Elevated Interleukin 8 and T-Helper 1 and T-Helper 17 Cytokine Levels Prior to Antiretroviral Therapy in Participants Who Developed Immune Reconstitution Inflammatory Syndrome During ACTG A5164

Potent combination antiretroviral therapy (ART) has dramatically reduced morbidity and mortality associated with human immunodeficiency virus (HIV), but its use can be complicated by immune reconstitution inflammatory syndrome (IRIS) [1]. Although no uniform definition exists, the diagnosis of IRIS requires the worsening of a recognized (“paradoxical” IRIS) or unrecognized (“unmasking” IRIS) preexisting infection in the setting of successful HIV suppression and improving immunologic function. IRIS has been reported in 3%–40% of patients initiating ART [2–6], with the wide range in reported incidence likely reflecting differences in case definitions and in the patient populations studied. The immunopathogenesis of IRIS remains poorly understood, but the prevailing view is that IRIS reflects the atypical restoration of pathogen-specific immune response to microbial antigens [7]. Although there may be differences between paradoxical and unmasking IRIS and according to target antigen, some aspects of IRIS pathogenesis are likely shared among all IRIS events. For example, markers of antigen-presenting cell activation such as interleukin (IL) 6 have been found to be elevated prior to the development of IRIS to Mycobacterium tuberculosis, cryptococcus, and herpesviruses [8–10]. Although IRIS generally does not portend an unfavorable long-term prognosis, the development of IRIS may lead to hospitalization, the need for invasive diagnostic and therapeutic procedures, or occasionally death [11]. Identifying biomarkers that predict the development of IRIS could lead to strategies to improve its diagnosis and reduce its incidence and associated morbidity and mortality. Although corticosteroids are frequently used to treat severe IRIS [12], the effects of corticosteroids on cytokine levels and the development of IRIS have not been studied to date. In this study, we compared levels of biomarkers and T-cell subsets prior to and at the time of IRIS (or a matched time point) between participants who developed IRIS and controls as well as the effect of corticosteroids on these biomarkers during a randomized trial examining the optimal timing of ART during an acute opportunistic infection (OI).