Biomarkers of immune restoration disease in HIV patients after they commence antiretroviral therapy

[Truncated abstract] Initiation of antiretroviral therapy (ART) in HIV patients may result in the restoration of pathogen-specific immune responses which cause immunopathology. This clinical phenomenon is referred to as immune restoration disease (IRD) and can occur in response to a variety of pathogens. Immune restoration disease associated with Mycobacterium tuberculosis (TB-IRD) is the most common form of IRD and presents as tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS), in which there is a paradoxical worsening of treated tuberculosis (TB) in HIV patients who commence ART while receiving anti-TB therapy. Tuberculosis also presents more frequently during the first three months of ART (ART-associated tuberculosis [ARTTB]) and some cases exhibit an atypical inflammatory response similar to TB-IRIS. This ‘unmasking’ of unrecognised TB may also be a form of IRD in most, if not all, patients. In the first part of my thesis, I investigated whether assessment of plasma biomarkers may elucidate more about the immunopathogenesis, prediction and diagnosis of TBIRD within a cohort of HIV patients from Cambodia, of whom 15 developed TB-IRIS and 11 developed ART-TB. Levels of cytokines and chemokines important in the immune response against M. tuberculosis were assayed in unstimulated plasma from a whole blood interferon-γ (IFN-γ) release assay (IGRA). TB-IRIS was associated with perturbations of inflammatory mediators produced by cells of the innate immune system, while ART-TB was associated with elevated levels of IL-18. Using ROC analyses, pre-ART levels of IL-18, CCL2 and CXCL10 were strongly predictive of TBIRIS (Chapter 2).