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INTRODUCTION Biomarkers are use to investigate potential biological methods to improve diagnosis or assessment of prognosis or as surrogate end points

in studies. Appropriate analysis of biomarkers depends on the research in question. (Grund B. and Sabin C. 2010) Biomarker is a combination of the words biological and marker and refers to a broad subcategory of medical signs that can be measured accurately and reproducibly. Biomarkers can be used to explore physiological and clinical outcomes in large numbers of individuals and have been used in clinical medicine for several decades. (Lundgren, J.D. 2010) Acquired immune deficiency syndrome or acquired immunodeficiency syndrome (AIDS) is a disease of the human immune system caused by the human immunodeficiency virus (HIV). This condition progressively reduces the effectiveness of the immune system and leaves individuals susceptible to opportunistic infections and tumors. HIV is transmitted through direct contact of a mucous membrane or the bloodstream with a bodily fluid containing HIV, such as blood, semen, vaginal fluid, preseminal fluid, and breast milk. This transmission can involve anal, vaginal or oral sex, blood transfusion, contaminated hypodermic needles, exchange between mother and baby during pregnancy, childbirth, breastfeeding or other exposure to one of the above bodily fluids.

Biomarkers and HIV-associated cardiovascular disease CVD Pre mature atherosclerotic cardiovascular disease CVD has become the leading cause of mortality and morbidity for patients with HIV infection, a disease that culminates in morbid events beginning with well described mechanisms that include inflammation, endothelial dysfunction plaque formation and thrombogenesis. Epidemiological data have demonstrated that HIV infection is associated with increases in well established markers of inflammation and thrombosis, and level of high sensitivity C-reactive protein, interleukin-6 and Ddimer predict CVD and mortality risks in HIV cohorts. Levels of interleukin-6,Ddimer and endothelial adhesion molecules increase when antiretroviral therapy is interrupted, suggesting that HIV replication may be driving CVD in this context. However data on changes in many CVD biomarkers after starting antiretroviral treatment are lacking. 1. Markers of inflammation Inflamation is a hallmark of HIV infection and a key element in the pathogenesis of CVD. In the general population higher levels of high sensitivity C-reactive protein (hsCRP) and Interleukin-6 (IL -6) are well established markers for CVD events and death from any cause. IL-6 is a pro inflammatory cytokine produced by monocytes, endothelial cells and lymphocyte. IL-6 has a wide range of effects including antiviral properties, induction of acute phrase reactants and promotion of hemostasis. hsCRP is an acute protein produced and released by hepatocytes, largely in response to IL-6. Multiple cross sectional studies have shown that these two are elevated in HIV infected persons as compared to uninfected ones. Chronic inflation in persons with HIV may be as a result of activation of lymphocytes and dendritic cells, damage to the mucosal barrier, injury to endothelial surfaces, metabolic changes and/or other factors related to HIV replication. 2. Markers of thrombotic activity High levels of D-dimer and fibrinogen have been associated with increased risk of all cause mortality both in HIV infected and uninfected populations. It is worth noting that D-dimer and fibrinogen are non specific markers which primarily

reflect increased activity in thrombotic process and may be elevated in response to inflammatory stimuli. An increase in procoagulant factors, (eg defficieancy of protein C and S), and platelet activation have all been reported with HIV infection. Another possibility is that HIV infection and/or immune activation increases expression of tissue factor and endothelial cells or leukocytes thereby upregulating the extrinsinic coagulant pathway. In a case control study of 127 HIV infected patients, tissue factor was elevated approximately four months prior to a CVD event when compared to controls who did not have an event. In another report HIV infected persons were found to have more tissue factor expression on circulating blood mononuclear cells compared with uninfected controls. In this study, expression of tissue factor correlated with HIV RNA levels , the proportion of CTL/CD8+ expressing immune activation markers and with D-dimer levels. (Baker, J.V and Duprez 2010) Biomarkers of HIV replication. Viremia provides a biomarker for HIV replication in various tissues. Viremia can be accurately measured down to the level of individual molecules using PCR methods to provide a real time measure of viral replication. Studies are being done to review and describe the precise relationship between viremia and viral replication particularly in the setting of high active antiretroviral therapy (HAART). Under certain conditions the level of viremia is a direct indictor of systemic viral replication. The relationship between viremia and viral replication is best understood using formal models of viral dynamics. In patients on suppressive HAART regimens, the low level of viremia mostly reflects virus release from stable reservoirs rather than ongoing cycles of replication. (Saliciano, J.D 2010) High sensitivity CRP High sensitivity CRP (hsCRP) which is a protein produced by the liver in response to interleukin 6 released from activated monocytes elsewhere. Elevated hsCRP has been associated with an increased risk of cardiovascular disease. Despite the lack of clarity regarding the precies role of CRP has in the disease process, and despite ongoing controversy as to whether CRP has prognostic significance independent of traditional cardiovascular risk factors, the measurement of hsCRP

is now being routinely performed in some clinical practices. In a recent study 17000 asymptomatic adults with normal lipid and elevated CRP levels, those randomized to receive rosuvastatin - a lipid lowering agent with putative antiinflammatory activities - had a lower risk of developing cardiovascular disease than those receiving placebo. (Lundgren, J.D) CD4+ T cell counts It was first recognized that there was a significant relationship between peripheral blood CD4+ T cell counts and the development of opportunistic infections in patients with HIV. Peripheral blood CD4+ T cell counts became a widely available test and a central biological marker in HIV disease monitoring in 1980s. During that time it was apparent that HIV infection was associated with chronic inflammation, and increase in a number of non inflammatory biomarkers. The subsequent discovery and introduction of quantitative measures of HIV viral load dramatically altered clinical practice and drug development. The demonstration of the profound association between higher HIV-RNA levels and more rapid depletion of CD4+ lymphocyte count on one hand and the risk of AIDs or death on the other hand, was a powerful and easy comprehended message. (Lundgren, J.D) Level of HIV-RNA in plasma Although the relationship between the two is unclear, circulating levels of HIVRNA in plasma and the total body level of active HIV replication is unclear, treatment mediated decreases in plasma HIV-RNA levels are a consistent marker of antiviral potential and long-term clinical efficacy. (Lundgren, J.D) Immune reconstitution inflammatory syndrome Immune reconstitution inflammatory syndrome (IRIS) is the paradoxical worsening or unmasking of an infection or neaoplasm masking in HIV-1- infected patients shortly after antiretroviral therapy (ART) initiation. New insights into pathogenesis of IRIS may help in indentifying of markers that could be useful in

predicting or diagnosing IRIS. Most cases of IRIS emerge within the first few weeks to few months of ART, at a time when morbidity and mortality still remain high and frequently in patients with severe CD4 lymphopenia who remain vulnerable to opportunistic diseases. Studies of immunopathogenesis have shown a significant activation of both innate and adaptive immune responses with elevation of plasma or serum chemokines and cytokines. Markers of inflammation such as C-reactive proteins interferon-inducible protein 10 or interferon gamma may be helpful as predictors of IRIS events. (Sereti 2010)

REFFERENCES Grund B. and Sabin C. Analysis of Biomarker Data, Logs, odds ratios and receiver operating characteristic curves. Current Opinion on HIV and AIDs, 5:473-479 Baker, J.V and Duprez, D. Biomarkers and HIV-associated cardiovascular disease. Current Opinion on HIV and AIDs 2010, 5:511-516 Saliciano, J.D and Saliciano, R.F. Biomarkers of HIV replication. Current Opinion on HIV and AIDs 2010, 5:491-497 Lundgren, J.D et al, Biomarkers in HIV disease. Current Opinion on HIV and AIDs 2010, 5:459-462 Sereti, I et al;Biomarkers in immune reconstitution inflammatory syndrome signals for pathogenesis. Current Opinion on HIV and AIDs 2010, 5:504-510