpedtodraftthemanuscript.SE,JCD,LDcarriedoutthe
included may not have been representative, since they assaysandhelpedtodraftthemanuscript.TA,SMandLPperformedthe
statisticalanalysis.Allauthorsreadandapprovedthefinalmanuscript.
were followed in a French day-care hospital unit. On the
other hand, a high proportion of these patients were
Acknowledgements
exposed to HAART for a long period of time, which Theauthorsthankallthepatientsandthephysicianswhoparticipatedinthe
should strengthen the analysis of the association be- presentstudy,inparticularDrMarielleBuisson,DrMichelDuong,DrMichèle
Grappin,andDrAnneWaldner.TheyalsothankSandrineTreuvelotfortheir
tweenhypovitaminosisD andHAART.
helpinthemanagementofthestudy,andPhilipBastableforreviewingthis
manuscript.
Conclusions
Authordetails
Considering the high prevalence of SHD in our study
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