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Clinical Science

Periodontitis and Cytomegalovirus Associate With Atherosclerosis Among HIV Patients After 5 Years on ART

Wulandari, Endah A. T. DDSa,b; Wijaya, Ika Prasetya MDa,b; Karim, Birry MDa,b; Ariyanto, Ibnu M Biomedc; Tanudjaja, Selita Agnes MD,MPHd; Lee, Silvia PhDe; Price, Patricia PhDa,e

Author Information
JAIDS Journal of Acquired Immune Deficiency Syndromes: October 1, 2020 - Volume 85 - Issue 2 - p 195-200
doi: 10.1097/QAI.0000000000002417

Abstract

INTRODUCTION

Periodontitis is an inflammatory condition initiated by gingivitis, and causing progressive destruction of alveolar bone leading to tooth loss. Several studies have linked cardiovascular disease (CVD) with oral inflammation and periodontitis in the general population.1–3 For example; periodontitis was linked with myocardial infarction in 1989,4 and periodontitis associates with greater carotid intima-media thickness (cIMT) and impaired flow-mediated dilatation.2 Moreover CVD and periodontitis share predisposing factors, such as age, low socioeconomic and educational status, poor oral hygiene, smoking habits, and inflammatory genotypes.2,5

With the use of antiretroviral therapy (ART), people living with HIV (PLWH) now have longer life expectancies and face age-related conditions such as CVD.6 One pooled analysis of 5 large cohorts linked HIV infection with elevated cIMT at a younger ages.7 The increased risk of CVD among HIV-infected patients probably reflects HIV-associated inflammation and endothelial dysfunction, so associations with periodontal disease warrant consideration.

In addition, several studies link a high burden of cytomegalovirus (CMV) with accelerated T-cell differentiation and CVD in HIV patients stable on ART (reviewed in Ref. 8). In a seminal study, PLWH stable on ART had significantly higher cIMT compared with healthy controls, but the difference was minimal after controlling for CMV-specific immune responses used to measure the burden of CMV.9 Moreover, use of valganciclovir as CMV prophylaxis can reduce T-cell activation and may thus reduce risk of atherosclerosis.10 Our study of white Australian patients stable after more than 2 years on ART correlated levels of antibody reactive with a lysate of CMV-infected fibroblasts with D:A:D scores.11 However, studies of CVD in the younger HIV patients seen in Asia are rare, and the roles of persistent opportunistic infections (including CMV) and periodontitis remain unclear.

Here, we explore the roles of CMV, periodontitis, and other factors that may influence cIMT among Indonesian HIV patients followed for 5 years on ART. In this “JakCCANDO” cohort, levels of CMV immediate early-1 (IE-1) antibody correlated directly with cIMT after 6 and 12 months on ART,12 suggesting a weak effect of bursts of CMV replication evidenced by CMV IE-1 antibodies. It is plausible that CMV may drive periodontal inflammation as it replicates in salivary acinar cells and hence is available to local tissues. Conversely, inflammation arising from gingivitis/periodontitis may reactivate CMV replication. Either would accord with evidence that the prevalence of CMV DNA in mouth swabs is higher in patients with aggressive periodontitis13 and severe periodontal disease associated with high titers of antibodies reactive with CMV.14

MATERIALS AND METHODS

Subjects and Oral Health Examinations

JakCCANDO is a comprehensive survey of clinical and immunological responses in 82 patients beginning ART in the outpatient HIV clinic of an inner city tertiary hospital (Cipto Mangunkusumo Hospital, Jakarta, Indonesia) with <200 CD4 T cells/μL.15 A subset of 32 HIV-infected patients attended a 5-year follow-up. Other patients could not be recalled because of moves to different health facilities, changed phone numbers and/or home addresses, refusal to participate, or AIDS-related death. Thirty-two healthy controls were recruited from hospital staff. We confirmed that they were matched groupwise with the patients by age and gender. Ethical approval for this study was obtained from Health Research Ethic Committee Faculty of Medicine Universitas Indonesia & Cipto Mangunkusumo Hospital (no: 133/UN2.FI/ETIK/2018).

All oral examinations were performed by one oral medicine specialist (E.A.T.W.), so no interexaminer calibration was needed. Oral hygiene was assessed using oral hygiene index-simplified,16 based on the presence of debris and calculus. Periodontal health was assessed using community periodontal index of treatment needs17,18 and then categorized into periodontitis present (index >2) or absent (index ≤2).19 Candidiasis and oral hygiene were assessed as described previously.15

cIMT

The carotid Doppler was assessed using an ESAOTE (Genova, Italy) echocardiography machine and a LA522E probe.12 The cIMT measurement was performed by a single operator (BK) on grey scale 2D pictures, at sites that had no focal lesions.

Soluble Tumor Necrosis Factor Receptor, C-Reactive Protein, and ICAM-1

Plasma samples were aliquoted and stored at −80C. Soluble tumor necrosis factor receptor (sTNFR), C-reactive protein (CRP), and ICAM-1 were measured using enzyme-linked immunosorbent assays based on commercial antibody pairs (R&D Systems, Minneapolis, MN). Samples were serially diluted from 1:3000 for CRP, 1:100 for ICAM-1, and 1:10 for sTNFR.20

CMV Immediate Early (IE)-1, Lysate and Glycoprotein B (gB) Antibodies

CMV-reactive immunoglobulin G was quantified by enzyme-linked immunosorbent assay. Parallel plates were coated with a CMV lysate from sonicated human foreskin fibroblast infected with CMV AD169, recombinant IE-1 (produced in Escherichia coli, Miltenyi Biotech; Cologne, Germany), and recombinant gB (kindly provided by Sanofi Pasteur, Lyon, France). Plasma samples were serially diluted from 1:10,000 (CMV lysate and gB) or 1:500 (IE-1). Binding was detected using goat anti-human immunoglobulin G-horseradish peroxidase followed by tetramethylbenzidine substrate (Sigma Aldrich, Castle Hill, Australia). Antibodies were assessed relative to standard plasma pool assigned a value of 1000 arbitrary units.12,20

Statistical Analyses

Healthy controls and PLWH were compared using nonparametric Mann–Whitney tests, paired data were assessed using Wilcoxon Signed Rank tests, while categorical data were assessed by χ2 and Fisher exact tests. P-values <0.05 were accepted as indicating a significant difference, but P < 0.10 is noted when it marks a consistent trend. Simple linear regressions were used to identify associations between cIMT and exposure variables (periodontitis, patient characteristics, and biomarkers) that achieved P < 0.20. Multiple linear regression models were then optimized by sequential elimination to identify factors that independently predict cIMT. Correlation between the independent variables was low (Variance Inflation Factor, VIF<5) so analyses were not hampered by collinearity. The adjusted models controlled for age and sex. Regression analyses were performed in Stata SE 14.2 (StataCorp LP, College Station, TX).

RESULTS

Several Parameters Improve After 5 Years of ART, but Periodontitis Persists

Oral health, cardiovascular parameters, and CD4 T-cell counts were assessed before ART and after 3 months (V0, V3; n = 80) and a subset were re-tested after 60 months (V60; n = 32). At V60, CD4 T-cell counts had improved but remained lower than healthy controls (n = 32). Four patients had <200 CD4 T cells/μL at V60 as their treatment had been interrupted. Oral candidiasis was found in 59% of HIV patients at V0, and remained at V60 in one patient who had <200 CD4 T cells/μL. At V0 and V3, 25% of patients had poor oral hygiene—this dropped to 9.4% of patients at V60. Despite this, periodontitis retained a prevalence of 50% at V60, compared with 40.6% at V0 and 37.5% at V3 (Table 1, see Figure 1, Supplemental Digital Content, http://links.lww.com/QAI/B488). At V0, 18.8% of patients had healthy periodontium and only 6.3% had severe periodontitis (periodontal pocket >6 mm), but at V60 only 3.1% had healthy periodontium and 12.5% had severe periodontitis (data not shown).

TABLE 1. - CD4 T-Cell Counts Improve and Oral Candidiasis Resolves, But Periodontitis Remains Common After 5 Years on ART
Healthy Control (n = 32) HIV-Infected (n = 32) P
V0a V3 V60
a b c d a vs b a vs c a vs d
Age, yr 36 (24–50) 36 (24–52) 0.89
Male gender 59% 56% 1.00
Declared smoking habit
 Never 56% 38% 50% 50% 0.003 0.23 0.23
 Stop >12 months 19% 3% 6% 6%
 Stop ≤12 months 0 28% 3% 3%
 Current 25% 31% 41% 41%
Oral hygiene
 Good 28% 25% 22% 25% 0.01 0.01 0.21
 Moderate 72% 50% 53% 66%
 Poor 0 25% 25% 9%
Periodontitis 38% 41% 38% 50% 1.00 1.00 0.45
Tuberculosis 0 56% <0.0001
Oral candidiasis 0 59% 22% 6% <0.0001 0.01 0.49
CD4 T-cells/µL 769 (321–1344) 61 (2–195) 173 (7–601) 458 (13–958) <0.0001 <0.0001 <0.0001
Healthy Control HIV-Infected (n = 32) P
V0 V60
a b d a vs b a vs d
cIMT
 Right, mm 0.52 (0.35–0.76)* 0.58 (0.39–0.71) 0.57 (0.39–0.98) 0.02 0.77
 Left, mm 0.48 (0.35–0.77) 0.58 (0.45–0.89) 0.56 (0.32–0.9) 0.002 0.12
sTNFR, ng/mL 319 (154–606) 436 (202–935) 358 (203–807) 0.0008 0.13
CRP, µg/mL 502 (24–2384) 1012 (73–19,235) 711 (118–12,854) 0.01 0.07
ICAM-1, µg/mL 199 (122–402) 412 (205–1020) 245 (110–673) 0.002 0.02
CMV lysate antibody (AU) 3087 (133–36,508) 20,765 (2882–306960) 18,536 (1682–270661) <0.0001 <0.0001
CMV IE-1 antibody (AU) 17,511 (3664–142174) 21,518 (2106–422809) 14,777 (3563–64,183) 0.21 0.7
CMV gB antibody (AU) 7347 (0–28,081) 11,228 (1901–146991) 12,642 (1821–74,611) 0.02 0.0006
Bold values refer to differences that achieve P<0.05.
AU, arbitrary unit.
*Visit (V) 0 was at the start of ART, V3 at 3 months and V60 at 5 years.
Median (range).
Mann–Whitney tests for continuous data, χ2 or Fisher Exact test for categorical data.

Before ART, HIV patients had significantly higher cIMT readings (right and left) and levels of plasma biomarkers except CMV IE-1 antibody, compared with healthy control subjects. At V60, only ICAM-1, CMV lysate, and gB antibodies remained elevated (Table 1). cIMT measurements were similar at V0, V3, and V60, and right and left readings were similar at all timepoints (see Figure 1, Supplemental Digital Content, http://links.lww.com/QAI/B488).

HIV Patients With Periodontitis had Higher cIMT Readings at V60

The presence of periodontitis did not influence cIMT at V0 or V3. However, at V60, periodontitis was more common in patients who were older (P = 0.03) and had moderate-to-poor oral hygiene (P = 0.05) with a marginal association with pulmonary tuberculosis (P = 0.07). Periodontitis at V60 was not associated with CD4 T-cell counts at V0 or V60, or levels of CMV-reactive antibodies (Table 2).

TABLE 2. - Periodontitis Associated With Older Age and Poor Oral Hygiene After 5 years on ART
Periodontitis absent (n = 16) Periodontitis Present (n = 16) P
Age, yr 34 (24–45)* 38.5 (26–52) 0.03
Male gender 62% 50% 0.72
Declared smoking habit
 Never 44% 56% 0.34
 Stop > 12 months 12% 0
 Stop ≤12 months 0 6%
 Current 44% 38%
History of tuberculosis 38% 75% 0.07
History of oral candidiasis 62% 56% 1.00
Oral hygiene
 Good 44% 6%
 Moderate 50% 81% 0.05
 Poor 6% 12%
CD4 T cells/μL at V0 64 (18–195) 45 (2–191) 0.27
CD4 T cells/μL at V60 556 (13–958) 397 (170–904) 0.51
CMV lysate antibody (AU) 12,742 (1682–209182) 25,296 (1860–270661) 0.66
CMV IE-1 antibody (AU) 14,931 (4859–61,959) 13,471 (3563–64,183) 0.87
CMV gB antibody (AU) 11,019 (1821–36,142) 16,372 (2738–74,611) 0.34
Bold values refer to differences that achieve P<0.05.
*Median (range).
Mann–Whitney tests for continuous data, χ2 or Fisher exact tests for categorical data.
AU, arbitrary unit.

When we compared the cIMT between patients with and without periodontitis, and healthy controls and HIV patients at V60, those with periodontitis had greater right and left cIMT (Fig. 1A). Moreover, HIV patients with periodontitis had greater cIMT values than healthy controls matched by periodontitis (Fig. 1B).

FIGURE 1.
FIGURE 1.:
Associations between cIMT and periodontitis. A, Right and left cIMT were elevated in patients with periodontitis at V60. B, Right and left cIMT patients with periodontitis at V60 were higher than healthy controls. Data are presented as median (range) and analyzed using Mann–Whitney tests; R: Right cIMT; L: Left cIMT; (P+): Periodontitis present; (P−): Periodontitis absent.

Linear Regressions Establish Periodontitis as a Strong Determinant of cIMT, With a Small Effect of CMV

Simple linear regressions were performed to explore which variables have significant effects individually on right or left cIMT. Variables were selected from published studies and included periodontitis, age, gender, smoking, taking alcohol, oral hygiene, tuberculosis, body mass index, CMV IE-1 antibody, CMV lysate antibody, CMV gB antibody, CD4 T-cell counts, sTNFR, ICAM-1, and CRP. These showed that right and left cIMT were influenced by periodontitis, age and oral hygiene with gender and CMV lysate antibody also reaching the cut-off for inclusion in multiple regressions (P < 0.20; Table 3). Optimal models (Table 4) confirmed that periodontitis was a strong predictor for both left and right cIMT. The inclusion of CMV lysate antibody improved the models for both right and left cIMT. The final model (B) explained 40.0% of the variability of the right cIMT (P = 0.001) and 45.0% of the variability of left cIMT (P < 0.001) with adjustment for age and gender. On average, patients with periodontitis had 0.101 mm (P = 0.052) thicker right cIMT and 0.119 mm (P = 0.016) thicker left cIMT compared with those without periodontitis, after controlling for levels of CMV lysate antibody. The models were not improved by log transformation of CMV antibody levels (data not shown).

TABLE 3. - Individual Linear Regressions Show Significant Relationships Between cIMT at V60 and Periodontitis, Age, Oral Hygiene, and CMV Lysate Antibody
Right cIMT Left cIMT
Coefficient (β) P Coefficient (β) P
Periodontitis (+) 0.147 0.010 0.158 0.004
Demographic factors
 Age, yr 0.013 0.001 0.013 0.002
 Gender (male) 0.107 0.079 0.101 0.084
 Oral hygiene 0.027 0.048
  Moderate 0.172 0.011 0.150 0.022
  Poor 0.205 0.056 0.196 0.063
 Tuberculosis 0.005 0.937 0.002 0.971
 CD4 T cells/µL 0.00004 0.754 −6.71 × 10−6 0.956
Plasma biomarkers
 sTNFR, ng/mL −0.00003 0.903 −0.00007 0.756
 CRP, µg/mL −0.00001 0.389 −3.29 × 10−6 0.777
 ICAM-1, µg/mL −0.0002 0.503 −0.0002 0.484
 CMV lysate antibody (AU) 9.40 × 10−7 0.064 9.72 × 10−7 0.045
 CMV IE-1 antibody (AU) −4.1 × 10−8 0.980 7.62 × 10−8 0.962
 CMV gB antibody (AU) 2.38 × 10−6 0.266 2.87 × 10−6 0.127
Bold values refer to differences that achieve P<0.05.
AU, arbitrary unit.

TABLE 4. - Multivariable Regression Models* Identified Periodontitis as Strong Determinant of cIMT at V60, With a Small Effect of CMV Lysate Antibody
Right cIMT Model A Model B
Coefficient (β) P 95% CI Coefficient (β) P 95% CI
Adjusted R2 = 0.363, P = 0.0013 Adjusted R2 = 0.400, P = 0.001
Periodontitis present 0.096 0.071 −0.009 to 0.202 0.101 0.052 −0.0001 to 0.227
CMV lysate antibody 6.75 ×10−7 0.108 −1.59 ×10−7 to 1.51 × 10−6
Left cIMT Model A Model B
Coefficient (β) P 95% CI Coefficient (β) P 95% CI
Adjusted R2 = 0.393, P = 0.0001 Adjusted R2 = 0.450, P = 0.001
Periodontitis present 0.114 0.026 0.015 to 0.212 0.119 0.016 0.024 to 0.213
CMV lysate antibody 7.35 ×10−7 0.060 −3.36 × 10−8 to 1.50 × 10−6
*Adjusted for age and gender.
CI, confidence interval.

We also analyzed both left and right cIMT at V0 (data are not shown). Neither periodontitis nor CMV lysate antibody were significant predictors for right or left cIMT. A significant model could be derived for left cIMT only and was based on age (adjusted R2 = 0.222, P = 0.004).

DISCUSSION

Periodontitis can be assessed noninvasively without costly equipment or reagents, and so warrants careful evaluation as a screening tool to predict risks of associated conditions such as CVD, autoimmune diseases, and diabetes mellitus.5,21 Moreover inflammation of periodontal tissues can breach the mucosal barrier to systemic circulation, allowing periodontal bacteria, their products, and inflammatory mediators to enter systemic circulation and accelerate the development of atherosclerosis. This model was based on a study of over 800 subjects in Sweden where moderate-to-severe periodontitis was independently associated with myocardial infarction.22 If periodontal disease is the primary lesion, it will be a valid therapeutic target to combat CVD. Our study uses community periodontal index of treatment need as a rapid screening tool to identify patients with periodontitis. Because it is based on the pocket depth recorded adjacent to 10 index teeth, it does not fully define the damage to the periodontium or tooth loss. However, in our hands, it correlated with age and oral hygiene and was a significant predictor of increased cIMT.

A study from the Netherlands recently confirmed that severe periodontitis is more prevalent in HIV-infected patients than in age-matched controls. Increasing age and male gender were significant risk factors for severe periodontitis, but patients' responses to ART were not associated with prevalence or severity.23 The prevalence of periodontitis among HIV patients was high (86%) in a study from Brazil24 and a little lower (46%) in a recent study from India.25 Our results are within this range and show no decline on ART. Moreover, periodontal disease was the strongest determinant of CVD as assessed by cIMT measurements at V60. Associations were unclear at earlier time points.

Most people are infected by CMV during childhood, so ∼90% of people in developing countries are seropositive. The viral burden is particularly high in HIV patients because CMV establishes latency with reactivations triggered by inflammation and promoted by immunodeficiency.26 All HIV patients in the JakCCANDO cohort are seropositive with very high levels of antibody that declined during the first year on ART,27 but remained higher than local healthy controls after 5 years (Table 1). At V0, around 50% had circulating CMV DNA detectable using an in-house quantitative polymerase chain reaction assay.12

Several studies have linked local CMV replication with periodontal disease.13,14,28 However, we observed no association between levels of CMV antibodies and periodontitis (Table 2). An association has been detected in healthy Asians,14 but HIV patients in the JakCCANDO cohort all have a very high burden of CMV. This may mask associations with antibody levels,12,27 so we cannot conclude that CMV promotes periodontitis or vice versa in our cohort.

Meta-analyses have now confirmed links between the burden of CMV (assessed by seropositivity or levels of CMV-reactive antibodies) and CVD in the general population.29 This likely reflects the replication of CMV in endothelial cells triggering the formation of atherosclerotic plaques.30 In the present cohort, levels of antibody reactive with CMV IE-1 at V6 and V12 correlated directly with the right cIMT,12 suggesting a small effect of CMV in patients responding to ART and hence able to make antibodies in proportion to their burden of CMV. Here, multiple linear regressions showed that periodontitis and CMV antibody levels optimally predicted greater right and left cIMT after 5 years on ART. The results suggest parallel and synergistic but distinct mechanisms whereby CMV and periodontitis promote atherosclerosis in HIV patients stabilized on ART. The findings warrant verification in a larger cohort with local CMV replication assessed in saliva and periodontal tissues.

ACKNOWLEDGMENTS

The authors thank patients and controls who participated in this study, and Ms. Faizah and staff of the HIV clinic who managed examination schedules.

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Keywords:

atherosclerosis; CMV; HIV; periodontal disease

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