Utility of MODS for Diagnosis of MDR-TB and Second-Line Antituberculous Drug Susceptibility Testing in Mali

Approximately one-third of the world s population is infected with tuberculosis (TB), and
over 1 million deaths occur annually worldwide because of it (1,2). Accurate diagnosis and TB
drug susceptibility testing is necessary to treat the infection appropriately and bring this
epidemic under control. Inappropriate treatment of TB, on the other hand, has led to the
recent spread in multidrug-resistant TB (MDR-TB), estimated to affect over half of million
people worldwide (2,4,5). Sputum smear microscopy, the diagnostic method commonly used in
developing countries, is not as sensitive at detecting TB as culture-based techniques
utilized in developed countries. Furthermore, drug-susceptibility testing is not routinely
performed in resource-limited settings. Consequently, many individuals with TB in developing
countries are treated with inadequate regimens, and MDR-TB continues to spread.

The microscopic-observation drug-sensitivity (MODS) assay has been recently developed for
rapid diagnosis of TB and simultaneous detection of resistance to first-line TB medications
in resource-limited settings (11). MODS has been shown to be as sensitive as traditional
culturebased methods for the detection of TB, providing results for drug susceptibility
testing that are highly concordant with standard techniques (10).

We propose to study the utility of the MODS assay for the diagnosis of TB in subjects who are
sputum-smear positive or sputum-smear negative, and those with chronic TB. Susceptibility
testing will be performed for first-line antituberculous drugs and, subsequently, second-line
drugs, if subjects are found to have MDR-TB. The first primary objective is to calculate the
sensitivity of detection of the MODS assay, compared with the Middlebrook culture method, in
subjects suspected of having TB who are sputum-smear positive by microscopy. The second
primary objective is to calculate the concordance of drug-susceptibility testing between the
MODS assay and the agar proportion method for subjects who are sputum-smear positive,
sputum-smear negative, or diagnosed with chronic TB.

Secondary objectives include evaluating the utility of the MODS assay in the diagnosis of TB
in subjects who are sputum-smear negative and those with chronic TB, the performance of
second-line drug-susceptibility testing using the MODS assay in subjects diagnosed with
MDRTB, the utility of the MODS assay in the diagnosis of TB in subjects coinfected with human
immunodeficiency virus (HIV)-1 or -2, and the ability of the MODS assay to identify
nontuberculous mycobacteria in subjects harboring these organisms.

- INCLUSION CRITERIA:

Individuals (12 years of age) who meet the following criteria are eligible for enrollment
in the study:

Have a sputum smear that is positive for acid-fast bacilli by microscopy or have clinical
symptoms and abnormal findings compatible with active TB on a previously performed chest
radiograph.

Have either completed at least 5 months of treatment with antituberculous therapy within
the past year or have not received any antituberculous treatment in the preceding 5 years.

Willingness to provide a sputum sample for the study.

Ability to follow verbal instructions for producing sputum.

Willingness to undergo testing for HIV.

Willingness to allow storage of samples for future research.

EXCLUSION CRITERIA:

Subjects who meet any of the following criteria are not eligible for enrollment in the
study:

Any condition that in the investigator s opinion places the subject at undue risk by
participating in the study.

Subjects younger than 12 years of age will be excluded from the study due to the difficulty
of obtaining adequate sputum samples for the diagnosis of TB in this population and because
there are no means for obtaining gastric aspirates at the reference centers.