Tuberculosis

New Tuberculosis Test Enables Faster Diagnosis and Accurate Identification of Drug Resistance

Researchers have developed a new molecular test -- known as Xpert MTB/RIF -- that can quickly and accurately diagnose tuberculosis (TB) and show whether an individual carries drug-resistant TB strains. As described in the September 9, 2010 New England Journal of Medicine, a study of more than 1700 people with suspected infection found that the new test successfully identified 98% of all confirmed TB cases and 98% of patients with rifampin-resistant bacteria in less than 2 hours.

Catharina Boehme from the Foundation for Innovative New Diagnostics in Geneva and an international team of colleagues evaluated the new MTB/RIF assay, a fully automated test developed by a public-private research partnership that uses real-time polymerase chain reaction technology to sequence the Mycobacterium tuberculosisrpoB gene. The test is designed to detect TB cases and show whether bacteria are resistant to rifampin, a widely used TB drug.

Only a small fraction of the estimated 500,000 people with multidrug-resistant tuberculosis and 1.37 million people coinfected with TB and HIV each year have access to tests that are sufficiently sensitive to detect all cases or determine drug susceptibility, the study authors noted as background. TB is usually diagnosed by detecting bacteria in samples or "smears" of sputum (fluid and mucus from the lungs and bronchial tubes) examined under a microscope, and by growing bacteria in laboratory cultures. Missed diagnosis of "smear-negative" TB contributes to additional disease transmission, delayed treatment, and increased mortality.

Between July 2008 and March 2009, the investigators looked at a total of 1730 people with suspected drug-sensitive or multidrug-resistant pulmonary tuberculosis at 5 trial sites in Baku, Azerbaijan; Cape Town and Durban, South Africa; Lima, Peru; and Mumbai, India. Participants were drawn from populations selected for their diverse range of TB prevalence, HIV coinfection, and multidrug resistance.

All participants were adults with symptoms suggesting pulmonary TB or multidrug-resistant TB who provided 3 adequate sputum samples. People at risk for pulmonary TB were eligible only if they had not taken TB medications during the past 2 months. The group considered at risk for multidrug-resistant TB included some patients who had undergone previous treatment, some currently receiving treatment, and contacts of individuals with known multidrug-resistant TB.

Results

• Of the 1462 patients (4386 samples) included in the final analysis:
  • 567 (38.8%) had smear-positive and culture-positive TB;
  • 174 (11.9%) had smear-negative but culture-positive TB;
  • 105 (7.2%) had clinically defined TB;
  • 616 (42.1%) had no clinical evidence of tuberculosis.
• Among patients with culture-positive samples, 207 of 741 (27.9%) were found to have multidrug resistance using conventional drug-susceptibility testing.
• Within the culture-positive group, a single MTB/RIF test identified 551 out of 561 patients (98.2%) with smear-positive TB and 124 out of 171 patients (72.5%) with smear-negative TB.
• Among the subset of patients with culture-positive but smear-negative TB, adding a second MTB/RIF test increased sensitivity by 12.6% and a third test raised it another 5.1%, reaching a total of 90.2%.
• The test had 99.2% specificity, meaning it correctly identified 604 out of 609 patients without tuberculosis.
• Compared with phenotypic drug-susceptibility testing (exposing TB to drugs in the laboratory to see which ones are active), MTB/RIF correctly identified 200 out of 205 patients (97.6%) with rifampin-resistant bacteria and 504 out of 514 (98.1%) with rifampin-sensitive bacteria.

Based on these findings, the investigators concluded, "The MTB/RIF test provided sensitive detection of tuberculosis and rifampin resistance directly from untreated sputum in less than 2 hours with minimal hands-on time."

"In our study, an assay that was designed for point-of-treatment use in low-income countries accurately detected pulmonary tuberculosis and screened for rifampin resistance," they elaborated in their discussion. "Performance both for case detection and discrimination of rifampin resistance was similar across diverse sites, suggesting that the findings are likely to be widely applicable."

In an accompanying editorial, however, Peter Small from the Bill and Melinda Gates Foundation and Madhukar Pai from McGill University pointed out some issues that may limit global use of the new test, including its high cost, testing only for resistance to rifampin and not other TB drugs, and inability to indicate which patients are " smear-positive" for public health reporting and treatment monitoring.

"As with any diagnostic test or intervention, its actual impact will depend on the system in which it is used," they wrote. "Health systems must be strengthened so that patients do not delay in seeking care and have prompt access to appropriate treatment once they receive a diagnosis...Despite these challenges, it is clear that improvements in diagnostics are driving a virtuous cycle in care: the promise of improved tests drives their uptake, their uptake results in better health outcomes, improved outcomes attract more funding for health care systems, and better-funded systems are an incentive to the development of even better technologies."

Investigator affiliations: Foundation for Innovative New Diagnostics, Geneva; Forschungszentrum Borstel, Borstel, Germany; Department of Clinical Laboratory Sciences, University of Cape Town, and National Health Laboratory Service, Cape Town, and the Unit for Clinical and Biomedical TB Research, South African Medical Research Council, Durban, South Africa; P.D. Hinduja National Hospital and Medical Research Centre (Hinduja), Mumbai, India; Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Per; Special Treatment Institution, Baku, Azerbaijan; Division of Infectious Diseases, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ; Cepheid, Sunnyvale, CA; Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC.

9/10/10

References

CC Boehme, P Nabeta, D Hillemann, and others. Rapid Molecular Detection of Tuberculosis and Rifampin Resistance. New England Journal of Medicine. 363: 1005-1015 (Free full text). September 9, 2010.

PM Small and M Pai. Tuberculosis Diagnosis -- Time for a Game Change (Editorial). New England Journal of Medicine. 363: 1070-1071 (Free full text). September 9, 2010.

Other Source

National Institutes of Health. New TB Diagnostic Proves Effective, Expedient, Study Finds. NIH News. September 1, 2010.