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      Inflammation, Coagulation and Cardiovascular Disease in HIV-Infected Individuals

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          The SMART study was a trial of intermittent use of antiretroviral therapy (ART) (drug conservation [DC]) versus continuous use of ART (viral suppression [VS]) as a strategy to reduce toxicities, including cardiovascular disease (CVD) risk. We studied the predictive value of high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6) and D-dimer with CVD morbidity and mortality in HIV-infected patients who were enrolled in SMART beyond other measured CVD risk factors.


          A blood sample was available in 5098 participants who were enrolled in the SMART study for the measurement of IL-6, hsCRP and D-dimer. Hazard ratios (HR) with 95% CI for CVD events were estimated for each quartile (Q) for each biomarker vs the 1 st quartile and for 1 SD higher levels. For both treatment groups combined, unadjusted and adjusted HRs were determined using Cox regression models.


          There were 252 participants who had a CVD event over a median follow-up of 29 months. Adjusted HRs (95% CI) for CVD for Q4 vs Q1 were 4.65 (2.61, 8.29), 2.10 (1.40, 3.16), and 2.14 (1.38, 3.33) for IL-6, hsCRP and D-dimer, respectively. Associations were similar for the DC and VS treatment groups (interaction p-values were >0.30). The addition of the three biomarkers to a model that included baseline covariates significantly improved model fit (p<0.001). Area under the curve (AUC) estimates improved with inclusion of the three biomarkers in a model that included baseline covariates corresponding to other CVD risk factors and HIV factors (0.741 to 0.771; p<0.001 for difference).


          In HIV-infected individuals, IL-6, hsCRP and D-dimer are associated with an increased risk of CVD independent of other CVD risk factors. Further research is needed to determine whether these biomarkers can be used to improve CVD risk prediction among HIV positive individuals.

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          Most cited references 23

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          Decline in the AIDS and death rates in the EuroSIDA study: an observational study.

           O Kirk,  A Mocroft,  B Knysz (2003)
          Since the introduction of highly active antiretroviral therapy (HAART), little is known about whether changes in HIV-1 mortality and morbidity rates have been sustained. We aimed to assess possible changes in these rates across Europe. We analysed data for 9803 patients in 70 European HIV centres including ones in Israel and Argentina. Incidence rates of AIDS or death were calculated for overall and most recent CD4 count in 6-monthly periods and in three treatment eras (pre-HAART, 1994-1995; early-HAART, 1996-1997; and late-HAART, 1998-2002). The incidence of AIDS or death fell after September, 1998, by 8% per 6-month period (rate ratio 0.92, 95% CI 0.88-0.95, p<0.0001). When AIDS and death were analysed separately, the incidence of all deaths during the late-HAART era was significantly lower than that during the early-HAART era in patients whose latest CD4 count was 20 cells/microL or less (0.43, 0.35-0.53, p<0.0001), but at higher CD4 counts, did not differ between early-HAART and late-HAART. Incidence of AIDS was about 50% lower in late-HAART than in early-HAART, irrespective of latest CD4 count (p<0.0001). In multivariate Cox's models, with early-HAART as the reference, there was an increased risk of AIDS (relative hazard 1.39; 95% CI 1.16-1.67, p=0.0004) and all deaths (1.29; 1.08-1.56, p=0.0065) in the pre-HAART era, and a reduced risk of AIDS (0.62; 0.50-0.77, p<0.0001) and all deaths (0.66; 0.53-0.82, p=0.0002) in the late-HAART era. The initial drop in mortality and morbidity after the introduction of HAART has been sustained. Potential long-term adverse effects associated with HAART have not altered its effectiveness in treating AIDS.
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            Improved survival among HIV-infected individuals following initiation of antiretroviral therapy.

            Clinical trials have established the efficacy of antiretroviral therapy with double- and triple-drug regimens for individuals infected with the human immunodeficiency virus (HIV), but the effectiveness of these regimens in the population of patients not enrolled in clinical trials is unknown. To characterize survival following the initiation of antiretroviral therapy among HIV-infected individuals in the province of British Columbia. Prospective, population-based cohort study of patients with antiretroviral therapy available free of charge (median follow-up, 21 months). Province of British Columbia, Canada. All HIV-positive men and women 18 years of age or older in the province who were first prescribed any antiretroviral therapy between October 1992 and June 1996 and whose CD4+ cell counts were less than 0.350 x 10(9)/L. Rates of progression from initiation of antiretroviral therapy to death or a primary acquired immunodeficiency syndrome (AIDS) diagnosis for subjects who initially received zidovudine-, didanosine-, or zalcitabine-based therapy (ERA-I) and for those who initially received therapy regimens including lamivudine or stavudine (ERA-II). A total of 1178 patients (951 ERA-I, 227 ERA-II) were eligible. A total of 390 patients died (367 ERA-I, 23 ERA-II), yielding a crude mortality rate of 33.1%. ERA-I group subjects were almost twice as likely to die as ERA-II group subjects, with a mortality risk ratio of 1.86 (95% confidence interval [CI], 1.21 -2.86; P=.005). After adjusting for Pneumocystis carinii and Mycobacterium avium prophylaxis use, AIDS diagnosis, CD4+ cell count, sex, and age, ERA-I participants were 1.93 times (95% CI, 1.25-2.97; P=.003) more likely to die than ERA-II participants. Among patients without AIDS when treatment was started, ERA-I participants were 2.50 times (95% CI, 1.59-3.93; P<.001) more likely to progress to AIDS or death than ERA-II participants. The HIV-infected individuals who received initial therapy with regimens including stavudine or lamivudine had significantly lower mortality and longer AIDS-free survival than those who received initial therapy with regimens limited to zidovudine, didanosine, and zalcitabine.
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              Epidemiological evidence for cardiovascular disease in HIV-infected patients and relationship to highly active antiretroviral therapy.


                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                10 September 2012
                : 7
                : 9
                [1 ]University of Minnesota, Minneapolis, Minnesota, United States of America
                [2 ]University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
                [3 ]University of Vermont, Burlington, Vermont, United States of America
                [4 ]Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
                [5 ]Saint-Pierre Hospital, Brussels, Belgium
                [6 ]Kirby Institute, Faculty of Medicine, University of New South Wales, Sydney, Australia
                [7 ]National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
                [8 ]University Hospital Zurich, University of Zurich, Zurich, Switzerland
                [9 ]University of Copenhagen, Copenhagen, Denmark
                [10 ]Virginia Commonwealth University, Richmond, Virginia, United States of America
                [11 ]Medical Research Council Clinical Trials Unit, London, United Kingdom
                [12 ]Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America
                UCL Institute of Child Health, University College London, United Kingdom
                Author notes

                Competing Interests: The authors have read the journal’s policy and have the following conflicts. Russell Tracy declares the following work: Merck – seminar and consulting related to biomarkers in the setting of HIV; Abbott - seminar and consulting related to biomarkers in the setting of HIV; Tibotec-Johnson & Johnson - consulting related to biomarkers in the setting of HIV. All authors except Dr. Tracy have declared that no competing interests exist. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

                Conceived and designed the experiments: DAD LHK RT HCL JL JDN. Performed the experiments: RT WB SDW FD HCL BL JL DN NIP RJP. Analyzed the data: JN JDN. Contributed reagents/materials/analysis tools: RT DAD RJP. Wrote the paper: DAD JN JDN. Edited the manuscript: LHK RT WB SDW FD HCL BL JL DN NIP RJP.


                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 8
                Support for this work was provided by NIAD, United States National Institutes of Health grants UO1AI068641, U01AI042170, and U01AI046362. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article
                Clinical Immunology
                Clinical Research Design
                Clinical Trials
                Biomarker Epidemiology
                Cardiovascular Disease Epidemiology
                Coagulation Disorders
                Infectious Diseases
                Viral Diseases



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