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. 2023 Jun 8;76(11):1969-1979.
doi: 10.1093/cid/ciad033.

Leukocyte Count and Coronary Artery Disease Events in People With Human Immunodeficiency Virus: A Longitudinal Study

Emma F Avery  1 , Julia N Kleynhans  1 , Bruno Ledergerber  2 , Isabella C Schoepf  1   3   4 , Christian W Thorball  5 , Neeltje A Kootstra  6 , Peter Reiss  7 , Lene Ryom  8 , Dominique L Braun  2   9 , Maria C Thurnheer  3 , Catia Marzolini  10 , Marco Seneghini  11 , Enos Bernasconi  12 , Matthias Cavassini  13 , Hélène Buvelot  14 , Roger D Kouyos  2   9 , Jacques Fellay  5   15 , Huldrych F Günthard  2   9 , Philip E Tarr  1 ; Swiss HIV Cohort Study
Collaborators, Affiliations

Leukocyte Count and Coronary Artery Disease Events in People With Human Immunodeficiency Virus: A Longitudinal Study

Emma F Avery et al. Clin Infect Dis. .

Abstract

Background: People with human immunodeficiency virus (HIV; PWH) have increased cardiovascular risk. Higher leukocyte count has been associated with coronary artery disease (CAD) events in the general population. It is unknown whether the leukocyte-CAD association also applies to PWH.

Methods: In a case-control study nested within the Swiss HIV Cohort Study, we obtained uni- and multivariable odds ratios (OR) for CAD events, based on traditional and HIV-related CAD risk factors, leukocyte count, and confounders previously associated with leukocyte count.

Results: We included 536 cases with a first CAD event (2000-2021; median age, 56 years; 87% male; 84% with suppressed HIV RNA) and 1464 event-free controls. Cases had higher latest leukocyte count before CAD event than controls (median [interquartile range], 6495 [5300-7995] vs 5900 [4910-7200]; P < .01), but leukocytosis (>11 000/µL) was uncommon (4.3% vs 2.1%; P = .01). In the highest versus lowest leukocyte quintile at latest time point before CAD event, participants had univariable CAD-OR = 2.27 (95% confidence interval, 1.63-3.15) and multivariable adjusted CAD-OR = 1.59 (1.09-2.30). For comparison, univariable CAD-OR for dyslipidemia, diabetes, and recent abacavir exposure were 1.58 (1.29-1.93), 2.19 (1.59-3.03), and 1.73 (1.37-2.17), respectively. Smoking and, to a lesser degree, alcohol and ethnicity attenuated the leukocyte-CAD association. Leukocytes measured up to 8 years before the event were significantly associated with CAD events.

Conclusions: PWH in Switzerland with higher leukocyte counts have an independently increased risk of CAD events, to a degree similar to traditional and HIV-related risk factors.

Keywords: HIV infection; coronary artery disease; leukocytes; multivariable analysis; white blood cells.

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Conflict of interest statement

Potential conflicts of interest. B. L. received personal fees from Kantonsspital Baselland (for consultancy and statistical analyses), Liestal, Switzerland, during the conduct of the study, and reports personal fees from Gilead Switzerland SARL for lectures and ViiV for advisory board service, outside the submitted work. I. C. S.'s institution received a lecture fee from ViiV, outside the submitted work. P. R., through his institution, has received independent scientific grant support from Gilead, ViiV, Merck (all investigator-initiated study grants), and Janssen, honorarium paid to institution for lecture (content fully under author's control) from Merck & Co and has served on scientific advisory boards for Gilead, ViiV, and Merck, for which his institution has received remuneration. E. B. has received consulting fees from Gilead, MSD, ViiV, Pfizer, and AbbVie and travel support from Gilead, MSD, ViiV Healthcare, Abbvie, and Pfizer AG, and reports grants or contracts from Merck Sharp & Dohme and participation on a Data Safety Monitoring Board or Advisory Board with Merck Sharp & Dohme, Gilead Sciences, ViiV Healthcare, Pfizer AG, Ely Lilly, and Moderna, all paid to their institution and all outside the submitted work. D. L. B. received honoraria for advisory boards from Gilead, ViiV, and MSD and consulting fees from ViiV, Gilead, MSD, Pfizer, and Astra Zeneka. M. C. reports grants/support from Gilead, MSD, and ViiV, payment for expert testimony from Gilead, MSD, and ViiV, and travel support from Gilead, all paid to their institution and all outside the submitted work. R. K. reports grants/support from Gilead, paid to their institution, and grants or contracts from Swiss National Science Foundation, National Institutes of Health, outside the submitted work. H. F. G., outside this study, reports grants from Gilead (unrestricted research grant), the National Institutes of Health and the Yvonne Jacob Foundation (Swiss National Science Foundation, Swiss HIV Cohort Study), all paid to their institution; personal fees as an advisor/consultant for Merck, ViiV, and Gilead, and data and safety monitoring board remuneration from Merck, paid to their institution, and a travel grant from Gilead Sciences, paid to author, and paid participation on a Data Safety Monitoring Board or Advisory Board for Merck, Gilead Sciences, ViiV, Janssen, Johnson and Johnson, Novartis, and GSK, all outside the submitted work. P. E. T.'s institution reports unrestricted and educational grants from Gilead, ViiV, and MSD, and advisory fees from Gilead and ViiV, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Gilead, ViiV, MSD, and Daiichi Sankyo, all outside the submitted work. C. M. reports speaker honoraria from MSD, ViiV, and Pfizer, unrelated to this work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Study flowchart. Abbreviations: CAD, coronary artery disease; MI, myocardial infarction.
Figure 2.
Figure 2.
Distribution of leukocyte count in 1464 controls without coronary artery events (white bars) and in 536 cases with coronary artery events (gray bars). We divided CAD cases and CAD event-free controls into 5 quintiles according to their clinical CAD risk and their latest leukocyte count before the matching date. We show here the number, percentage, and 95% confidence intervals of participants in each quintile, plus the range of leukocyte counts in each quintile. Distribution of cases and controls according to latest leukocyte count before matching date. There were 78 (20.1%) cases versus 311 (79.9%) controls in the first quintile, 90 (21.9%) versus 321 (78.1%) in the second quintile, 100 (26.3%) versus 280 (73.7%) in the third quintile, 124 (29.5%) versus 296 (70.5%) in the fourth quintile, and 144 (36%) versus 256 (64%) in the fifth quintile. Abbreviations: CAD, coronary artery disease; CI, confidence interval.
Figure 3.
Figure 3.
A–G, Descriptive longitudinal trends for leukocyte count, leukocyte subsets, HIV-RNA, and neutrophil count in cases and controls. Descriptive (observed) trajectories of total leukocytes and different leukocyte subtypes (A–D) and HIV RNA (E) over time for controls versus cases. The lines show the cell counts and the shaded areas denote the 95% confidence intervals created with local polynomial smoothing. We considered only parameters that were from regular (per protocol) 6-monthly follow-up SHCS visits up until 1 d before the CAD event (cases) and matching date (controls). F, The leukocyte count stratified by different smoking amount categories. G, The observed trajectories of total neutrophils for the University of Zurich subpopulation over time for controls versus cases. The graphs portray an open cohort design (all participants are included, regardless of observation duration). The graphs portraying a closed cohort (in which only participants with ≥15-y observation time are included) can be found in the Supplementary Figure 1. Abbreviations: CAD, coronary artery disease; cig, cigarettes.
Figure 4.
Figure 4.
ORs for CAD events (with 95% CIs), according to individual clinical risk factors and latest leukocyte quintiles. Results show univariable and bivariable conditional logistic regression of associations of latest leukocyte count with CAD events for 536 cases and 1464 controls. Latest leukocyte count (fifth [highest] vs first [lowest] was significantly associated with CAD events in univariable analysis and in multivariable analysis [ie, adjusted for all variables shown]). Note: All odds ratios and 95% CIs shown in Figure 4 are also tabulated in Supplementary Table 3. The right-hand panel shows median leukocyte counts (cells/µL) in cases and controls in the different categories. Abbreviations: CAD, coronary artery disease; CI, confidence interval; OR, odds ratio.
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