Higher Levels of CRP, D-dimer, IL-6, and Hyaluronic Acid Before Initiation of Antiretroviral Therapy (ART) Are Associated With Increased Risk of AIDS or Death

Antiretroviral therapy (ART) has substantially reduced morbidity and mortality in human immunodeficiency virus (HIV)-infected persons [1–4]. Yet even with adequate HIV virologic suppression, substantial morbidity and mortality still occurs during the first year of ART as a result of immune reconstitution inflammatory syndrome (IRIS), progression of preexisting or new infections, toxic effects of medication, or noninfectious events [5–9]. Although many studies have confirmed persistently high morbidity and mortality during the first year and particularly the first 6 months of ART, identifying patients prior to starting ART who are at high subsequent risk remains a clinical challenge. Certain clinical variables, such as hemoglobin level, preexisting AIDS-defining illness, CD4 T-cell count, and injection drug use, have been identified as predictors of morbidity or mortality in the first months after ART initiation [10–13]. Biomarkers could also be important in guiding intense monitoring of selected subgroups of high-risk patients and could be used to elucidate pathogenesis pathways amenable to targeted therapeutic interventions. Data from the Strategies for the Management of Antiretroviral Therapy (SMART) study have shown that elevated levels of interleukin 6 (IL-6), D-dimer, and C-reactive protein (CRP) are strong predictors of all-cause mortality [14]. More recently using SMART samples, sCD14, a marker of monocyte activation, was also associated with mortality [15]. In another SMART nested case-control study focusing on AIDS events, elevated CRP and IL-6 levels at baseline and proximal to the event were significant predictors [16]. The majority of participants in SMART were receiving ART, and it is unclear whether the same markers would have similar predictive value among people starting ART for the first time. In a small study of ART-naive patients starting therapy, pre-ART CRP and D-dimer levels also showed promise as predictors of IRIS [17]. We hypothesized that biomarkers can be used to identify persons at high risk for clinical events who may require closer monitoring upon ART initiation. We sought to determine whether inflammatory, coagulation, and tissue fibrosis markers could predict AIDS or death. Secondarily, we assessed whether any biomarkers were predictive of future IRIS events. We focused on biomarkers identified in the SMART study [16], as well as inflammatory biomarkers hypothesized as related to IRIS pathogenesis, including type-1 T-helper (Th1) and inflammatory cytokines and chemokines [18]. To that end, we conducted a nested case-control study using samples from a clinical trial of first-line ART (the Flexible Initial Retrovirus Suppression Therapies [FIRST] trial) [8].