Does an Index Composed of Clinical Data Reflect Effects of Inflammation, Coagulation, and Monocyte Activation on Mortality Among Those Aging With HIV?

Veterans Affairs Connecticut Healthcare System, West Haven, CT 06516, USA.
Clinical Infectious Diseases (Impact Factor: 8.89). 04/2012; 54(7):984-94. DOI: 10.1093/cid/cir989
Source: PubMed


When added to age, CD4 count and human immunodeficiency virus type 1 (HIV-1) RNA alone (Restricted Index), hemoglobin, FIB-4 Index, hepatitis C virus (HCV), and estimated glomerular filtration rate improve prediction of mortality. Weighted and combined, these 7 routine clinical variables constitute the Veterans Aging Cohort Study (VACS) Index. Because nonroutine biomarkers of inflammation (interleukin 6 [IL-6]), coagulation (D-dimer), and monocyte activation (sCD14) also predict mortality, we test the association of these indices and biomarkers with each other and with mortality.
Samples from 1302 HIV-infected veterans on antiretroviral therapy were analyzed. Indices were calculated closest to date of collection. We calculated Spearman correlations stratified by HIV-1 RNA and HCV status and measured association with mortality using C statistics and net reclassification improvement (NRI).
Of 1302 subjects, 915 had HIV-1 RNA <500 copies/mL and 154 died. The VACS Index was more correlated with IL-6, D-dimer, and sCD14 than the Restricted Index (P < .001). It was also more predictive of mortality (C statistic, 0.76; 95% confidence interval [CI], .72-.80) than any biomarker (C statistic, 0.66-0.70) or the Restricted Index (C statistic, 0.71; 95% CI, .67-.75). Compared to the Restricted Index alone, NRI resulted from incremental addition of VACS Index components (10%), D-dimer (7%), and sCD14 (4%), but not from IL-6 (0%).
Among HIV-infected individuals, independent of CD4, HIV-1 RNA, and age, hemoglobin and markers of liver and renal injury are associated with inflammation. Addition of D-dimer and sCD14, but not IL-6, improves the predictive accuracy of the VACS Index for mortality.

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Available from: Kendall J Bryant, Aug 04, 2014
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    • "Untangling if and how inflammation causes these diseases in adults is the topic of intense research. Because many diseases can either indirectly or directly contribute to an inflammatory state (Justice et al., 2012), defining the cause and effect relationships has been challenging. Indeed, in analysis of a large cohort of US military veterans with and without HIV disease, controlling for the presence of comorbidities such as cardiovascular disease, hypertension, diabetes mellitus, hyperlipidemia, and substance abuse attenuated the association between HIV infection and levels of IL-6, D-dimer, and sCD14 (Armah et al., 2012). "
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    ABSTRACT: Combination antiretroviral therapy for HIV infection improves immune function and eliminates the risk of AIDS-related complications but does not restore full health. HIV-infected adults have excess risk of cardiovascular, liver, kidney, bone, and neurologic diseases. Many markers of inflammation are elevated in HIV disease and strongly predictive of the risk of morbidity and mortality. A conceptual model has emerged to explain this syndrome of diseases where HIV-mediated destruction of gut mucosa leads to local and systemic inflammation. Translocated microbial products then pass through the liver, contributing to hepatic damage, impaired microbial clearance, and impaired protein synthesis. Chronic activation of monocytes and altered liver protein synthesis subsequently contribute to a hypercoagulable state. The combined effect of systemic inflammation and excess clotting on tissue function leads to end-organ disease. Multiple therapeutic interventions designed to reverse these pathways are now being tested in the clinic. It is likely that knowledge gained on how inflammation affects health in HIV disease could have implications for our understanding of other chronic inflammatory diseases and the biology of aging.
    Immunity 10/2013; 39(4):633-45. DOI:10.1016/j.immuni.2013.10.001 · 21.56 Impact Factor
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    • "Several reports suggest that human immunodeficiency virus (HIV) infection and hepatitis C (HCV) co-infection with HIV are associated with increased cardiovascular disease (CVD) risk [1-4]. Prior studies also link chronic inflammation, monocyte activation and/or altered coagulation with acute myocardial infarction and death in HIV infected people [5-8]. Whether HIV and HCV mediate their effects on CVD risk through these mechanisms is not known. "
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    ABSTRACT: Assessing whether hepatitis C (HCV) co-infection with human immunodeficiency virus (HIV) is associated with increased inflammation is complex. The liver, integral to inflammatory biomarker synthesis, is compromised by HCV and alcohol abuse. Using single liver-synthesized biomarkers (e.g. C-reactive protein) to represent inflammation may not be appropriate in HIV/HCV co-infection. We hypothesized that 1) detectable HIV/HCV RNA was independently associated with increased inflammation; 2) a composite inflammation measure describes inflammation differently from single inflammatory biomarkers. We compared inflammation by HIV/HCV group in a cohort of 361 HIV infected participants from the HIV-Longitudinal Interrelationships of Viruses and Ethanol study. Inflammatory biomarkers >75th percentile were considered elevated. Associations between HIV/HCV group and elevated biomarkers were analyzed as a composite measure (inflammatory burden) or individually. We defined inflammatory burden as number of concurrently elevated biomarkers. Biomarkers included interleukin-6 (IL-6), C-reactive protein (CRP), cystatin C, serum amyloid-A (SAA), tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10). Covariates: alcohol, liver fibrosis, comorbidities, CD4 count, antiretroviral therapy, substance use. Detectable HIV and HCV RNA (OR = 2.49; 95%CI = 1.05--5.89) and detectable HCV RNA alone (2.95; 1.08--8.01) were independently associated with increased odds of having a greater inflammatory burden compared to undetectable viremia. Elevated IL-10 (7.79; 1.90--31.97) and TNF-alpha (7.70; 1.42--41.83) were independently associated with detectable HIV and HCV RNA. Elevated IL-10 was also associated with detectable HCV RNA alone (5.51; 1.17, 25.84). Detectable HIV and HCV replication versus undetectable replication was associated with inflammatory burden and certain inflammatory biomarkers independently of alcohol consumption, liver fibrosis and other comorbidities.
    BMC Infectious Diseases 08/2013; 13(1):399. DOI:10.1186/1471-2334-13-399 · 2.61 Impact Factor
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    • "Biomarkers are used extensively in the assessment of HIV infection, from monitoring of CD4 count and HIV RNA viral load to assess response to ART, to the use of indices such as the (Veterans Aging Cohort Study) VACS Index to predict morbidity and mortality (Justice et al., 2012). Candidate biomarkers of ageing have been proposed in HIV-uninfected elderly population cohorts in other settings, as well as their relationship with frailty e.g. the Newcastle 85+ study (Collerton et al., 2012; Martin-Ruiz et al., 2011). "
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    ABSTRACT: HIV-infected individuals have an increased risk of age-related morbidity despite antiretroviral treatment (ART). Several anatomic and functional ophthalmological parameters are associated with increasing chronological age. These may, therefore, potentially serve as biomarkers of ageing. We investigated associations between ocular parameters (lens density, retinal vessel calibre, corneal endothelium and retinal nerve fibre layer thickness) and two 'cellular' biomarkers of ageing (leukocyte telomere length and CDKN2A expression) and with frailty in a cross-sectional study of 216 HIV-infected individuals. All ocular parameters, telomere length and frailty were associated with chronological age, whereas CDKN2A expression was not. Retinal venular calibre and lens density were associated with shorter telomere length (p-trend=0.04, and 0.08, respectively), whereas CDKN2A expression and frailty status were not associated with ocular parameters. Longitudinal studies are warranted to assess the integration of retinal vascular calibre and lens density with systemic markers to develop an overall index of biological ageing in HIV infection.
    Mechanisms of ageing and development 08/2013; 134(9). DOI:10.1016/j.mad.2013.08.002 · 3.40 Impact Factor
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