Validation of Transcriptional Signature to Predict Active TB Disease among Advanced HIV Patients

This study was terminated June 20, 2021.

There have been tremendous advances in the diagnosis of patients with tuberculosis (TB) based on nucleic acid amplification of bacteria in the sputum. The GenXpert MTB/RIF provides results in 2 hours. However, in HIV-infected sputum smear is often negative for AFB and the sensitivity of GenXpert MTB/RIF is only 67%. TB cases with advanced HIV are at double jeopardy. They are likely to have smear negative or extrapulmonary TB so diagnosis based on sputum is problematic. Second prompt and proper diagnosis of TB is urgent as immediate institution of antiretroviral therapy may be life-saving. In preliminary studies we performed a case-control analysis of whole blood RNAseq in 16 HIV-infected participants with smear (+) or microbiologically confirmed TB (TB-HIV), 15 HIV-infected participants (HIV) that had no clinical symptoms of TB and 2 TB-HIV participants on ART (unmasked TB) were studied. The study subjects had a CD4+ T cell count <100 cells/µl.

Hierarchical clustering of the transcriptional profiles showed that, in general, HIV-infected individuals with TB (TB-HIV) clustered separately (Cluster 1) from those without TB (Cluster 2).Ingenuity Pathway Analysis and blood transcriptional modular analysis indicated that the TB-HIV signature was characterized by an increase in transcripts belonging to inflammatory signaling pathways and did not overlap with published TB signatures. A prediction model of the differentially expressed genes in Cluster 1 and Cluster 2 provided a 15 gene biomarker set.

In conclusion, this study found a blood transcriptional and cytokine signature of prevalent TB in advanced HIV. Additional discovery and validation studies are still needed to obtain a TB risk signature in HIV-infected with advanced disease who have the highest risk of progressing to TB disease. Therefore the goal of the present application between RePORT Brazil and RePORT India is to conduct a case/control study in HIV participants (asymtomatic patients) with and without TB to test and validate the 15 gene TB signature of active TB in severely immunosuppressed TB-HIV participants prior to initiation of TB treatment.

Objectives

1. 
   To conduct testing and validation of the 15-gene signature to predict active TB disease among advanced HIV patients with CD4 <100 cells/ ml 
2. 
   To assess and compare the cytokine/chemokine signature that may be predictive for active TB among advanced TB-HIV and HIV patients in India and Brazil.