Sputum M. tuberculosis DNA Kinetics during TB Treatment in Patients with HIV
The WHO estimates that 1.7 million people died of tuberculosis (TB) in 2009 and that 22% of those deaths occurred in people with HIV. HIV infection drove the 80% increase in TB cases in sub-Saharan over the last decade; the number of deaths and cases of drug resistance has also increased markedly.1 TB treatment's duration - at least 6-8 months for drug-sensitive disease - makes it challenging to complete in low-income countries. Research shows that intermittent or shortened TB therapy in patients with HIV leads to poor outcomes. 2 A reliable marker of treatment response could improve clinical decision-making, identifying patients likely to fail early and minimizing the development of drug resistance. In addition, and perhaps more importantly, it could speed the development of more potent drug combinations that would shorten therapy. Both advances are critical to the control of the HIV and TB co-epidemics. A simple test to assess TB treatment response is urgently needed. The Cepheid GeneXpert nucleic acid amplification system may serve this purpose. It 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.3 The GeneXpert (GX) is a fully automated, self-contained device that offers a simple way to quantify the amount Mycobacterium tuberculosis (MTB) DNA in a sputum specimen by targeting the rpoB gene for amplification with quantitative polymerase chain reaction (QPCR). Therefore, we propose to evaluate the use of GX-based QPCR to assess TB treatment response. Our overall hypothesis is that differences in the rate of MTB DNA clearance from sputum will predict sputum culture status after 2 months of treatment. To test this hypothesis, we will first describe the changes over time in sputum MTB DNA quantity, measured by GX-based QPCR, in a small group of HIV-positive patients with pulmonary TB (Specific Aim 1). Using this descriptive data, we will conduct an analysis to determine the three (3) time points at which measurements must be made in order to accurately represent quantitative DNA changes. The purpose is to find the most efficient sampling method. Finally, we will measure sputum MTB DNA by QPCR with the more limited sampling method in a larger group of patients in order to identify the group of patients with a greater likelihood of positive cultures after two months of treatment (Specific Aim 2). These are the first steps in defining the utility of this new test for assessing TB treatment response; they will lead directly to additional studies to evaluate its predictive accuracy for clinical outcomes. The proposed research fits squarely within NIAID's stated mission to support the "discovery, development, and optimization of therapies and treatment strategies for HIV infection and its complications and co-infections."
Public Health Relevance Statement:
Tuberculosis (TB) is the most common cause of death among people with HIV and AIDS in sub-Saharan Africa. Two major problems facing TB treatment are that it takes 6-8 months to complete, even with drug- sensitive disease, and treatment completion does not rule out the possibility of recurrence. TB drug trials seek to identify more potent drug regimens that could shorten treatment duration and, thereby, increase treatment completion and success; but they are inefficient because they must follow study subjects for so long. A simple, accessible test to accurately assess response early in the course of TB treatment would speed up clinical decision-making by months to years, while at the same time helping researchers shorten drug trials and bring new, more powerful drugs to market faster. This project proposes a preliminary study to evaluate a new test of TB treatment response.