Association between Immune Markers and Surrogate Markers of Cardiovascular Disease in HIV Positive Patients: A Systematic Review

Abstract

BackgroundHIV infection is associated with an increased risk of cardiovascular disease (CVD). Chronic low-grade immune activation is likely one of the driving mechanisms. This systematic review provides an overview of the evidence addressing the relation between immune markers and surrogate markers of CVD (except CIMT) in HIV infection.MethodsA systematic search was performed in PubMed, Embase and Cochrane Library identifying all articles from 1996 to April 2015. It addressed the relation between immune markers and surrogate markers of CVD (except Carotid Intima-media Thickness) in HIV-positive adults. Two authors, using predefined criteria, independently conducted the selection of articles, critical appraisal and extraction of the data. Analysis focused on immune markers that were assessed most frequently. The review was conducted according to the PRISMA guideline and performed as part of an overarching review registered with PROSPERO (CRD42014010516).FindingsTwenty-nine articles were selected, describing 34 immune markers and nine different CVD surrogate outcomes: coronary calcium score (13 times) and flow-mediated dilation (10 times) were used most frequently. Twenty-seven studies had a cross-sectional design. CRP, IL-6 and sVCAM-1 were assessed most frequently. None of the immune markers were clearly associated with any of the surrogate CVD outcomes. No effect estimate could be calculated due to marked heterogeneity in study populations, immune markers, outcomes and statistical approaches.InterpretationThis review could not identify a clear association between any of the immune markers and surrogate CVD outcomes. This may reflect a true lack of association, or may be explained by heterogeneity across studies and lack of follow-up data. Future research should focus on longitudinal studies measuring a select set of immune markers and surrogate CVD outcomes awaiting the primary outcome of clinical cardiovascular events.

Coronary artery calcium, HIV and inflammation in Uganda compared with the USA

“…Chronic inflammation is a well-described risk factor for CVD. Among PLWH, markers of inflammation and immune activation have been variably associated with subclinical vascular disease, including CAC, non-calcified plaque and high-risk plaque features 9–12 25. No studies have previously evaluated these associations among HIV and HIV-uninfected persons in low-income and middle-income countries, such as Uganda.…”

“…The inflammatory milieu of chronic HIV infection that persists despite antiretroviral therapy (ART)—reflected by increased biomarkers of endothelial and monocyte activation in peripheral blood—may explain the higher ASCVD risk among PLWH 8. Studies of inflammation biomarkers and subclinical vascular disease among PLWH have, however, been mixed,9 with markers of monocyte activation (eg, soluble CD163 (sCD163) and soluble CD14 (sCD14)) showing the most consistent positive associations with the disease 10–12. In rural south-west Uganda, higher sCD14 and interleukin-6 (IL-6) levels 6 months after ART initiation appear to be associated with higher carotid intima-media thickness years later 13.…”

Integrating HIV pre‐exposure prophylaxis and harm reduction among men who have sex with men and transgender women to address intersecting harms associated with stimulant use: a modelling study

“…Associations between HIV infection and suicidality have been consistently reported. Similarly, there is evidence for higher risk of CVD among HIV-positive patients [66][67][68]. Additionally, a range of nonfatal harms are associated with both stimulant use and HIV, including increased incidence of STI and depression [69,70].…”

Rationale and design of the Mechanistic Substudy of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE): Effects of pitavastatin on coronary artery disease and inflammatory biomarkers

“…11 However, results have varied depending on endpoints and study design and a recent meta-analysis of studies in HIV positive patients could not identify a clear association between any of the immune markers and surrogate CVD outcomes. 12 This maybe due to insensitivity of the primary surrogate markers used (CAC and arterial stiffness) or may be explained by heterogeneity across studies and lack of follow-up data. Overall though, it emphasizes the need for a well powered and conducted study to establish an association and moreover provide preliminary data on whether this association drives outcomes.…”