Impact of Different Integrase Inhibitor Based Regimen on Markers of Inflammation and Immune Activation Among HIV naïve Patient During the First Year of Effective First-line Combination

INTRODUCTION AND BACKGROUND Combination antiretroviral therapy (cART) controls HIV-1 plasma viral load in most patients, leading to a reduction in morbidity and mortality [Egger M, BMJ 1997; Detels R, JAMA 1998].

Despite efficient treatment persistent low-level viral replication and immune activation remain an important therapeutic challenge. Immune activation is associated with more rapid disease progression and with less efficient CD4+ cell recovery during cART [Hunt PW, J Infect Dis 2003; Lederman MM, J Infect Dis 2011], while plasma biomarkers of inflammation have been linked to a risk of mortality and non-AIDS-defining events such as cardiovascular disease and non-AIDS-defining cancers [Kuller LH, PLoS Med. 2008; Ipp H, Clin Chim Acta. 2013].

A potential link between HIV-associated inflammation and disease progression and mortality was shown for the first time in a randomized clinical trial of continuous versus intermittent antiretroviral therapy (the Strategies for Management of Antiretroviral Therapy study - SMART study) [Neuhaus J, J Infect Dis 2010]. In this study HIV-infected persons were randomized to continuous antiretroviral therapy (ART) or CD4- T cell count- driven ART. Subjects randomized to the second arm had a higher risk of morbidity and mortality. ART interruption resulted in a rapid increase in inflammation- and coagulation-associated biomarkers that were associated with increased risks of death, AIDS, and cardiovascular disease (CVD).

Further studies have confirmed that HIV-infected individuals have elevated levels of inflammatory and cellular activation markers and suppression of viral replication by ART decreases, but does not normalize those markers [Regidor DL, AIDS 2011; Widney DP, J Interferon Cytokine Res 2005; Kaplan RC, J Acquir Immune Deficiency Syndr 2012].

Soluble biomarkers are a convenient way of assessing immune activation and inflammation in HIV-infected patients receiving cART. Interleukin-6 (IL-6) is a biomarker of inflammation and was found to be associated with all-cause mortality and cardiovascular diseases in the SMART study [Neuhaus J, J Infect Dis 2010]. Interferon-γ-inducible protein-10 (IP-10) and monokine induced by interferon-γ (MIG) are two chemokines produced by different cells and target lymphocytes, particularly activated T cells. Elevated plasma IP-10 levels during the primary phase of HIV-1 infection were predictive of earlier decline in the CD4 cell count in a recent study [Liovat AS, PLOS One 2012; Jiao Y, Viral Immunology 2012; N. Noel, IAS 2013]. Soluble CD14 (sCD14) is a marker of monocyte activation that binds to lipopolysaccharides in plasma. Plasma levels of sCD14 are an independent predictor of mortality among HIV-infected patients [D Sandler et al , JID 2011; E Krastinova, J Infect Dis. 2015] .