Soluble biomarkers and morbidity and mortality among people infected with HIV: summary of published reports from 1997 to 2010

Purpose of reviewPublished articles from 1997 through May 2010 that reported findings on the relationship of soluble biomarkers with clinical outcomes among people infected with HIV were identified, and studies that examined the incremental value (over that of CD4+ cell count and HIV RNA level) that biomarkers had for predicting clinical outcomes were summarized. Recent findingsOver 1500 articles were identified on MEDLINE databases that met selected medical subject heading terms. Thirty-eight met criteria for inclusion in the review. Fifteen of the articles were published since 2008. Most evaluated biomarkers reflecting inflammation and immune activation. For 25 studies, the relationship between the biomarker and all-cause mortality was evaluated. Samples stored in specimen repositories were used for many studies, and those that did not usually focused on biomarkers that are measured as part of routine care. Eight of the reports utilized a case–control design and most of these were nested within a cohort study or a clinical trial. SummaryEstablishing the relationship between a biomarker and a clinical outcome is an important step in biomarker evaluation. To advance research on biomarkers relevant to people with HIV, large studies with long follow-up, carefully documented clinical events, and specimen repositories will be needed.

[1]  R. Stoltzfus,et al.  Elevated iron stores are associated with HIV disease severity and mortality among postpartum women in Zimbabwe , 2009, Public Health Nutrition.

[2]  J M Taylor,et al.  The prognostic value of cellular and serologic markers in infection with human immunodeficiency virus type 1. , 1990, The New England journal of medicine.

[3]  H. Ullum,et al.  High Plasma Levels of Intact and Cleaved Soluble Urokinase Receptor Reflect Immune Activation and Are Independent Predictors of Mortality in HIV-1-Infected Patients , 2005, Journal of acquired immune deficiency syndromes.

[4]  C. Lewis,et al.  Association of HIV Infection, Demographic and Cardiovascular Risk Factors With All-Cause Mortality in the Recent HAART Era , 2010, Journal of acquired immune deficiency syndromes.

[5]  M. Woodward,et al.  Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis , 2010, The Lancet.

[6]  Samy Suissa,et al.  The nested case-control study in cardiology. , 2003, American heart journal.

[7]  P. Ridker,et al.  Low-Density Lipoprotein Particle Concentration and Size as Determined by Nuclear Magnetic Resonance Spectroscopy as Predictors of Cardiovascular Disease in Women , 2002, Circulation.

[8]  R. Detels,et al.  Elevated levels of CD38+ CD8+ T cells in HIV infection add to the prognostic value of low CD4+ T cell levels: results of 6 years of follow-up. The Los Angeles Center, Multicenter AIDS Cohort Study. , 1993, Journal of acquired immune deficiency syndromes.

[9]  K. Marder,et al.  An evaluation of neurocognitive status and markers of immune activation as predictors of time to death in advanced HIV infection. , 2007, Archives of neurology.

[10]  K. Covinsky,et al.  Towards a combined prognostic index for survival in HIV infection: the role of ‘non‐HIV’ biomarkers , 2010, HIV medicine.

[11]  J Schüpbach,et al.  Human immunodeficiency virus type 1 p24 concentration measured by boosted ELISA of heat-denatured plasma correlates with decline in CD4 cells, progression to AIDS, and survival: comparison with viral RNA measurement. , 2000, The Journal of infectious diseases.

[12]  H. Ullum,et al.  Serum level of soluble urokinase-type plasminogen activator receptor is a strong and independent predictor of survival in human immunodeficiency virus infection. , 2000, Blood.

[13]  D. DeMets,et al.  Surrogate End Points in Clinical Trials: Are We Being Misled? , 1996, Annals of Internal Medicine.

[14]  Nancy R Cook,et al.  Advances in Measuring the Effect of Individual Predictors of Cardiovascular Risk: The Role of Reclassification Measures , 2009, Annals of Internal Medicine.

[15]  Holly Janes,et al.  Pivotal Evaluation of the Accuracy of a Biomarker Used for Classification or Prediction: Standards for Study Design , 2008, Journal of the National Cancer Institute.

[16]  R. Detels,et al.  Prognostic significance of plasma markers of immune activation, HIV viral load and CD4 T‐cell measurements , 1998, AIDS.

[17]  J. Feldman,et al.  C-Reactive Protein Is an Independent Predictor of Mortality in Women With HIV-1 Infection , 2003, Journal of acquired immune deficiency syndromes.

[18]  D. Fuchs,et al.  Serum HIV–1 RNA Levels Compared to Soluble Markers of Immune Activation to Predict Disease Progression in HIV–1–Infected Individuals , 1998, International Archives of Allergy and Immunology.

[19]  H. Cohen,et al.  Coagulation and activation of inflammatory pathways in the development of functional decline and mortality in the elderly. , 2003, The American journal of medicine.

[20]  D. Brand,et al.  Predictors of death within six months in patients with advanced AIDS , 2005, Palliative and Supportive Care.

[21]  A. Phillips,et al.  Interruption of Antiretroviral Therapy and Risk of Cardiovascular Disease in Persons with HIV-1 Infection: Exploratory Analyses from the SMART Trial , 2008, Antiviral therapy.

[22]  S. Hazen,et al.  Higher Plasma Myeloperoxidase Levels Are Not Associated with an Increased Risk for Cardiovascular Events in HIV-Infected Adults , 2008, HIV clinical trials.

[23]  Mardge H. Cohen,et al.  The Impact of Kidney Function at Highly Active Antiretroviral Therapy Initiation on Mortality in HIV-Infected Women , 2010, Journal of acquired immune deficiency syndromes.

[24]  J. Fahey,et al.  Serum neopterin, an immune activation marker, independently predicts disease progression in advanced HIV-1 infection. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[25]  L. Myer,et al.  Plasma levels of soluble urokinase-type plasminogen activator receptor (suPAR) and early mortality risk among patients enrolling for antiretroviral treatment in South Africa , 2007, BMC infectious diseases.

[26]  D. DeMets,et al.  Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework , 2001, Clinical pharmacology and therapeutics.

[27]  A. Phillips,et al.  Short-term risk of AIDS according to current CD4 cell count and viral load in antiretroviral drug-naive individuals and those treated in the monotherapy era , 2003, AIDS.

[28]  H. Whittle,et al.  Immunological predictors of survival in HIV type 2-infected rural villagers in Guinea-Bissau. , 2005, AIDS research and human retroviruses.

[29]  F. Miedema,et al.  Persistent immune activation in HIV-1 infection is associated with progression to AIDS , 2003, AIDS.

[30]  P. Morlat,et al.  Early evolution of plasma soluble TNF-alpha p75 receptor as a marker of progression in treated HIV-infected patients. , 2008, AIDS research and human retroviruses.

[31]  H. Ullum,et al.  Impaired production of cytokines is an independent predictor of mortality in HIV-1-infected patients , 2003, AIDS.

[32]  O. Kirk,et al.  Predicting the risk of cardiovascular disease in HIV-infected patients: the Data collection on Adverse Effects of Anti-HIV Drugs Study , 2010, European journal of cardiovascular prevention and rehabilitation : official journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology.

[33]  P. Ridker,et al.  Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. , 2000, Circulation.

[34]  John W. Mellors,et al.  Predictive Value of Immunologic and Virologic Markers After Long or Short Duration of HIV‐1 Infection , 2002, Journal of acquired immune deficiency syndromes.

[35]  J. Danesh,et al.  C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis , 2010, The Lancet.

[36]  A. Evans,et al.  C-Reactive Protein, Interleukin-6, and Fibrinogen as Predictors of Coronary Heart Disease: The PRIME Study , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[37]  D. Follmann,et al.  HIV infection-associated immune activation occurs by two distinct pathways that differentially affect CD4 and CD8 T cells , 2008, Proceedings of the National Academy of Sciences.

[38]  H. Ullum,et al.  p24 as a Predictor of Mortality in a Cohort of HIV-1-Infected Adults in Rural Africa , 2008, Journal of acquired immune deficiency syndromes.

[39]  D. Vlahov,et al.  Serum albumin as a prognostic indicator for HIV disease progression. , 2006, AIDS research and human retroviruses.

[40]  L. Kuller,et al.  Activation and coagulation biomarkers are independent predictors of the development of opportunistic disease in patients with HIV infection. , 2009, The Journal of infectious diseases.

[41]  W. Fawzi,et al.  C-reactive protein independently predicts HIV-related outcomes among women and children in a resource-poor setting , 2007, AIDS.

[42]  S. Hammer,et al.  Human immunodeficiency virus type 1 RNA level and CD4 count as prognostic markers and surrogate end points: A meta-analysis , 2000 .

[43]  Lewis H Kuller,et al.  Inflammatory and Coagulation Biomarkers and Mortality in Patients with HIV Infection , 2008, PLoS medicine.

[44]  M. Lederman,et al.  Pretreatment levels of soluble cellular receptors and interleukin-6 are associated with HIV disease progression in subjects treated with highly active antiretroviral therapy. , 2010, The Journal of infectious diseases.

[45]  R. Collins,et al.  Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55 000 vascular deaths , 2007, The Lancet.

[46]  B. Lau,et al.  C-reactive protein is a marker for human immunodeficiency virus disease progression. , 2006, Archives of internal medicine.

[47]  M. Lederman,et al.  Serum Interleukin-6 (IL-6), IL-10, Tumor Necrosis Factor (TNF) Alpha, Soluble Type II TNF Receptor, and Transforming Growth Factor Beta Levels in Human Immunodeficiency Virus Type 1-Infected Individuals with Mycobacterium avium Complex Disease , 2001, Journal of Clinical Microbiology.

[48]  D. Katzenstein,et al.  The evaluation of the HIV/AIDS Drug Access Initiatives in Côte D'Ivoire, Senegal and Uganda: how access to antiretroviral treatment can become feasible in Africa , 2003, AIDS.

[49]  D. Jacobs,et al.  Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection. , 2010, The Journal of infectious diseases.

[50]  A. Phillips,et al.  The role of HIV in serious diseases other than AIDS , 2008, AIDS.

[51]  N. Pantazis,et al.  Elevated serum levels of soluble immune activation markers are associated with increased risk for death in HAART-naive HIV-1-infected patients. , 2003, AIDS patient care and STDs.

[52]  R. D'Agostino,et al.  Development of appropriate coronary heart disease risk prediction models in HIV-infected patients. , 2008, Circulation.

[53]  H. Cohen,et al.  Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. , 1999, The American journal of medicine.

[54]  R. Salamon,et al.  Factors Associated with Mortality in Human Immunodeficiency Virus Type 1–Infected Adults Initiating Protease Inhibitor–Containing Therapy: Role of Education Level and of Early Transaminase Level Elevation (APROCO–ANRS EP11 Study) , 2002 .

[55]  L. Kuller,et al.  Lipoprotein particle subclasses, cardiovascular disease and HIV infection. , 2009, Atherosclerosis.

[56]  R Peto,et al.  Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. , 1998, JAMA.

[57]  G. Sirugo,et al.  Mortality in HIV infection is independently predicted by host iron status and SLC11A1 and HP genotypes, with new evidence of a gene-nutrient interaction. , 2009, The American journal of clinical nutrition.

[58]  C. Sabin,et al.  Markers of HIV-1 disease progression in individuals with haemophilia coinfected with hepatitis C virus: a longitudinal study , 2002, The Lancet.

[59]  D. Freedman,et al.  Relations of lipoprotein subclass levels and low-density lipoprotein size to progression of coronary artery disease in the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC-I) trial. , 2002, The American journal of cardiology.

[60]  A. Zolopa,et al.  Inflammation and Mortality in HIV-Infected Adults: Analysis of the FRAM Study Cohort , 2010, Journal of acquired immune deficiency syndromes.

[61]  L. Kuller,et al.  Serum Amyloid P and Cardiovascular Disease in Older Men and Women: Results from the Cardiovascular Health Study , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[62]  Karla Kerlikowske,et al.  Using Clinical Factors and Mammographic Breast Density to Estimate Breast Cancer Risk: Development and Validation of a New Predictive Model , 2008, Annals of Internal Medicine.

[63]  Mardge H. Cohen,et al.  Serum Albumin Is a Powerful Predictor of Survival Among HIV‐1‐Infected Women , 2003, Journal of acquired immune deficiency syndromes.

[64]  L. Szczech,et al.  Development of Proteinuria or Elevated Serum Creatinine and Mortality in HIV-Infected Women , 2003, Journal of acquired immune deficiency syndromes.

[65]  J. Danesh,et al.  Fibrin D-Dimer and Coronary Heart Disease: Prospective Study and Meta-Analysis , 2001, Circulation.

[66]  M. Clerici,et al.  Tumor Necrosis Factor β and Soluble APO-1/Fas Independently Predict Progression to AIDS in HIV-Seropositive Patients , 1998 .

[67]  K. Marder,et al.  Evaluation of HIV RNA and markers of immune activation as predictors of HIV-associated dementia , 2004, Neurology.

[68]  G. Beall,et al.  Infection with HIV is associated with elevated IL-6 levels and production. , 1990, Journal of immunology.

[69]  H Tunstall-Pedoe,et al.  Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. , 2005, JAMA.

[70]  Roger Detels,et al.  Plasma Viral Load and CD4+ Lymphocytes as Prognostic Markers of HIV-1 Infection , 1997, Annals of Internal Medicine.

[71]  S. Reis,et al.  Serum Amyloid A as a Predictor of Coronary Artery Disease and Cardiovascular Outcome in Women: The National Heart, Lung, and Blood Institute–Sponsored Women’s Ischemia Syndrome Evaluation (WISE) , 2004, Circulation.