Rapid Molecular Test Detects Tuberculosis and Rifampin Resistance

Laurie Barclay, MD

September 02, 2010

September 2, 2010 — A rapid molecular test for sputum (Xpert MTB/RIF; Cepheid) detects tuberculosis and rifampin resistance, according to the results of a study reported online September 1 in the New England Journal of Medicine.

"Global control of tuberculosis is hampered by slow, insensitive diagnostic methods, particularly for the detection of drug-resistant forms and in patients with human immunodeficiency virus infection," write Catharina C. Boehme, MD, from the Foundation for Innovative New Diagnostics in Geneva, Switzerland, and colleagues. "Early detection is essential to reduce the death rate and interrupt transmission, but the complexity and infrastructure needs of sensitive methods limit their accessibility and effect."

In this study, 1730 patients from Peru, Azerbaijan, South Africa, and India with suspected drug-sensitive or multidrug-resistant pulmonary tuberculosis were tested with MTB/RIF, an automated molecular test for Mycobacterium tuberculosis (MTB) and rifampin resistance (RIF). Each patient provided 3 specimens, 2 of which were processed with N-acetyl-L-cysteine and sodium hydroxide before microscopy, solid and liquid culture, and the MTB/RIF test, and 1 of which was tested directly with microscopy and the MTB/RIF test.

For patients with positive tuberculosis culture, a single MTB/RIF test was positive in 551 of 561 patients (98.2%) with positive smear for tuberculosis and was negative in 124 of 171 patients (72.5%) with negative smear. Specificity of the MTB/RIF test in patients without tuberculosis was 99.2% (604/609 patients).

For patients with positive tuberculosis culture but negative smear, adding a second MTB/RIF test increased sensitivity by 12.6 percentage points, and adding a third increased sensitivity by 5.1 percentage points — improving sensitivity to 90.2%.

MTB/RIF testing correctly identified 200 of 205 patients (97.6%) with rifampin-resistant bacteria and 504 of 518 patients (98.1%) with rifampin-sensitive bacteria, based on phenotypic drug-susceptibility testing. Sequencing resolved all but 2 cases in favor of the MTB/RIF test.

"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," the study authors write.

Limitations of this study include a possible lack of generalizability to settings with less controlled conditions, and the high costs of the manufacturing technology needed for the MTB/RIF test.

In an accompanying editorial, Peter M. Small, MD, from the Global Health Program, Bill and Melinda Gates Foundation, and the Institute for Systems Biology in Seattle, Washington, and Madhukar Pai, MD, from McGill University and the Montreal Chest Institute in Montreal, Canada, note the challenges involved in ensuring availability of the MTB/RIF test and similar technology.

"Emerging economies have the potential to become global leaders in innovative product development and delivery," Dr. Small and Dr. Pai write. "If these countries successfully tackle their own tuberculosis problems, the elimination of tuberculosis by 2050 might become a reality."

The Foundation for Innovative New Diagnostics, the National Institutes of Health, and the Bill and Melinda Gates Foundation supported this study. Several study authors have disclosed receiving reimbursement from the Foundation for Innovative New Diagnostics and/or from the National Institute of Allergy and Infectious Diseases in the form of individual and/or institutional grants, travel support, honoraria, and/or consultancy fees. Several authors also disclose serving as board members or employees for and/or receiving stock options, travel support, and/or grant funding from Cepheid. Dr. Small was a founding board member of the Foundation for Innovative New Diagnostics, is an employee of the Bill and Melinda Gates Foundation, and owns stock or stock options in Johnson & Johnson.

N Engl J Med. Published online September 1, 2010.

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