Precision targeting of preventative therapy for tuberculosis

Background: Scale-up of preventative treatment for tuberculosis (TB) represents a cornerstone of global control efforts. I examined a range of approaches to enable more precise targeting of preventative treatment to people at highest risk. Methods: I evaluated whether prognostic tests for TB (tuberculin skin test (TST), QuantiFERON Gold-in-tube (QFT-GIT) and T-SPOT.TB) may be optimised by implementing higher thresholds, or by a newer generation assay (QuantiFERON-TB Gold Plus; QFT-Plus). Next, I conducted a systematic review and individual participant data meta-analysis (IPD-MA) to examine TB risk among people tested for latent infection (LTBI) in settings with low TB transmission and to develop a multivariable prognostic model for incident TB. Finally, I performed a systematic review and IPD-MA of whole-blood RNA sequencing data to evaluate blood transcriptomic signatures as next-generation biomarkers. Results: In a UK cohort of 9,610 adults, higher TST, QFT-GIT and T-SPOT.TB results were associated with increased incident TB risk. Implementing higher cut-offs led to a marginal improvement in positive predictive value, but at the cost of a marked loss in sensitivity. The newer generation QFT-Plus had similar ... (continues)