Vitamin D, d-dimer, Interferon γ, and sCD14 Levels are Independently Associated with Immune Reconstitution Inflammatory Syndrome: A Prospective, International Study

• We compared immunologic patterns in 267 AIDS patients in South Africa and Mexico based on IRIS development after starting ART
• Prior to starting ART, elevated markers of Th1 response, monocyte activation, coagulation and low vitamin D predicted IRIS
• Our results support future IRIS prevention studies that aim to decrease immune activation and increase vitamin D levelsOver 36 million people are now infected with HIV, and almost all reside in developing countries. HIV antiretroviral treatment saves lives by promoting immune system recovery. Unfortunately, treatment can cause a serious condition called immune reconstitution inflammatory syndrome (IRIS) in up to one-third of patients. Experts think IRIS results from unbalanced recovery of the immune system and it is difficult to predict which patients will develop it. We found that prior to starting treatment, low vitamin D and a unique immunological pattern predicted risk. Our results suggest that IRIS prevention studies should focus on decreasing inflammation and increasing vitamin D levels.

To determine the immunological profile most important for IRIS prediction, we evaluated 20 baseline plasma biomarkers in Acquired Immunodeficiency Syndrome (AIDS) patients initiating antiretroviral therapy (ART). Patients were enrolled in a randomized, placebo-controlled ART initiation trial in South Africa and Mexico to test whether maraviroc could prevent IRIS. Participants were classified prospectively as having IRIS within 6 months of ART initiation. Twenty plasma biomarkers were measured at study enrollment for 267 participants. Biomarkers were tested for predicting IRIS with adjustment for covariates chosen through forward stepwise selection. Sixty-two participants developed IRIS and of these 19 were tuberculosis (TB)-IRIS. Baseline levels of vitamin D and higher d-dimer, interferon gamma (IFNγ), and sCD14 were independently associated with risk of IRIS in multivariate analyses. TB-IRIS cases exhibited a distinct biosignature from IRIS related to other pathogens, with increased levels of C-reactive protein (CRP), sCD14, IFNγ, and lower levels of Hb that could be captured by a composite risk score. Elevated markers of Type 1 T helper (Th1) response, monocyte activation, coagulation and low vitamin D were independently associated with IRIS risk. Interventions that decrease immune activation and increase vitamin D levels warrant further study.