Researchers, from the Cochrane Infectious Diseases Group, McGill University and the Foundation for Innovative New Diagnostics (FIND), analysed data from 18 studies, spread over 27 distinct centres, and involving a total of 7,816 adults supposed to be having pulmonary TB or multidrug-resistant TB (MDR-TB)--with or without HIV infection--with a view to assess the diagnostic accuracy of the Xpert® MTB/RIF test--a rapid, automated diagnostic test endorsed by the World Health Organization (WHO) in 2010 that simultaneously detects TB and resistance to rifampicin, as an indicator of multi-drug resistance.
Most of these studies (55.6%) were carried out in low- and middle-income countries. This systematic review published in The Cochrane Library provides timely advice to clinicians and policymakers in countries where TB is a major public health problem.
Accurate and rapid detection of TB and drug resistance are critical for improving patient care and decreasing the spread of TB. MDR-TB is defined as resistance to rifampicin and isoniazid-- two of the most effective and widely used anti-TB drugs. Like sputum smear microscopy, which relies on detecting TB with a microscope in a laboratory, Xpert requires a sample of sputum. However, while thousands of bacteria must be present in each millilitre of sample for TB to be detected under the microscope, Xpert can detect TB bacteria at much lower concentrations.
In addition, the conventional microscopy approach does not detect drug resistance. This presents problems, especially for MDR-TB, due both to the length of time required for the cultures to grow and the specialized laboratories and highly skilled staff needed. Xpert can detect both TB and rifampicin resistance, within two hours after starting the test, with very little skilled expertise required, but it is more expensive than conventional sputum microscopy.
The main objectives of the Cochrane meta-analysis were to assess (i) the diagnostic accuracy of Xpert for pulmonary TB detection--both where Xpert was used as an initial test replacing microscopy, and where Xpert was used as an add-on test following a negative smear microscopy result; and (ii) the diagnostic accuracy of Xpert for rifampicin resistance detection where Xpert was used as the initial test, replacing conventional culture-based drug susceptibility testing.
The results show that when Xpert is used as a replacement for smear microscopy to screen 1,000 people, 150 of whom have TB, it picks up 132 of the 150 cases (88%) and falsely diagnoses 17 (2%) with TB. In a scenario where Xpert is used as a replacement for culture-based drug susceptibility testing, it is also able to detect the equivalent of 141 out of 150 cases (94%) of rifampicin resistance. When Xpert is used as a follow-on test, after conventional smear microscopy has already produced a negative result, it picks up 101 out of 150 cases (67%)—cases that would have been missed by microscopy as smear-negative TB is not picked up by smear microscopy.
Although a sensitivity of 67% may be considered low, it is precisely in smear-negative patients that improvements in diagnostic tests are needed and where any improved diagnostic test will have the biggest impact. Therefore, Xpert may also be valuable as an add-on test following smear microscopy.
“This study represents the most comprehensive review on the diagnostic accuracy of Xpert to date and may help countries make decisions about scaling up its use for management of TB and drug-resistant TB,” said lead researcher, Karen Steingart, of Cochrane Infectious Diseases Group to Citizen News Service – CNS.
Lucica Ditiu, Executive Secretary of the Stop TB Partnership, said, “We welcome the Cochrane Review of Xpert, an innovation that represents a major milestone in our quest to achieve the goal of zero deaths from TB – which is curable but still takes the life of three people every minute. The Stop TB Partnership is making every effort to help countries understand how best to use this new technology. Our TB REACH initiative is deploying Xpert to numerous countries through projects that seek to increase the number of TB cases detected and treated, and these projects will deliver data that can provide an evidence base for determining how Xpert should be used for the greatest impact.”
Summary of main results
• When used as an initial test replacing smear microscopy, Xpert achieved 88% modest sensitivity and 98% high specificity for TB detection.
• When used as an add-on test following smear microscopy, Xpert yielded a sensitivity of 67%.
• Xpert sensitivity for smear-positive, culture-positive TB was very high and consistent (98%); Xpert sensitivity for smear negative, culture-positive TB was lower and more variable (68%).
• Xpert detected 80% of pulmonary TB cases in people living with HIV and 89% of pulmonary TB cases in people without HIV infection.
• When used as an initial test replacing conventional drug susceptibility testing, Xpert detected 94% of rifampicin-resistant TB with high specificity (98%).
• The proportion of indeterminate Xpert results was very low (1.1%).
These findings lend support to the WHO recommendations on the use of Xpert as an initial diagnostic test for TB detection and rifampicin resistance detection in patients supposed to be having MDR-TB or HIV-associated TB. When used as an initial test replacing conventional drug susceptibility testing, it has high sensitivity and specificity for rifampicin resistance detection. Xpert, however, does not eliminate the need for subsequent culture and phenotypic drug susceptibility testing, which are required to monitor treatment progress and to detect resistance to drugs other than rifampicin.
The high sensitivity in smear-positive TB and modest sensitivity in smear-negative TB, along with the high specificity of Xpert mean that Xpert may be used as the initial diagnostic test for TB detection in individuals supposed to be having TB, MDR-TB, or HIV-associated TB. Xpert may also be valuable as an add-on test following microscopy for patients who have previously been found to be smear-negative.
Compared with culture and conventional drug susceptibility testing, Xpert MTB/RIF assay could have considerable advantages for scaling up programmatic management of TB by offering rapid diagnosis nearer to the point of care, standardized testing, potential for high throughput, and fewer requirements for laboratory biosafety.
The study authors found that Xpert results for TB detection were usually reported within two hours or on the same day, compared with liquid culture results which were reported in around 16 to 20 days. However, early detection of rifampicin resistance may not lead to improved patient outcomes if the result is not linked to appropriate treatment, services, and supervision.
The authors caution that an Xpert result that is positive for rifampicin resistance should be carefully interpreted and take into consideration the risk of MDR-TB in a given patient and the expected prevalence of MDR-TB in a given setting. For example, in a hypothetical cohort of 1000 individuals suspected of having rifampicin resistance (a proxy for MDR-TB), where the prevalence of rifampicin resistance is 30%, on average, Xpert would wrongly identify 14 patients as being rifampicin resistant.
In most of the countries represented in this review, among patients who had previously never been treated for TB, the prevalence of MDR-TB was only around 1% to 2%. In a hypothetical cohort, where the prevalence of rifampicin resistance is 2%, the number of individuals wrongly identified as rifampicin resistant would increase from 14 (when rifampicin resistance prevalence is 30%) to 20, an increase of 43%.
These individuals may be unnecessarily treated with second-line anti-TB drugs and experience serious adverse events. Thus, in a setting with very low prevalence of MDR-TB, an Xpert result indicating rifampicin resistance should prompt confirmation by a more definitive test.
Moreover, sensitivity and specificity depend on the performance of a test in a particular situation, defined by the population, the setting, and prior testing, and they are likely to change in a different population/setting/testing strategy.
Hence, the findings from this review may not be applicable in resource-constrained areas that lack high-quality laboratory infrastructure and highly trained personnel, and the accuracy of Xpert may be lower in routine practice settings.
Also, since the majority of studies included in the analysis were from low and middle-income countries where advanced, smear-positive TB is common, the findings may not directly apply to high-income countries where most TB cases are smear-negative, have minimal disease, and induced sputum samples are often necessary for diagnosis.
The Cochrane analysis represents the most comprehensive review on the diagnostic accuracy of Xpert and provides evidence that may help countries make decisions about scaling up Xpert for programmatic management of TB and drug-resistant TB.
However, policy makers will also need to take into account other factors relating to cost and operational concerns such as the feasibility of the use of Xpert in peripheral laboratories and health centres, cost, and operational considerations, including the ability to maintain an uninterrupted and stable electrical power supply, temperature control, and maintenance of the cartridge modules.
Karin Weyer, Coordinator, Laboratories, Diagnostics and Drug Resistance at the WHO said, “This Cochrane Review provides high quality evidence that reinforces WHO's endorsement of this test.
Recent price reductions (from$16.86 to $9.98 per cartridge) have greatly facilitated roll-out of this technology, including a new three-year initiative called the TB Xpert Project, funded by UNITAID and executed by WHO and the Stop TB Partnership. 1.4 million test cartridges and over 200 GeneXpert instruments for the rapid detection of TB and rifampicin resistance will be distributed in 21 countries with a high burden of TB.”
Shobha Shukla, Citizen News Service - CNS
(The author is the Managing Editor of Citizen News Service - CNS. She is a J2J Fellow of National Press Foundation (NPF) USA. She received her editing training in Singapore, has worked earlier with State Planning Institute, UP and taught physics at India's prestigious Loreto Convent.
She also authored a book on childhood TB, co-authored a book (translated in three languages) "Voices from the field on childhood pneumonia", reports on Hepatitis C and HIV treatment access issues, and MDR-TB roll-out.
Email: [email protected], website: http://www.citizen-news.org)