Factors Associated With Systemic Immune Activation Indices in a Global Primary Cardiovascular Disease Prevention Cohort of People With Human Immunodeficiency Virus on Antiretroviral Therapy

Abstract

Background: Among antiretroviral therapy (ART)-treated people with human immunodeficiency virus (PWH), persistent systemic immune activation contributes to atherogenesis atherosclerotic, cardiovascular disease (CVD) events, and mortality. Factors associated with key immune activation indices have not previously been characterized among a global primary CVD prevention cohort of PWH.

Methods: Leveraging baseline Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) data, we evaluated factors associated with soluble CD14 (sCD14) and oxidized low-density lipoprotein (oxLDL).

Results: The primary analysis cohort included 4907 participants from 5 global-burden-of-disease regions (38% female, 48% Black, median age 50 years). In fully adjusted models for sCD14, female sex and White race (among those in high-income regions) were associated with higher sCD14 levels, while higher body mass index (BMI) and current use of nucleoside reverse transcriptase inhibitor + integrase strand transfer inhibitor ART were associated with lower sCD14 levels. In fully adjusted models for oxLDL, male sex, residence in high-income regions, White race (among those in high-income regions), and higher BMI were associated with higher oxLDL levels. In a subanalysis cohort of 1396 women with HIV, increased reproductive age was associated with higher sCD14 levels but not with higher oxLDL levels.

Conclusions: Factors associated with sCD14 and oxLDL, 2 key indices of immune-mediated CVD risk, differ. Future studies will elucidate ways in which medications (eg, statins) and behavioral modifications influence sCD14 and oxLDL and the extent to which dampening of these markers mediates CVD-protective effects.

Clinical trials registration: NCT0234429.

Trial registration: ClinicalTrials.gov NCT00234429.

Keywords: HIV; cardiovascular disease risk; immune activation markers; reproductive aging; women.

Conflict of interest statement

Potential conflicts of interest. S. E. L. reports travel reimbursement from the Association of Nurses in AIDS Care as an invited presenter and receipt of a 1-time conference travel reimbursement. A. K. reports grants from NIH/NIAID and NIH/NHLBI during the conduct of the study. T. H. B. reports equity in Excision Bio Therapeutics and serves on their scientific advisory board outside the submitted work. J. S. C. reports consulting fees from Merck and Company and Resvirlogix. C. J. F. reports grant support through his institution from Gilead Sciences, ViiV Healthcare, GlaxoSmithKline, Janssen, AbbVie, Merck, Amgen, and Cytodyn outside the submitted work and serves as chair of the data and safety monitoring board (DSMB) for the Intrepid Study. E. T. O. reports grant support through his institution from NIH, Gilead Sciences, ViiV, and GlaxoSmithKline and personal fees from Merck, ViiV Healthcare, and Theratechnologies outside the submitted work. J. A. A. reports institutional research support for clinical trials from Atea, Emergent Biosolutions, Frontier Technologies, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Pfizer, Regeneron, and ViiV Healthcare and personal fees for advisory boards from GlaxoSmithKline/ViiV Healthcare and Merck, all outside the submitted work. C. D. M. reports personal fees from Gilead Sciences and ViiV Healthcare for participation in advisory board meetings outside the submitted work. K. M. E. reports grant support from Gilead Sciences and consulting fees from Gilead Sciences, ViiV Healthcare, and Janssen Therapeutics (all paid to the University of Colorado) outside the submitted work. M. C. reports serving as an executive board member for HIV Medicine Association and participation on boards for ViiV Healthcare and Gilead Sciences. M. M. reports personal fees from Merck and Company, Gilead Sciences, and ViiV outside the submitted work. M. T. L. reports grant support through his institution from Kowa Pharmaceuticals America, Inc, for the conduct of the study and reports grant support from MedImmune/AstraZeneca and personal fees from PQBypass outside the current work. S. K. G. reports grant support through his institution from Kowa Pharmaceuticals America, Inc, Gilead Sciences, and ViiV Healthcare for the conduct of the study, as well as grants from Theratechnologies and Navidea and personal fees from Theratechnologies Consulting, Navidea, and ViiV Healthcare Consulting, all outside the submitted work. H. J. R. reports grants from NIH/NIAID and NIH/NHLBI during the conduct of the study, as well as grants from NIH/NIAID, NIH/NHLBI, NIH/National Institute of Diabetes and Digestive and Kidney Diseases, and NIH/National Institute on Aging outside the submitted work. M. V. Z. reports grant support through her institution from NIH/NIAID and Gilead Sciences, relevant to the conduct of the study, as well as grants from NIH/NIAID and NIH/NHLBI outside the submitted work; support for the Conference on Retroviruses and Opportunistic Infections and International Workshop for HIV and Women from the conference organizing committee as an abstract reviewer and/or speaker; and participation in DSMB for NIH-funded studies and received no payment.

© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Multivariable linear regression analyses relating covariates of interest (sex, age, enrollment region) to sCD14. Abbreviations: CI, confidence interval; sCD14, soluble CD14.

Figure 2.

Multivariable linear regression analyses relating covariates of interest (sex, age, enrollment region) to oxLDL. Abbreviations: CI, confidence interval; oxLDL, oxidized low-density lipoprotein.

Figure 3.

Multivariable linear regression analyses relating covariates of interest (sex, age, enrollment region, race in high-income regions, cigarette smoking status, substance use, hypertension, waist circumference, BMI, nadir CD4, total ART use, ART regimen class, and entry CD4 count) to sCD14 and to oxLDL, respectively. Abbreviations: ART, antiretroviral therapy; BMI, body mass index; CI, confidence interval; INSTI, integrase strand transfer inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; oxLDL, oxidized low-density lipoprotein; PI, protease inhibitor; sCD14, soluble CD14.