R01AI170158

Determining the Performance and Accuracy of Silvamp TB LAM and Cost-Effectiveness of Diagnostic Testing for TB Meningitis - Project Summary

Tuberculous meningitis (TBM) is the second most common cause of meningitis in sub-Saharan Africa. Neurologic disability and mortality are common, with mortality rates of at least 50% in people with HIV. TBM diagnosis remains difficult, and diagnostic delay or missed diagnosis are major contributors to poor outcomes.

Acid fast bacilli smear of cerebrospinal fluid (CSF) is cheap and fast but has a sensitivity of only around 10% in most settings. CSF culture has improved sensitivity (approximately 50-60%) but is slow, taking up to six weeks. Our studies on GeneXpert MTB/RIF and the re-engineered GeneXpert MTB/RIF Ultra have shown improved sensitivity (50-80%) with these rapid tests that provide results in about two hours. However, these tests have inadequate negative predictive value to rule out TBM, require expensive instruments and cartridges, and their availability is inconsistent in areas with the highest TB incidence. Therefore, alternative or additional tests for TBM are crucial needs to improve outcomes.

A previous lipoarabinomannan (LAM) antigen test (Alere) had only around 20% sensitivity in CSF. Our study of the Silvamp TB LAM (Fujilam) assay in CSF found 52% sensitivity in definite or probable TBM compared to 55% for Xpert Ultra. However, this study was small and requires confirmation. Of the 58 cases of definite or probable TBM, six were positive by Fujilam but not Xpert Ultra, and eight were positive by Xpert Ultra but not Fujilam. This study was unable to systematically and thoroughly address cases that were possibly false by Fujilam. Furthermore, formal cost-benefit analysis for this test, and other important tests for TBM, has not been done. Given that cost remains a major limitation in accessing TB diagnostic tests, the lack of research in this area is problematic.

Our overall objective is to reduce mortality and morbidity due to TBM by improving diagnostic accuracy, rapidity, and cost-effectiveness. To accomplish these objectives, the aims of this proposal are to:

1) Determine the accuracy of Silvamp TB LAM (Fujilam) in CSF to diagnose TBM in comparison to uniform TBM case definitions.
2) Determine whether positive Silvamp TB LAM (Fujilam) tests without corroboration by other TBM tests are false or true positives, using autopsy and metagenomics next-generation sequencing.
3) Determine the cost and cost-effectiveness of TBM diagnostic testing strategies, including Fujilam and GeneXpert MTB/RIF Ultra.

The first two aims focus on better defining the diagnostic accuracy of Fujilam, an easy-to-use, rapid test that requires limited technological infrastructure or expertise. The third aim focuses on the cost-effectiveness of this test and other commonly used tests. These studies will impact clinical practice by better informing our understanding of the diagnostic tools for TBM.

This proposal has the potential to shift the paradigm of TBM diagnosis to two rapid tests, Fujilam and Xpert Ultra, influencing international WHO guidelines while providing valuable costing data for stakeholders and ministries of health to consider investment and implementation.

Regents Of The University Of Minnesota

NOT APPLICABLE

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Minneapolis, Minnesota 554551507 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 400% from $663,516 to $3,316,315.