Oc 8405 identification of an mtb-specific soluble host signature for risk of development of active tb in hiv-positive mtb-exposed contacts

BackgroundWith 2 billion people infected with Mycobacterium tuberculosis (Mtb) worldwide, identification of those most at-risk of progressing to active disease would provide a targeted, cost-effective approach for preventative therapy strategies. The GC6–74 project recruited Mtb-exposed HIV-positive (HIV+) contacts from 5 African countries with the aim of identifying molecular and protein signatures for identification of ‘at-risk’ subjects by comparing those who progressed to active disease (progressors) to those who remained asymptomatic (controls).MethodsFor this arm of the project, we analysed longitudinal samples from 12 HIV +progressors and 28 HIV +matched controls from Uganda (Makerere University, MAK) and South Africa (Stellenbosch University, SUN). Diluted whole blood was stimulated for 7 days with 7 Mtb-specific antigens plus controls. Supernatant was collected and a 38-plex multiplex assay performed following identification of confirmed progressors and controls.ResultsThe median time to progression to active disease was 510 days for SUN and 425 days for MAK participants. Baseline CD4 counts were 163 cells/µl for progressors and 154 cells/µl for controls. Baseline responses showed significantly lower IL-4 production in progressors following ESAT-6/CFP-10 (EC) stimulation (p=0.0309) and significantly higher macrophage-derived chemokine (MDC) following both Rv3019 and TB10.4 stimulation. For the time-point closest to progression, IL-10 production following EC stimulation and IFN-γ production following Rv3019 stimulation were significantly higher in progressors than controls (p=0.0024 and p=0.0028 respectively). A combination of 12 analytes following EC and TB10.4 stimulation gave 84.4% and 91.1% correct classification respectively.ConclusionWe have defined a soluble signature for detecting likely progression to active TB in HIV +subjects 1 year prior to progression. Following validation in other cohorts, this could be exploited for development of a field-friendly test for targeted interventional therapy.