Point of care testing

Detecting drug-resistant tuberculosis: the importance of rapid testing

Hoek KG, Van Rie A, van Helden PD, Warren RM, Victor TC, Mol Diagn Ther. 2011 Aug 1;15(4):189-94. doi: 10.2165/11593780-000000000-00000

Despite numerous intervention strategies, including the direct observed short-course treatment strategy and improved diagnostic methods, the incidence of multidrug-resistant and extensively drug-resistant tuberculosis (TB) continues to rise globally. Many treatment policies are based on the model that acquisition of drug resistance in already infected individuals drives the drug-resistant TB epidemic, hence the focus on drug-resistance testing of retreatment cases. However, molecular epidemiology and mathematical modelling suggest that the majority of multidrug-resistant TB cases are due to ongoing transmission of multidrug-resistant strains. This is most likely the result of diagnostic delay, thereby emphasizing the need for rapid diagnostics and comprehensive contact tracing, as well as active case finding. Current diagnosis of TB in low-income, high-burden regions relies on smear microscopy and clinical signs and symptoms. However, this smear-centred approach has many pitfalls, including low sensitivity in HIV patients and children, the inability of smear to reveal drug-resistance patterns, and the need for sampling on consecutive days. In order to address these limitations, efforts have been made to expand access to Mycobacterium tuberculosis culture and drug susceptibility testing. However, the slow growth rate of the causative agent, M. tuberculosis, contributes to significant diagnostic delay. Molecular-based diagnostic methods, targeting mutations that are known to confirm drug resistance, are capable of significantly reducing diagnostic delay. Two such methods, the line-probe assay and the real-time PCR-based Xpert® MTB/RIF assay, have been described. The latter test shows particular promise for smear-negative and extrapulmonary specimens. This may prove especially useful in settings where co-infection rates with HIV are high. However, since most research focuses on the performance of both of these assays, further investigations need to be done regarding the impact of the routine implementation of these assays on TB control programs and the cost effectiveness thereof.

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Editor’s note: Over two-thirds of multi-drug resistant tuberculosis (MDR-TB) cases are now believed to result from ongoing transmission of drug resistant virus rather than from acquiring drug resistance while being treated. Detecting this resistance at the time of TB diagnosis so that treatment regimens can be adjusted not only saves lives, it can save time and money while preventing onward transmission. This article tracks the development of molecular-based diagnostic methods leading to WHO’s recommendation in December 2010 to use the Xpert™ MTB/RIF real-time PCR (polymerase chain reaction) assay to detect simultaneously TB and resistance to rifampin, a key first-line TB drug. With countries such as South Africa introducing Xpert™ widely, it is time to determine the most cost-effective ways to use these new tools. The first step is to study the impact of routine implementation on treatment decisions and, most importantly, on treatment outcomes. In particular, will additional testing be needed for people living with HIV who have negative Xpert™ results since the test can miss 30% of smear-negative, culture-positive specimens? Operations research, phased implementation research and trials, and health economics studies are all needed – and the opportunity to conduct them is now.

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