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HATIP 204: Xpert MTB/RIF For TB Diagnosis: Global Update
HATIP 204: Xpert MTB/RIF For TB Diagnosis: Global Update
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In this issue:
Xpert MTB/RIF diagnostic test for TB: a global update; by Lesley Odendal page 2
Background: Improving TB diagnosis through use of the Xpert MTB/RIF assay World Health Organization recommendations on use of Xpert MTB/RIF Global update on the use of Xpert MTB/RIF Addressing funding constraints Xpert MTB/RIF roll-out Diagnostic yield Using Xpert MTB/RIF in active case finding Xpert MTB/RIF for detection of rifampicin resistance The use of Xpert MTB/RIF in combination with other diagnostic methods Conclusion Further resources
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Key points
Xpert MTB/RIF assay is a new test which allows The the diagnosis of tuberculosis within two hours from a
single sputum sample. Its use as the initial diagnostic test is recommended by the World Health Organization for all people with suspected multidrug-resistant TB (MDR-TB) and for all people with HIV who have suspected TB. Its use is also recommended as a follow-on test after smear microscopy where MDR-TB or HIV is of lesser concern, especially in suspected smear-negative TB. The roll-out of the Xpert MTB/RIF test is being supported by funding from several donors across a wide range of countries with a high prevalence of MDR-TB and/or HIV. The test improves the rate of diagnosis of both drug-sensitive and drug-resistant TB. The test also supports active case finding, by both improving the diagnostic yield and by limiting the waiting time for results. This reduces loss to follow-up. Very rapid initiation of TB treatment has been achieved by use of Xpert MTB/RIF supported by Community Health Facilitators, who provide the link between the labs, the clinics and the community health workers. Use of Xpert MTB/RIF has also been shown to reduce the delay in treatment initiation in smear-negative TB patients. While Xpert MTB/RIF and culture testing may have similar positivity rates, Xpert MTB/RIF significantly decreases the turnaround time for diagnosis of rifampicin resistance and can be placed in decentralised settings. Testing for susceptibility to isoniazid and second-line drugs should be done for all patients identified as rifampicin-resistant by the GXP.
This edition of HATIP was kindly supported by the HIV/AIDS Department of the World Health Organization. Thanks to Dr Linh Nhat Nguyen and Dr Wayne Van Gemert of the Stop TB department (WHO) and Dr Eyerusalem Negussie of the HIV/AIDS department (WHO) for their review of this edition.
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clinical management algorithms incorporating the new technology is needed.
These are the two groups of people who will benefit most from this diagnostic. HIV-infected individuals co-infected with TB are more difficult to diagnose with smear microscopy, resulting in delays in diagnosis, which can lead to death in HIV-infected individuals. We also want to diagnose people suspected of having MDR-TB as quickly as possible to ensure that they are started on effective treatment without delay, which in turn reduces the risk of transmission of MDR-TB in the community, Dr Christopher Gilpin of the WHO Stop TB Department told the conference.2
and invalid results: In a small but significant number of Errors sites, errors and invalid results in the initial phase of implementation raised anxiety regarding use of Xpert MTB/RIF.
up treatment capacity to match diagnostic capacity: Scaling Treatment of rifampicin-resistant TB cases that are diagnosed by Xpert MTB/RIF was a major concern in many sites which did not have the effective second-line drugs to treat newly diagnosed patients. Correct diagnosis in the absence of appropriate treatment nevertheless allows for patients to protect the health of their families.
Xpert MTB/RIF may be considered as a follow-on test to microscopy in settings where MDR-TB or HIV is of lesser concern, especially in further testing of smear-negative specimens. (Conditional recommendation acknowledging major resource implications.)
for innovation: Technical innovation is needed to allow for Need Xpert MTB/RIF to be used in more settings at levels closer to the point of care, where lack of reliable electricity and high temperatures may otherwise prevent the reliable use of the test. Implementation of electronic information management systems and mHealth initiatives through the use of mobile telephones will facilitate stronger links between diagnosis and follow-up care.
These recommendations apply to the use of Xpert MTB/RIF in sputum specimens only, as data on the utility of Xpert MTB/RIF in extra-pulmonary specimens are still limited. Based on the generalisation of data from adults, these recommendations also apply to children. Although studies have shown that multiple sputum specimens increase the sensitivity of the Xpert MTB/RIF, WHO recommends the use of one sputum specimen for diagnostic testing, given the resource implications of using multiple specimens. WHO acknowledges the need for a review of the accuracy of GXP in detecting extra-pulmonary TB and paediatric TB, and organised an Expert Group meeting to evaluate the evidence base in May 2013.
sector access: Adoption of Xpert MTB/RIF by the large Private private sector in many high-burden countries would be highly beneficial for increasing patient access to rapid and reliable diagnosis, and at the same time replacing technologies that are not endorsed by WHO. The establishment of collaborations between private providers and national TB control programmes would be mutually beneficial, allowing for private providers to access concessional prices and for national TB control programmes to ensure that patients whose TB is diagnosed in the private sector are duly reported and subsequently registered for appropriate treatment.
for price reduction: The price of the test cartridge was Need repeatedly stated as the main obstacle to an accelerated and sustainable roll-out of the test (but it should be noted that this consultation took place before the price reduction to USD 9.89).
and clinical algorithms: Investment in time and Diagnostic resources to develop and implement effective diagnostic and
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and culture sub-districts: two smears in low-MDR risk Smear patients, and two smear plus culture and drug susceptibility testing in high-MDR risk patients.
MTB/RIF sub-districts: two sputum samples collected from Xpert all suspected TB cases. If sample 1 was negative and the patient was HIV negative the second sample was discarded. If sample 1 was negative and the patient was HIV positive the second sample was submitted for culture. If sample 1 was positive but rifampicin-sensitive, a confirmatory smear was carried out on sample 2. If sample 1 was positive and rifampicin-resistant, sample 2 was submitted for smear, culture, LPA and second-line drug susceptibility testing.
what level of the health system should access to Xpert At MTB/RIF be prioritised? How does it perform in peripheral health centres?
can TB programmes best use this valuable new tool for How detection and management of rifampicin resistance? can we effectively evaluate this test in routine practice, How where access to culture is generally non-existent and where
Research presented at the 2012 World Lung Health meeting began to address some of these questions, relating to diagnostic yield, to use of Xpert MTB/RIF to support TB and drug-resistant TB diagnosis in peripheral health centres, and in relation to diagnosis of drug-resistant TB.
Diagnostic yield
Xpert MTB/RIF implementation is intended to improve case detection of both drug-sensitive and rifampicin-resistant TB cases. Studies presented from South Africa, India and Cambodia showed that in settings with a high burden of TB and DR-TB, Xpert MTB-RIF resulted in encouraging improvements in diagnostic yield. The studies also showed that increases in diagnostic yield could be achieved when testing was decentralised to lower levels of the health system. South Africa In Cape Town, South Africa, the phased introduction of Xpert MTB/RIF across five of the citys eight sub-districts resulted in an increase of approximately 20% in diagnostic yield in the first quarter after introduction, although this increase was not sustained in subsequent quarters.7 All TB suspects were screened according to the following algorithm:
The 2011 fourth-quarter mean diagnostic yield across the sub-districts for DS-TB was found to be 20.3% for the Xpert MTB/RIF algorithm compared to 16.9% for the standard-of-care smear microscopy/culture algorithm. However, this difference was not sustained for the second time period. For the second quarter of 2012, the Xpert algorithms mean diagnostic yield decreased to 16.8% compared to 16.3% for the smear/culture algorithm. The mean MDR-TB yield for the Xpert MTB/RIF algorithm was 7.3% and 5.3% in the first and second time periods respectively compared to 4.7% and 5.3% for the smear/culture algorithm. The increase in the MDR-TB diagnostic yield suggests some benefit for DR-TB, but extra time points would be needed, said Dr Naidoo. In this study, it is important to note that the yield refers to the algorithm and that the number of sub-districts implementing the Xpert MTB/RIF testing algorithm increased from two in the fourth quarter of 2011 to three in the first quarter of 2012. This may have had an effect on the result. In addition, not all suspected TB cases in the districts implementing the Xpert MTB/RIF algorithm underwent Xpert MTB/RIF testing, making the decline in yield in the second quarter of 2012 hard to interpret. India A 7.2% increase in the diagnostic yield when using Xpert MTB/RIF for TB case finding compared to smear microscopy was found in a feasibility and impact study of using the test at decentralised laboratories in India, as reported by Dr Naraj Raizada, Project Manager of Xpert MTB/RIF projects for FIND in India.8 All patients with suspected pulmonary TB (PTB) and drug-resistant TB (DR-TB) were offered a single Xpert MTB/RIF test situated at 18 sites in varying settings across India serving a population of 8.7 million people. 22,345 pulmonary TB and 1,738 DR-TB suspected cases were tested between March and October 2012. The study compared the diagnostic yield of TB before and after the establishment of the Xpert MTB/RIF testing facilities. Of the 9124 suspected TB cases tested using smear microscopy at baseline, 1312 confirmed cases of TB were detected (a 14.3% smear positivity rate). This resulted in an average of 29 TB cases per site per month. This increased to 47 TB cases per site per month when using Xpert MTB/RIF. 4422 of the 22,345 TB suspected cases were confirmed as having TB when the Xpert MTB/RIF tests were used (a 20% positivity rate). However, they also conducted an internal comparison of diagnostic yield by performing smear microscopy on the same sputum specimens used in the Xpert MTB/RIF testing. Smear microscopy yielded a positivity rate of only 12.8%, compared to the 20% positivity rate using Xpert MTB/RIF on the same sputum specimens. 1559 cases of TB were missed using smear microscopy. Xpert MTB/RIF also diagnosed 569 cases of rifampicin-resistant TB
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referred for Xpert MTB/RIF testing as a result of door-to-door case finding were found to have active TB, compared with 9% of presumptive TB cases referred for testing within health facilities. One of the most important reasons for implementing Gene Xpert testing is because it has the potential to reduce the delay between identification of a presumptive TB case, delivery of a positive result and the initiation of TB treatment. The longer that treatment is delayed the greater the risk of death and transmission of TB to others. In a sample of patients referred for testing between January and June 2012, Prof. Hausler showed that 40% of those diagnosed with active TB started TB treatment within 48 hours of providing a sputum sample, and 27% within two to five days. We are hoping that this is going to translate into reduced TB transmission in the community, said Dr Hausler. Whats even more exciting is that around 40% of drug-resistant TB patients are started on an MDR regimen within 48 hours. At one site, Pholela community health clinic, Prof. Hausler showed that TB treatment initiation within five days of giving sputum had risen from 10% of patients in the April to June 2011 period to 89% of patients in the same quarter in 2012, and 61% of patients diagnosed with active TB at that clinic started TB treatment less than 24 hours after giving their sputum sample, an impressive vindication of the argument that Xpert MTB/RIF scale up has the potential to dramatically limit the time during which people can transmit TB to others. This rapid turnaround is underpinned by the involvement of Community Health Facilitators, lay people who form the link between the labs and the clinics. They are responsible for checking Xpert results on a daily basis and passing that information back to the clinics as quickly as possible. Community health workers are then tasked with getting people diagnosed with TB onto treatment as quickly as possible by following them up in the community. Anyone who tests HIV-positive will also be initiated onto ART as quickly as possible. Kenya In cases where TB is suspected but microscopy yields a smear-negative result, the delay to treatment that results from referral for culture means that patients will continue to deteriorate. Smear-negative TB is more likely to be diagnosed in people living with HIV, who will also be in need of antiretroviral therapy if they are found to have TB. Xpert MTB/RIF has the potential to greatly reduce the delay before treatment initiation in smear-negative patients. Dr Jane Carter, the TB/HIV technical advisor for USAID AMPATH presented on the results of using the Xpert MTB/RIF on smear-negative patients in an existing TB REACH programme at 200 primary health care facilities in the north west of Kenya.11 We found that the Gene Xpert can be rolled out swiftly and effectively to peripheral health units to aid in TB diagnosis, said Dr Carter. Five thousand patients with smear-negative TB are to be offered culture diagnosis as part of the project. The culture laboratory is centralised in Eldoret, which is six to eight hours drive from some of the sites. Xpert MTB/RIF testing is to be offered to 2000 smear-negative TB patients. Gene Xpert facilities were established at three peripheral sites in three sub-districts, with the aim of bringing diagnostic services closer to patients. A hub transport system was established to transport specimens, request forms and result forms to and from the health facilities to the testing sites which were between two and 26km apart. If a patient had a smear negative result, the same sputum specimen would be used for both the culture and Xpert MTB/RIF test. This was to avoid the inconvenience and cost to the patient of
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TB/HIV Care Associations intervention in Sisonke district in KwaZulu-Natal, South Africa13 (described previously) detected 140 cases of rifampicin-resistant TB (a diagnostic yield of 9.9%) compared to 8.7% in the rest of the province. DR-TB patients have been initiated on treatment at a decentralised hospital at sub-district level, compared to the standard approach of being hospitalised at a centralised facility, 150 km from Sisonke district. This has alleviated the burden on the patients family members to visit their relatives. DR-TB patients are also discharged after two consecutive negative smears, as opposed to the policy in the province of only discharging patients at the end of the six-month injectables period. TB/HIV Care Association is also using outreach teams made up of an enrolled nurse and a counsellor to provide patients with injections at home. The use of Xpert MTB/RIF has also allowed for the time from sputum collection to treatment initiation to be dramatically reduced, rendering patients uninfectious sooner. Between January and June 2012, 36% of MDR-TB patients were initiated on treatment less than 48 hours after providing a sputum specimen, while 18% were initiated on treatment between two and five days after providing sputum. FIND has also established 12 new Xpert MTB/RIF testing sites in difficult-to-reach areas in India for rifampicin drug-sensitivity testing to supplement the capacity of the existing reference laboratory network of the National TB Programme.14 It aims to conduct 24,000 rifampicin-resistance tests and expects to detect 7,000 cases of MDR-TB annually. Six of the 12 Xpert MTB/RIF testing sites had been established and used between August and October 2012. Of the 2900 suspected DR-TB cases tested using the Xpert MTB/RIF, 462 (16%) were diagnosed with MDR-TB.
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https://extranet.who.int/xpertmtbrif/content/home
References
[1] World Health Organization.Rapid implementation of the Xpert MTB/RIF diagnostic test: technical and operational How-to practical considerations. Geneva, March 2011 [2] Gilpin, C. Introduction and status of the global roll-out of Xpert MTB/RIF for the diagnosis of tuberculosis.43rd Union World Conference on Lung Health, Kuala Lumpur, 2012. [3] http://www.who.int/tb/laboratory/mtbrifrollout/en/ [4] World Health Organization Stop TB Department.Update: Implementation and roll-out of Xpert MTB/RIF. May 2012 [5] Gilpin, C. op cit [6] Cohen D, Corbett S. Evidence supports TB test, so what now?[editorial]. Cochrane Database of Systematic Reviews 2013 Jan 31;1:ED000051. doi: 10.1002/14651858.ED000051. [7] Naidoo, P. Does the introduction of the Xpert MTB/RIF test result in an increased TB diagnostic yield in a routine operational setting in Cape Town? 43rd Union World Conference on Lung Health, Kuala Lumpur, 2012. [8] Raizada, N. Experience with implementation of Xpert MTB/RIF in India. 43rd Union World Conference on Lung Health, Kuala Lumpur, 2012. [9] Boy, S. The impact of the Xpert MTB/RIF assay for detecting Mycobacterium tuberulosis among TB suspects in Cambodia. 43rd Union World Conference on Lung Health, Kuala Lumpur, 2012. [10] Hausler, H. Using community resources and new tools for active TB case detection in South Africa.43rd Union World Conference on Lung Health, Kuala Lumpur, 2012. [11] Carter, J. Providing access to new diagnostics for vulnerable rural populations in Kenya.43rd Union World Conference on Lung Health, Kuala Lumpur, 2012. [12] Anisimova,V et al. Rifampicin resistance as a proxy for multi-drug resistant tuberculosis in Botswana. 43rd Union World Conference on Lung Health, Kuala Lumpur, abstract OP-101-15, 2012. [13] Hausler, H. op cit [14] Raizada, N. op cit [15] Shah, M. Comparative performance of rapid urinary lipoarabinomannan assays and Xpert MTB/RIF in HIV+ TB suspects: Uganda. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta, abstract 127, 2013.
Conclusion
While the introduction of Xpert MTB/RIF has been hailed as one of the greatest achievements for the diagnosis of TB and MDR-TB, the price of the machine and the cartridges is the main obstacle which implementers face, despite the decrease in the price. Innovations to reduce the price are necessary to ensure that this useful technology can be scaled up and used effectively globally. As the India study showed, the use of this technology is feasible when certain measures are put in place. Xpert MTB/RIF has demonstrated significant gains in intensified case finding of TB and MDR-TB, as shown by numerous studies presented at last years Union World Lung Health Conference. In every study conducted in operational settings, there was a significant increase in diagnostic yield, demonstrating the potential for Xpert MTB/RIF to assisting in detecting all TB cases. The Xpert MTB/RIFs superior sensitivity in detecting TB, especially in smear-negative cases is also greatly beneficial to people with TB/HIV co-infection. Most importantly, the two-hour turnaround time from sputum specimen to result means that the time to treatment initiation can be decreased significantly, as shown in the Sisonke District study by TB/HIV Care Association. However, challenges remain such as ensuring reliable electricity supply and giving staff adequate training and supervision to avoid uninterpretable results. These are aspects which will need to be addressed going forward.
Further resources
Stop TB Department Xpert MTB/RIF roll out monitoring WHO website
http://www.who.int/tb/laboratory/mtbrifrollout/en/index.html
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