title: Association between Immune Markers and Surrogate Markers of Cardiovascular Disease in HIV Positive Patients: A Systematic Review.
abstract: BACKGROUND
  HIV 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.
  
  
  METHODS
  A 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).
  
  
  RESULTS
  Twenty-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.
  
  
  CONCLUSIONS
  This 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.
authors.affiliation: Julius Global Health, The Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.|Department of Internal Medicine & Infectious Diseases, University Medical Center Utrecht, Utrecht, The Netherlands.|School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Alinda G
authors.initials: AG
authors.lastname: Vos
authors.affiliation: Julius Global Health, The Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Annelieke
authors.initials: A
authors.lastname: Hulzebosch
authors.affiliation: Julius Global Health, The Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Diederick E
authors.initials: DE
authors.lastname: Grobbee
authors.affiliation: Department of Internal Medicine & Infectious Diseases, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Roos E
authors.initials: RE
authors.lastname: Barth
authors.affiliation: Julius Global Health, The Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.|Division of Epidemiology and Biostatistics, School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Klipstein-Grobusch
mesh_terms: D015415:Biomarkers / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000175:diagnosis* / Q000209:etiology / Q000378:metabolism; D015658:HIV Infections / Q000150:complications* / Q000821:virology; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans
chemical_list: D015415:Biomarkers