2.1. Procedure for developing policies
In 2008 WHO adopted the international GRADE process (Grading of Recommendations Assessment, Development and Evaluation)3 for synthesizing and evaluating evidence. The GRADE process underpins all WHO recommendations and guidelines. The process provides a systematic means for assessing the quality of evidence used to formulate policies as well as for rating the strength the recommendations; the process aims at achieving a balance among a test performance, its risks and benefits, and its impact on patients and public health4. At WHO, the process of developing policies is overseen by the Guidelines Review Committee, which was specifically established for this purpose.
WHO's Global TB Programme has developed a structured, evidence-based process to facilitate the rapid development of policies and guidance on the use of new TB diagnostic tools, new diagnostic methods, and novel approaches to diagnosis using existing tools.
The first step involves undertaking a systematic review and meta-analysis of the data where feasible, using standard methods appropriate for studies assessing diagnostic accuracy.
The second step involves convening an Expert Group to evaluate the strength of the evidence base using the GRADE process as well as the operational and logistical considerations relevant to mainstreaming the tools or approaches into national TB control programmes; the Expert Group also identifies any gaps that need to be addressed by future research.
The third step involves formulating WHO's policies and guidance on the use of these tools and approaches, and presenting them to WHO's Strategic and Technical Advisory Group for TB (STAG-TB); after endorsement by STAG-TB, the guidance is disseminated to Member States for implementation.
2.2. Initial policy recommendations and follow up
A meeting of the Expert Group was convened by WHO in September 2010. The Expert Group used the GRADE process to review data from published papers on Xpert MTB/RIF, as well as data from large multi-centre laboratory validation studies and demonstration studies coordinated by FIND, results from cost-effectiveness analyses5 and unpublished data from 12 investigator-driven, single-centre studies. The process of evidence synthesis confirmed that there was a solid evidence base to support the widespread use of Xpert MTB/RIF to detect pulmonary TB and rifampicin resistance.
STAG-TB supported the Expert Group's recommendations6 and advised that implementation of Xpert MTB/RIF technology should be phased in within the context of comprehensive national strategic plans addressing TB and MDR-TB. STAG-TB recommended that WHO should:
develop a global strategy to ensure the rapid uptake of Xpert MTB/RIF using a systematic and phased approach, including developing mechanisms to monitor and assess the roll out of Xpert MTB/RIF; the strategy should ensure there is a clear plan for documenting the impact on case-detection, the scaling up of responses to MDR-TB and evaluating cost effectiveness;
proceed with a Global Consultation to determine considerations for scaling up of the use of Xpert MTB/RIF under routine programme conditions, including developing diagnostic algorithms; evaluating logistical considerations, and procurement and distribution procedures; implementing quality assurance plans and methods of waste disposal;
assist countries by providing technical support and support for plans to include Xpert MTB/RIF in revised diagnostic algorithms.
At a Global Consultation convened by WHO during 30 November–2 December 2010, country representatives and technical partners discussed considerations for scaling up the use of Xpert MTB/RIF, and achieved broad consensus on the way forward. Key outcomes agreed at the consultation included interim diagnostic algorithms, optimal positioning of Xpert MTB/RIF at different levels of health-care system so that its use can be targeted at various risk groups, and advice on issues to be considered before the test is systematically rolled out in order to optimize its use and the benefits of the technology. The interim diagnostic algorithms were initially developed in consultation with the following Working Groups of the Stop TB Partnership: the Global Laboratory Initiative, the MDR-TB Working Group, the DOTS Expansion Working Group and the TB/HIV Working Group. The algorithms were discussed and then revised during the consultation.
Policy recommendations7 on Xpert MTB/RIF were issued by WHO early in 2011, supported by a Checklist for country implementation8 and a Rapid Implementation document9.
In April 2011, WHO convened a meeting with early implementers of the Xpert MTB/RIF assay to refine the interim diagnostic algorithms, develop a core set of variables to determine the impact of introducing the technology on laboratory workload, and to clarify operational and logistical issues.
A second meeting of early implementers was convened by WHO in April 2012 to give participants the opportunity to share their experiences of introducing the assay under routine programmatic conditions.
A third Global Forum of Xpert MTB/RIF Implementers10 was convened in April 2013 in association with the 5th GLI Partners Meeting, during which countries and their technical partners shared information about the lessons that had been learnt and the challenges encountered during scale-up, with a focus on evidence of the test's impact and how to link scaled-up diagnosis with scaled-up access to treatment.
2.3. Policy update
Since WHO's initial recommendations were made in 2010, evidence on the performance and use of Xpert MTB/RIF has rapidly accumulated. Given the amount of additional data that has emerged since 2010, an update of WHO's initial policy and guidance was warranted. WHO's Global TB Programme therefore commissioned three systematic reviews, including reviews of the utility of Xpert MTB/RIF in diagnosing TB and rifampicin resistance in pulmonary, extrapulmonary and paediatric TB. A review of published studies on the affordability and cost effectiveness of Xpert MTB/RIF was also performed.
In May 2013, an Expert Group convened by WHO reviewed the expanded body of evidence presented in the systematic reviews and applied GRADE process to the evidence. Based on the outcomes of the review and the recommendations of the Expert Group, which were presented to and supported by STAG-TB11 in June 2013, an updated policy statement was issued in October 2013.12
2.4. Summary of WHO's 2013 policy recommendations
2.4.1. Using Xpert MTB/RIF to diagnose pulmonary TB and rifampicin resistance in adults and children
Xpert MTB/RIF should be used rather than conventional microscopy, culture and DST as the initial diagnostic test in adults suspected of having MDR-TB or HIV-associated TB (strong recommendation, high-quality evidence).
Xpert MTB/RIF should be used rather than conventional microscopy, culture and DST as the initial diagnostic test in children suspected of having MDR-TB or HIV-associated TB (strong recommendation, very low-quality evidence).
Xpert MTB/RIF may be used rather than conventional microscopy and culture as the initial diagnostic test in all adults suspected of having TB (conditional recommendation acknowledging resource implications, high-quality evidence).
Xpert MTB/RIF may be used rather than conventional microscopy and culture as the initial diagnostic test in all children suspected of having TB (conditional recommendation acknowledging resource implications, very low-quality evidence).
Xpert MTB/RIF may be used as a follow-on test to microscopy in adults suspected of having TB who are not at risk of MDR-TB or HIV-associated TB, especially when further testing of smear-negative specimens is necessary (conditional recommendation acknowledging resource implications, high-quality evidence).
Remarks
These recommendations apply to the use of Xpert MTB/RIF for specimens of processed and unprocessed sputum.
These recommendations also apply to specimens of gastric lavage and aspirate from adults and children, the recommendation for adults is based on the generalization of data from children.
These recommendations support the use of a single sputum specimen for diagnostic testing, acknowledging that processing multiple specimens increases the sensitivity of Xpert MTB/RIF but also has resource implications.
Children suspected of having pulmonary TB but who have had a single negative result by Xpert MTB/RIF should undergo further diagnostic testing, and a child for whom there is a high clinical suspicion for TB should be treated even if an Xpert MTB/RIF result is negative or if the test is not available.
Conventional microscopy and culture remain essential for monitoring therapy and for performing DST for anti-TB agents other than rifampicin (including for isoniazid and second-line anti-TB agents).
Expanding the scope of the use of Xpert MTB/RIF and its placement in diagnostic algorithms will have significant implications for operational implementation, and its use should be phased in within the context of national strategic plans for TB.
Emerging data have shown that Xpert MTB/RIF detects some rifampicin-resistant strains that are identified as susceptible by phenotypic DST. Sequencing these discordant results usually resolves in favour of Xpert MTB/RIF, and patients missed by phenotypic DST have poor treatment outcomes on first-line treatment.
2.4.2. Using Xpert MTB/RIF to diagnose extrapulmonary TB and rifampicin resistance in adults and children
Xpert MTB/RIF should be used in preference to conventional microscopy and culture as the initial diagnostic test for cerebrospinal fluid (CSF) specimens from patients suspected of having TB meningitis (strong recommendation given the urgency of rapid diagnosis, very low-quality evidence).
Xpert MTB/RIF may be used as a replacement test for usual practice (including conventional microscopy, culture or histopathology) for testing specific nonrespiratory specimens (lymph nodes and other tissues) from patients suspected of having extrapulmonary TB (conditional recommendation, very low-quality evidence).
Remarks
Individuals suspected of having extrapulmonary TB but who have had a single negative result from Xpert MTB/RIF should undergo further diagnostic testing, and those for whom there is a high clinical suspicion for TB (especially children) should be treated even if an Xpert MTB/RIF result is negative or if the test is not available.
For CSF specimens, Xpert MTB/RIF should be preferentially used instead of culture if the sample volume is low or if additional specimens cannot be obtained in order to make a quick diagnosis. If sufficient volume of material is available, concentration methods should be used to increase the yield.
Pleural fluid is a suboptimal sample for the bacterial confirmation of pleural TB regardless of the method used. A pleural biopsy is the preferred sample. The sensitivity of Xpert MTB/RIF in testing samples of pleural fluid is very low. Nevertheless, any individual with a positive result from pleural fluid tested by Xpert MTB/RIF should be treated for pleural TB; those with a negative result from Xpert MTB/RIF should have other tests.
Conventional microscopy and culture are essential for monitoring therapy and for performing DST for anti-TB agents other than rifampicin (including for isoniazid and second-line anti-TB agents).
Emerging data have shown that Xpert MTB/RIF detects some rifampicin-resistant strains that are found to be susceptible by phenotypic DST. Sequencing these discordant results usually resolves in favour of Xpert MTB/RIF, and patients missed by phenotypic DST have poor treatment outcomes on first-line treatment.
These recommendations do not apply to samples of stool, urine or blood, given the lack of data on the utility of Xpert MTB/RIF for these specimens.
- 3
- 4
- 5
- 6
- 7
- 8
- 9
- 10
- 11
- 12
Automated real-time nucleic acid amplification technology for rapid and simultaneous detection of tuberculosis and rifampicin resistance: Xpert MTB/RIF system for the diagnosis of pulmonary and extrapulmonary TB in adults and children: policy update. Geneva: World Health Organization; 2013. (available at http://www.who.int/tb/laboratory/policy_statements/en/) [PubMed: 25473701].
