Can a fourth-generation interferon gamma release assay predict progression to TB disease?

Introduction: Tuberculosis (TB) is one of the leading causes of death from a single infectious agent - Mycobacterium tuberculosis (Mtb). A key aspect of TB control is the provision of TB Preventative Therapy (TPT) to prevent to progress to disease. Identification of those with Mtb infection who will progress to disease will aid in prioritising those who would maximally benefit from TPT. Literary evidence shows TB is more likely to develop in the first few years after infection, that is those recently infected are more likely to progress to disease as compared to those more remotely infected. Of the TBI tests, none have a high predictive value for progression to disease. One of these tests, a fourth-generation interferon gamma release assay the QuantiFERON-TB Plus (QFT-Plus) is reported to have a role in detecting recent infection and possibly in predicting progression to disease. We aimed to establish whether the QFT-Plus assay can provide evidence for progression from TB infection to disease.

Methods: The studies in this thesis were nested in a study in Zambia and South Africa where the incidence of TB infection was measured by QFT-Plus positivity in a cohort of adolescents and young people aged 15-24 years, followed up for two years. This thesis focused on exploring both qualitative and quantitative results of the assay (the responses of the QFT-Plus Mtb specific antigen tubes TB1 and TB2) to elucidate any potential signals of progression to TB disease in a TB/HIV endemic region. A series of studies were undertaken to explore this including a systematic review of the ability of QFT-Plus to distinguish recent from remote TBI, a cross-sectional study of the baseline prevalence of TBI determined by QFT-Plus positivity in AYP, a cohort analysis of QFT-Plus patterns in recent and remote infection, and evaluation of progression to disease of the cohort.

Results: A total of 4648 AYP were enrolled into the cohort, with valid QFT-Plus results available for 4529: 1977-South Africa and 2552-Zambia. Overall cohort baseline prevalence of infection measured by QFT-Plus was 47.6%. Disaggregated TBI prevalence by country showed South Africa had double the prevalence of Zambia (64.7% vs 34.3%, p<0.001). Of those QFT-Plus positive at baseline, 57.7% remained persistently positive at the 12- and 24-month visits (remote infection). Of those QFT-Plus negative at baseline, 13.3% converted within a 12-month period (recent infection). The quantitative QFT-Plus results were not markedly different in recent and remote infection. TB1 and TB2 responses were greater in remote than recent infection. In recent infection, TB2 responses were greater than TB1 responses. The TB incident rate ratio (IRR) of converters (recently infected) compared to those who those persistently negative was 10.49 (95% CI3.43-32.08), p<0.001. The IRR of those persistently positive (remotely infected) compared to persistently negative was 5.89 (95% CI 2.21-15.39), p<0.001. The TB incidence rate of those recently infected (converters) was 1.80 times higher than the incidence rate of those who were persistently positive (remotely infected), though there was insufficient evidence of a significant difference (95% CI 0.80-4.04), p=0.154.

Conclusion: Our data suggests the qualitative QFT-Plus assay results may be a predictor of progression to disease. There is however insufficient evidence that thequantitative results of the assay may be able to discriminate between recent and remote infection in high TB burden settings.