By Ben Butkus
The National Institutes of Health has awarded researchers from the University of North Carolina at Chapel Hill nearly $600,000 for the first year of a three-year project to investigate treatment outcomes of South African drug-resistant tuberculosis patients diagnosed with Cepheid's Xpert MTB/RIF assay.
According to the researchers, the evidence gathered during the study is expected to contribute to the successful implementation of Cepheid's assay into routine practice in resource-limited countries with a high TB/HIV burden.
Annelies Van Rie, an associate professor of epidemiology at the UNC Gillings School of Global Public Health, is leading the project, funding for which is being administered by the National Institute of Allergy and Infectious Diseases.
According to the World Health Organization, there were an estimated 8.8 million cases of TB and 1.4 million deaths from the disease in 2010, with over 95 percent of those deaths occurring in low- and middle-income countries. Furthermore, multidrug-resistant TB — defined as resistance to at least isoniazid and rifampicin — is present in virtually all of these countries and poses an important threat to TB control.
The fight against TB has been particularly challenging in resource-limited settings, where there is a dearth of laboratory capacity for traditional Mycobacterium tuberculosis culture and drug susceptibility testing. As such, in 2008, only 7 percent of the estimated 440,000 multidrug-resistant TB cases worldwide were detected, according to the researchers.
Cepheid's Xpert MTB/RIF, which the company launched in 2009, is a PCR-based diagnostic that runs on the company's benchtop GeneXpert system and simultaneously detects M. tuberculosis and rifampicin resistance within two hours.
Multiple studies have shown that Xpert MTB/RIF has equivalent or superior sensitivity and specificity to traditional culture-based methods for detecting M. tuberculosis and rifampicin resistance, and have supported the idea of using the test for rapid, point-of-care diagnosis of the bacterium in resource-poor areas of the world (PCR Insider 9/2/2010 and 4/21/2011).
In addition, in December 2010 WHO recommended Xpert MTB/RIF as the initial test in those suspected of MDR-TB or HIV-associated TB.
However, according to Van Rie and colleagues, while rapid diagnosis of rifampicin resistance could be a major weapon in the fight against MDR-TB, it will only result in improved patient outcomes if the rapid diagnosis is linked to rapid access to optimal treatment. To ensure the latter and to avoid resistance amplification, knowledge of the complete resistance profile is required.
"The question really is: Does it have an impact at the patient level?" Van Rie told PCR Insider this week. "The assay has been promoted that it will revolutionize the care of people with drug-resistant TB. And that has to be proven, because there are many steps following the diagnosis of MDR-TB."
According to Van Rie, if somebody in a more industrialized nation is diagnosed with multi-drug-resistant TB, "it is rather obvious that they will get the right treatment relatively soon after the diagnosis."
Not so for resource-poor areas of the world, where there exists "a scarcity of drugs and healthcare workers that are familiar with providing these drugs. So if you decentralize the diagnosis of drug-resistant TB, now the patients are faced with a diagnosis … by a healthcare worker [who] is not used to making that diagnosis, and has not received training in how to provide these drugs … or often doesn't have access to these drugs."
The UNC study is concerned with the fate of these patients, who should and likely will be referred for treatment. "Referring a patient doesn't mean that two hours later he's at the place where he needs to be," Van Rie said. "There may be quite a few hours of travel involved, it may be costly, and so on. The question really is to what degree does having access to this rapid diagnosis of drug-resistant TB improve outcome of these individuals with drug-resistant TB? And then [we can] identify the hurdles so that we can make progress and actually optimize the outcome."
To that end, the group plans to comprehensively characterize phenotypic and genotypic resistance profiles of nearly 500 patients with rifampicin-resistant TB. Van Rie and colleagues plan to document treatment decisions made in this cohort and compare outcomes of 237 patients diagnosed with Xpert MTB/RIF and 237 patients diagnosed using culture-based methods over the first six months of treatment.
"We are doing this in tandem with the rollout of Xpert MTB-RIF in South Africa," Van Rie said. "So we first selected laboratories where they do culture-based diagnosis and do not yet have the Xpert instrument, and we are currently enrolling patients who were diagnosed with a culture-based drug susceptibility method. Then when the laboratories switch to Xpert, we will follow subsequent patients who were diagnosed with Xpert."
Defined outcomes will include survival, acquisition of additional resistance, drug toxicity, and time to culture conversion.
The overarching goal of the research is "to change the current paradigm for screening, diagnosis, and treatment of MDR-TB by building a robust knowledge base on the resistance profiles of patients diagnosed with rifampicin-resistant TB on Xpert MTB/RIF," according to the grant's abstract.
The research may also have implications for the adoption of rapid, point-of-care testing for other diseases in the developing world — an issue whose importance only stands to increase due to the rapid development of molecular testing methods.
Some results from these tests are very similar to the types of results that clinicians in these parts of the world are used to dealing with. "For example, for CD4 counts [in HIV patient management], whether you get the result immediately or two days later, it doesn't really change how you approach it," Van Rie said.
However, for more revolutionary molecular point-of-care tests like Cepheid's, the necessary infrastructure may not yet exist. "Point-of-care testing is a good evolution, but it places a lot of demands on clinics where the expertise does not yet exist … in using these instruments, managing the instruments, and what to do with the results," Van Rie said.
Cepheid is not participating in the study, Van Rie said.
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