Mentored Scientist Award

Tuberculosis (TB) is the leading cause of death in HIV-infected people in sub-Saharan Africa. Intermittent or shortened TB therapy in patients with HIV leads to poor outcomes, but the duration of TB therapy - 6-8 months for drug-sensitive disease - makes it logistically challenging in low-income countries. A reliable marker of TB treatment response could improve outcomes by identifying patients likely to fail or develop drug resistance early. In addition, it could speed the development of more potent drug combinations that would shorten therapy. The Cepheid GeneXpert (GX) - a newly-available, fully-automated, nucleic acid amplification system that uses quantitative polymerase chain reaction (QPCR) to identify Mycobacterium tuberculosis (MTB) DNA in sputum - has been shown to be accurate for TB diagnosis in low-income settings, but its role in the assessment of TB treatment response has not yet been explored. Therefore, we plan to evaluate the use of GX-based QPCR to assess TB treatment response in a prospective cohort of HIV-infected individuals initiating standard 4-drug TB therapy in Kampala, Uganda. The study has the following objectives: 1) to describe the kinetics of sputum MTB DNA clearance following TB treatment initiation using multiple repeated GX measures; 2) to identify 2 sampling time points ("minimum sampling frame") that accurately represent those kinetics; and 3) to use the minimum sampling frame to determine the association between the rate of sputum MTB DNA clearance and 2-month sputum culture positivity. Patients will be enrolled over the course of one year. The study will provide early data on this novel use of the GeneXpert and lead to future studies investigating the utility of widespread GX-based QPCR for monitoring treatment response in usual care settings, as well as to predict treatment failure or relapse and to monitor the emergence of rifampin resistance during treatment.