2.1. Initial diagnostic tests for diagnosis of TB with drug-resistance detection

2.1.1 LC-aNAATs for detection of TB and resistance to rifampicin

Rapid detection of TB and rifampicin resistance is a critical global priority. Over a decade ago, the first recommendation on molecular testing for the diagnosis of TB and detection of resistance significantly transformed the TB diagnostic landscape. These technologies have proven highly accurate compared with smear microscopy, and they can detect rifampicin resistance rapidly. They do not require highly skilled individuals or designated molecular laboratory infrastructure for testing. In addition, they are largely automated after sample loading, up to the final report generation. These features make this class of low-complexity automated tests appealing for use in low- and middle-income countries (LMIC).

Uptake of these technologies has been slowed by barriers related to costs, the supply chain, equipment maintenance and technical support. The lack of a healthy competitive environment has also been a contributory factor. The WHO Prequalification (PQ) programme for TB in vitro diagnostics (IVDs) has opened a pathway to allow more products to come to market and ensure quality. The current guidelines facilitated this process with the introduction of classbased recommendations for low-complexity NAATs. WHO PQ assessment progress for all low-complexity NAATs is reported on the WHO PQ website.⁴

Diagnostic class description

The features shown in Table 2.1.1.1 define the class of LC-aNAATs.:

Table 2.1.1.1 Class criteria for LC-aNAATs

DNA: deoxyribonucleic acid; LC-aNAAT: low-complexity automated nucleic acid amplification test; PCR: polymerase chain reaction; TB: tuberculosis.

The products for which eligible data met the class-based performance criteria for LC-aNAATs were:

Xpert MTB/RIF Ultra (Cepheid, Sunnyvale, United States of America [USA]) – for pulmonary TB, extrapulmonary TB and resistance to rifampicin; and
Truenat MTB Plus and Truenat MTB-RIF Dx (Molbio, Goa, India) – for pulmonary TB and resistance to rifampicin.

Data on Truenat MTB Plus and MTB-RIF Dx were more limited than those for Xpert Ultra.

Regulatory approval from national regulatory authorities or other relevant bodies is required before implementation of these diagnostic tests. Extrapolation to other brand-specific tests cannot be made, and any new in-class technologies, or new indications for technologies currently included in the class, will need to be evaluated by WHO PQ and WHO/GTB, respectively.

The publication WHO operational handbook on tuberculosis. Module 3: Diagnosis describes the tests included in this class.

Recommendations

Remarks

For adults, respiratory samples include sputum (expectorated or induced), tracheal aspirate or bronchoalveolar lavage (BAL).
The term “person screened positive” refers to a person in whom a screening test has yielded a positive result.⁵
Children and specifically children living with HIV are discussed in the section on the concurrent use of initial TB diagnostic tests in children.
Adults and adolescents living with HIV are discussed in the section on the concurrent use of initial TB diagnostic tests in people living with HIV.
The products for which eligible data met the class-based performance criteria for LC-aNAATs for this recommendation were Xpert MTB/RIF Ultra (Cepheid, Sunnyvale, United States of America [USA]) and Truenat MTB Plus (Molbio, Goa, India). Data on Truenat MTB Plus and MTB-RIF Dx were more limited than those for Xpert Ultra.

Remarks

This recommendation applies to all people living with HIV.
The recommendation was extrapolated to children based on the generalization of data from adults and limited data from children. For children, respiratory samples include sputum, BAL, induced sputum, nasopharyngeal aspirate and gastric aspirate.
The recommendation was extrapolated to people with extrapulmonary TB based on the generalization of data from adults with pulmonary TB.
The products for which eligible data met the class-based performance criteria for LC-aNAATs for this recommendation were Xpert MTB/RIF Ultra (Cepheid, Sunnyvale, United States of America [USA]) and Truenat MTB-RIF Dx (Molbio, Goa, India). Data on MTB-RIF Dx were more limited than those for Xpert Ultra.

Remarks

This recommendation applies to all people with signs and symptoms of TB meningitis, including people living with HIV and children.
Where possible, culture may be performed in addition to automated NAAT testing, to maximize the opportunity for diagnosis and detection of DR-TB.
The product for which eligible data met the class-based performance criteria for LC-aNAATs for this recommendation was Xpert MTB/RIF Ultra (Cepheid, Sunnyvale, United States of America [USA]). Data on Truenat MTB Plus and MTB-RIF Dx were limited and variable and thus were insufficient for evaluation.

Remarks

This recommendation applies to all people with signs and symptoms of the respective form of extrapulmonary TB, including people living with HIV and children.
Data on the performance of LC-aNAATs when used with urine and blood samples were limited or inconsistent.
Where possible, culture may be performed in addition to automated NAAT testing, to maximize the opportunity for diagnosis and detection of DR-TB.
The product for which eligible data met the class-based performance criteria for LC-aNAATs for this recommendation was Xpert MTB/RIF Ultra (Cepheid, Sunnyvale, United States of America [USA]). Data on Truenat MTB Plus and MTB-RIF Dx were limited and variable and thus were insufficient for evaluation.

Justification and evidence

WHO/GTB initiated an update of the previous guidelines and commissioned a systematic review on the use of LC-aNAATs (Xpert Ultra, Truenat MTB Plus and Truenat MTB-RIF Dx assays) for the diagnosis of TB and resistance to rifampicin in people with signs and symptoms of TB, or who screened positive for TB. The data on the performance of LC-aNAATs alone in these populations, compared with smear microscopy and culture, are presented in Web Annexes B.1–B.4. Recommendations on concurrent testing for children and people living with HIV supersede the use of LC-aNAATs alone in these populations (see Section 2.3 of this document).

Detection of pulmonary TB

Should LC-aNAATs on respiratory samples be used to diagnose pulmonary TB in adults and adolescents with signs and symptoms or who screened positive for pulmonary TB, against a microbiological reference standard?

Thirty-five studies (14 845 participants) assessed diagnostic accuracy using sputum specimens and comparing with a microbiological reference standard (MRS); however, one of those studies had no people with TB (Zar 2019) and so sensitivity was not estimable. The sensitivities in the remaining 34 studies (14 840 participants) included in the meta-analysis were between 54% and 100%, and the specificities were between 71% and 100% (Fig. 2.1.1). The summary sensitivity was 90.4% (95% confidence interval [CI]: 88.0–92.4), and the summary specificity was 94.9% (95% CI: 93.0–96.3). The certainty of evidence for sensitivity and specificity was graded as “high”. For more details, see Web Annex B.1.

Fig. 2.1.1. Forest plot of LC-aNAAT sensitivity and specificity for detection of pulmonary TB in sputum samples and MRSᵃ

CI: confidence interval; FN: false negative; FP: false positive; LC-aNAAT: low-complexity automated nucleic acid amplification test; MRS: microbiological reference standard; TB: tuberculosis; TN: true negative; TP: true positive.

^a Studies are sorted by assay and author.

Detection of rifampicin resistance

Should LC-aNAATs on respiratory samples be used to diagnose rifampicin resistance in adults and adolescents with signs and symptoms or who screened positive for pulmonary TB, against an MRS?

Of the 13 studies (2553 participants) that evaluated sputum specimens, sensitivity for detecting rifampicin resistance was not estimable for two studies (Fig. 2.1.2). The sensitivities in the remaining 11 studies (2540 participants) included in the meta-analysis were between 53% and 100%, and the specificities were between 97% and 100%. The summary sensitivity was 95.1% (95% CI: 83.1–98.7), and the summary specificity was 98.1% (95% CI: 97.0–98.7). Only two of the 11 included studies assessed Truenat MTB-RIF Dx; one of them, a study from a single country, had a sensitivity outside of confidence interval limits (53%). Nevertheless, overall, the certainty of evidence for both sensitivity and specificity was considered high.

Fig. 2.1.2. Forest plot of LC-aNAAT sensitivity and specificity for detection of rifampicin resistance in respiratory specimens and MRSᵃ

^a Studies are sorted by assay and author.

Detection of TB meningitis

Should LC-aNAATs on cerebrospinal fluid (CSF) be used to diagnose TB meningitis in adults with signs and symptoms of TB meningitis, against an MRS?

LC-aNAAT summary sensitivity and specificity were 88.2% (95% CI: 83.7–91.6) and 96.0% (95% CI: 86.8–98.9), respectively, based on 16 Xpert Ultra studies (1684 participants); the certainty of evidence was high for sensitivity and moderate for specificity (Fig. 2.1.3). Only data on Xpert Ultra were included in the evaluation to answer this population, intervention, comparator and outcome (PICO) question. Of note, trace results from Xpert Ultra were considered positive and formed a significant proportion of positive results (16–63%). Data on Truenat were limited and variable and thus were not included. For more details, see Web Annex B.3.

Fig. 2.1.3. Forest plot of LC-aNAAT sensitivity and specificity for detection of TB meningitis in cerebrospinal fluid and MRSᵃ

CI: confidence interval; CSF: cerebrospinal fluid; FN: false negative; FP: false positive; LC-aNAAT: low-complexity automated nucleic acid amplification test; MRS: microbiological reference standard; TB: tuberculosis; TN: true negative; TP: true positive.

^aStudies are sorted by decreasing sensitivity.

Detection of extrapulmonary TB

Should LC-aNAATs on lymph node fluid be used to diagnose lymph node TB in adults and adolescents with signs and symptoms of lymph node TB, against an MRS?

LC-aNAAT summary sensitivity and specificity from nine Xpert Ultra studies (445 participants) to diagnose lymph node TB in lymph node fluid in adults and adolescents with signs and symptoms of lymph node TB (Fig. 2.1.4) were 85.3% (95% CI: 73.4–92.4) and 74.1% (95% CI: 63.5–82.5), respectively. The certainty of evidence was low for sensitivity and very low for specificity. Only data on Xpert Ultra were included in the evaluation to answer this PICO question. The diagnostic accuracy of LC-aNAATs against a composite reference standard (CRS) that comprised the MRS plus patients who received clinical diagnoses (but were bacteriologically unconfirmed) was also considered. The use of the CRS markedly increased specificity to 97.4% (95% CI: 82.2–99.7) but decreased sensitivity to 71.3% (95% CI: 64.3–77.4), highlighting the known challenges with culture-based confirmation of TB with this sample type (see Web Annex B.3). Data on Truenat were limited and thus were not included.

Fig. 2.1.4. LC-aNAAT sensitivity and specificity for detection of lymph node TB in lymph node aspirate and MRSᵃ

CI: confidence interval; FN: false negative; FP: false positive; LC-aNAAT: low-complexity automated nucleic acid amplification test; LN: lymph node; MRS: microbiological reference standard; TB: tuberculosis; TN: true negative; TP: true positive.

^aStudies are sorted by decreasing sensitivity.

Should LC-aNAATs on pleural tissue be used to diagnose pleural TB in adults and adolescents with signs and symptoms of pleural TB, against an MRS?

From two Xpert Ultra studies (105 participants), LC-aNAAT sensitivities were 80% and 100%, and specificities were 75% and 86% (Fig. 2.1.5); the certainty of evidence was low for sensitivity and very low for specificity. Only data on Xpert Ultra were included in the evaluation to answer this PICO question, as data on Truenat were not available. Given known challenges with culture-based confirmation of TB using this sample, the data using the CRS were also considered. The use of the CRS increased specificity of the LC-aNAAT on pleural tissue to 94–97%, but it decreased sensitivity to 54–81%⁶ (see Web Annex B.3).

Fig. 2.1.5. LC-aNAAT sensitivity and specificity for detection of pleural TB in pleural tissue and MRSᵃ

^a Studies are sorted by decreasing sensitivity.

Should LC-aNAATs on pleural fluid be used to diagnose pleural TB in adults and adolescents with signs and symptoms of pleural TB, against an MRS?

LC-aNAAT summary sensitivity and specificity were 74.0% (95% CI: 60.8–83.9) and 88.1% (95% CI: 78.8–93.6), respectively, from 13 Xpert Ultra studies (1041 participants) (Fig. 2.1.6). The certainty of evidence was low for sensitivity and very low for specificity. Only one study (Jose 2024) provided accuracy estimates for pleural fluid for Truenat MTB Plus (88 participants), with sensitivity of 100% (95% CI: 0.03–100) and specificity of 100% (95% CI: 0.95–100). Similar to lymph node fluid and pleural tissue, the data using the CRS were also considered for this sample type. The use of the CRS increased specificity of LC-aNAATs on pleural fluid to 99.2% (95% CI: 95.2%–99.9%) but decreased sensitivity to 71.3% (95% CI: 64.3%–77.4%) (see Web Annex B.3). Only data on Xpert Ultra were included in the evaluation to answer this PICO question. Data on Truenat were limited.

Fig. 2.1.6. LC-aNAAT sensitivity and specificity for detection of pleural TB in pleural fluid and MRSᵃ

^a Studies are sorted by decreasing sensitivity.

Should LC-aNAATs on synovial fluid be used to diagnose bone or joint TB in adults and adolescents with signs and symptoms of bone or joint TB, against an MRS?

LC-aNAAT summary sensitivity and specificity were 96.6% (95% CI: 87.2–99.1) and 91.1% (95% CI: 80.8–96.2), respectively, from three Xpert Ultra studies (126 participants) (Fig. 2.1.7); the certainty of evidence was low. Similar to other extrapulmonary TB sample types, the data using the CRS were also considered. The use of the CRS increased specificity of the LC-aNAAT on synovial fluid to 97.0% (95% CI: 85.0–100.0), whereas the impact on sensitivity was minimal (96%) and largely involved tightening of the confidence interval (95% CI: 91–99%). Only data on Xpert Ultra were included in the evaluation to answer this PICO question. Data on Truenat were limited.

Fig. 2.1.7. LC-aNAAT sensitivity and specificity for detection of bone or joint TB in synovial fluid or tissue and MRSᵃ

^aStudies are sorted by decreasing sensitivity.

Should LC-aNAATs on peritoneal fluid be used to diagnose peritoneal TB in adults and adolescents with signs and symptoms of peritoneal TB, against an MRS?

The sensitivities of the LC-aNAATs ranged from 33% to 67%, and the specificities from 94% to 100%, from three Xpert Ultra studies (69 participants); the certainty of evidence was very low for sensitivity and low for specificity (Fig. 2.1.8). Only data on Xpert Ultra were included in the evaluation to answer this PICO question. Data on Truenat were limited.

Fig. 2.1.8. LC-aNAAT sensitivity and specificity for detection of peritoneal TB in peritoneal fluid and MRSᵃ

^a Studies are sorted by decreasing sensitivity.

Should LC-aNAATs on pericardial fluid be used to diagnose pericardial TB in adults and adolescents with signs and symptoms of pericardial TB, against an MRS?

LC-aNAAT summary sensitivity and specificity were 84.0% (95% CI: 73.9–90.7) and 86.6% (95% CI: 79.5–91.5), respectively, from three Xpert Ultra studies (202 participants); certainty of evidence was low for both sensitivity and specificity (Fig. 2.1.9).

Fig. 2.1.9. LC-aNAAT sensitivity and specificity for detection of pericardial TB in pericardial fluid and MRSᵃ

^a Studies are sorted by decreasing sensitivity.

Should LC-aNAAT on extrapulmonary specimens be used to diagnose rifampicin resistance in adults and adolescents with presumed extrapulmonary TB?

LC-aNAAT summary sensitivity and specificity were 100.0% (95% CI: 93.4–100.0) and 99.4% (95% CI: 92.1–100.0), respectively, from 13 Xpert Ultra studies (446 participants) (Fig. 2.1.10); certainty of evidence was high for both sensitivity and specificity.

Fig. 2.1.10. LC-aNAAT sensitivity and specificity for detection of pericardial TB in pericardial fluid and MRSᵃ

^aStudies are sorted by sensitivity.

Cost–effectiveness analysis

This section deals with the following additional question:

What are the comparative costs, affordability and cost–effectiveness of implementation of LC-aNAATs?

WHO commissioned a systematic review to identify, evaluate and summarise the evidence on cost, affordability and cost-effectiveness of LC-aNAATs, among other technologies.

A total of 1534 studies were identified in the original search; after removing duplicates, 736 potentially relevant studies were screened. Of these, 107 were assigned for full-text review and were evaluated against the inclusion and exclusion criteria, and 29 studies were included in the final systematic review. Of the 29 included studies, 22 (76%) assessed Xpert MTB/RIF, six (21%) assessed Xpert Ultra, and one study (3%) evaluated Truenat tests (both Truenat MTB Plus and Truenat MTB-RIF Dx). Ten of the studies evaluating Xpert MTB/RIF were cost– effectiveness analyses, and 12 were cost analyses. All the included Xpert Ultra studies and the study evaluating Truenat were cost–effectiveness analyses.

The cost-effectiveness analysis on Xpert was considered because of similarity between two technologies and scarcity of the data on Ultra.

The studies included in the review were diverse, were conducted across various settings and covered all income levels. This broad spectrum of research provided a comprehensive view of the economic evidence on LC-aNAATs, with a focus on adults. Only three cost–effectiveness analyses included children. There were various comparator tests, including smear and culture. Most of the studies included sputum specimens. Six of the 10 cost–effectiveness analyses on Xpert MTB/RIF presented results in natural units (additional people with TB detected), and the other four presented utility outcomes (quality-adjusted life years and disability-adjusted life years [DALYs]).

The findings from the cost–effectiveness analyses showed that Xpert MTB/RIF was generally cost effective across the included studies when compared with smear or culture, except for one study from Thailand, where TB LAMP was the dominant strategy. In contrast, there was more heterogeneity in the methodology used in the cost–effectiveness studies for Xpert Ultra, and the findings showed that, for the Xpert Ultra versus sputum smear microscopy (SSM), an incremental cost–effectiveness ratio (ICER) ranged from US$ 72.72 to US$ 160.23 per DALY averted. In the only study on Truenat, it was found to be cost effective for children in India compared with Xpert MTB/RIF, with an ICER of US$ 94.72 per DALY averted.

In general LC-aNAATs are likely to be cost effective across various settings when compared with SSM and culture.

More details on the economic evaluation of LC-aNAATs are available in Web Annex B.9.

User perspective

This section deals with the following question:

Are there implications for user preferences and values, patient equity, accessibility, feasibility and human rights from the implementation of Xpert MTB/ RIF and Xpert Ultra?

This review included 49 qualitative studies, of which 17 were identified in the updated search (since 2022). All studies about LC-aNAATs for detection of TB and DR-TB were conducted in high TB burden settings in Africa, Asia and Eastern Europe. Two studies provided user perspectives on Xpert Ultra and the rest on Xpert MTB/RIF or other rapid molecular tests. The studies about Xpert Ultra were conducted in Africa and Eastern Europe and focused on all people with presumptive TB, DR-TB and extrapulmonary TB.

Although standard Xpert MTB/RIF has been superseded by Xpert Ultra and other rapid NAATs, qualitative evidence for the latter NAATs is limited. Whereas LC-NAATs are generally valued for their accuracy, ease of use and potential to reduce time to diagnosis, the most recent generation of NAATs, such as Xpert Ultra, are valued for their greater accuracy in hard-to-diagnose patients, ease of implementation on existing GeneXpert platforms and ease of integration with rapid testing for other diseases. Challenges limiting the realization of these values for more recent NAATs are similar to those with Xpert MTB/RIF – that is, weak infrastructure, fragmented systems, heavy workloads, and limited availability of NAATs and their supplies. We recommend that qualitative studies be conducted to ascertain perspectives on concurrent use of NAATs.

There was high confidence in the evidence contributing to the findings of this review. More details on the qualitative evaluation of LC-aNAATs are available in Web Annex B.10.

User preferences and values

Findings from Xpert MTB/RIF studies showed that providers valued its utility in making a diagnosis of drug resistance in people living with HIV, accuracy and resulting confidence in the test, rapid turnaround times, low costs of diagnostic testing for patients, and improved patient– provider relationships. Providers also valued the diversity of sample types that can be analysed by the test. Laboratory personnel valued its ease of use, and they reported increased staff satisfaction compared with sputum microscopy. People with TB valued receiving an accurate diagnosis, avoiding diagnostic delays and having low costs associated with diagnostic testing. Compared with Xpert MTB/RIF, providers valued Xpert Ultra’s capacity for improving TB case detection among hard-to-diagnose patients (those with extrapulmonary TB, paediatric TB or coinfection with HIV) and detecting more people with TB.

Compared with Xpert MTB/RIF, providers valued Xpert Ultra for its ease of implementation and integration with testing for other diseases (made possible by its having been built on existing Xpert platforms). Acceptability of Xpert Ultra among providers seemed high, but there was uncertainty about its accuracy, potentially leading to reduced trust and litigation in the event of a false diagnosis.

Patient equity

The limited availability of Xpert Ultra in health facilities and the high costs incurred by patients and health facilities for its use were reported as concerns in terms of equity.

Acceptability

There were challenges to using Xpert MTB/RIF in the health care system. These challenges included underuse of the test and delays in the diagnostic pathway because of poor sample quality, insufficient resources and maintenance of the testing platforms, lack of functional data connectivity systems or record systems, inefficient patient flows, unavailability of updated clinical guidelines, and poor ownership of and accountability for the tests by health facilities. Overreliance on test results, rather than clinical judgement, and a lack of data-driven implementation processes were reported.

Access to the test may be limited owing to lack of sustainable funding, restrictions by donors, poor referral systems, dependence on outreach workers, unavailability of community TB diagnostic facilities and too many eligibility restrictions.

Feasibility

As with Xpert MTB/RIF, implementation of Xpert Ultra could be hindered by infrastructural problems, such as power outages, staff shortages, limited availability of transportation for sputum samples and limited availability of Xpert testing platforms in health facilities.

Implementation considerations

Diagnostic products in the low-complexity classes of tests should be prequalified by WHO or approved by another regulator before clinical use.
Diagnostic test manufacturers, laboratory and programme managers, and policy-makers should be educated on the WHO PQ process for TB IVDs (https://extranet.who.int/prequal/).
Ensuring sufficient volume and specimen quality is important to obtain accurate results.
Safe waste disposal of used test consumables needs to be planned in advance to minimize environmental risk.
Trace positive results on respiratory samples may present false-positive results for TB disease (M. tb. non-viable but DNA detected) in those that are HIV negative or not at risk for HIV, and those with a prior history of TB and an end of treatment within the last 5 years.
For tests that do not have integrated rifampicin-resistance detection as an all-in-one test, reflex testing for resistance should be performed at the same time for all TB-positive patients to support universal access to DST for rifampicin, at a minimum, and to reduce the risk of loss to follow-up.
In settings with a very low prevalence of rifampicin resistance⁷ , i.e. less than 2%, a positive test result for rifampicin resistance may represent a false positive result, and indicate a need for further testing with an alternative method or, at a minimum, repeat testing.
If rifampicin resistance is detected, further resistance testing for fluoroquinolones and bedaquiline is essential to guide selection of a shorter multidrug-resistant TB or rifampicin-resistant TB (MDR/RR-TB) treatment regimen.
Use of a higher volume of CSF (≥6 mL) with concentration, where possible, is encouraged to increase the sensitivity of LC-aNAATs.

Monitoring and evaluation

Track unsuccessful and indeterminate test result rates for currently recommended products and new products to be introduced in this class.
Monitor the proportion of trace results from paucibacillary samples (e.g. CSF), including those that are culture-positive or culture-negative.
Undertake surveillance to monitor the frequency of mutations (e.g. I491F mutation) outside of a rpoB rifampicin-resistance determining region (RRDR) over time.
Monitor the proportion of people with bacteriologically confirmed TB without a rifampicin-resistance result or further recommended drug susceptibility reflex testing over time.

Research priorities

Review the field performance of the current technologies used in routine practice (programmatic settings).
Conduct operational research to ensure that tests are used optimally in terms of both clinical efficiency and cost efficiency in intended settings.
Evaluate the impact of LC-aNAAT testing on patient-important outcomes (cure, mortality, time to diagnosis and time to start of treatment).
Evaluate the strengths, weaknesses and cost differences of different LC-aNAAT products to inform country selection.
Evaluate the different classes of tests, including LC-aNAATs, to determine which classes or testing strategies yield superior diagnostic accuracy, cost–effectiveness and impact on equity and acceptability.
Evaluate the impact on incremental accuracy and case detection and the cost–effectiveness of alternative sample types that are easier to collect.
Evaluate the individual product performance with different paediatric and extrapulmonary TB sample types.
Develop new tools that are rapid, affordable, feasible and acceptable to children and their parents.
Optimize or develop tests or simple pre-step sample handling procedures for extrapulmonary TB.
Identify an improved reference standard that accurately defines TB disease in children, paucibacillary specimens, and people who cannot produce sputum, because the sensitivity of all available diagnostics is suboptimal.
Develop and apply standardized methods for cost–effectiveness and economic studies, to limit variability.

2.1.2 Moderate complexity automated NAATs for detection of TB and resistance to rifampicin and isoniazid

Rapid detection of TB and rifampicin resistance is increasingly available as new technologies are developed and adopted by countries. However, what has also emerged is the relatively high burden of isoniazid-resistant, rifampicin-susceptible TB that is often undiagnosed. Globally, isoniazid-resistant, rifampicin-susceptible TB is estimated to occur in 13.1% (95% CI: 9.9–16.9%) of new cases and 17.4% (95% CI: 0.5–54.0%) of previously treated cases (1).

A new class of technologies has come to market with the potential to address this gap. Several manufacturers have developed moderate complexity automated NAATs for detection of TB and resistance to rifampicin and isoniazid on high throughput platforms for use in laboratories. The tests belonging to this class are faster and less complex to perform than phenotypic culture-based drug susceptibility testing (DST) and line probe assays (LPA). They have the advantage of being largely automated following the sample preparation step. Moderate complexity automated NAATs may be used as an initial test for detection of TB and resistance to both first-line TB drugs simultaneously (rifampicin and isoniazid). They offer the potential for the rapid provision of accurate results (important to patients) and for testing efficiency where high volumes of tests are required daily (important to programmes). Hence, these technologies are suited to areas with a high population density and rapid sample referral systems.

Table 2.1.2.1 Class criteria for MC-aNAATs

Recommendation

There are several subgroups to be considered for this recommendation:

The recommendation is based on evidence of diagnostic accuracy in respiratory samples of adults with signs and symptoms of pulmonary TB.
The recommendation applies to people living with HIV (studies included a varying proportion of such individuals); performance on smear-negative samples was reviewed but was only available for TB detection, not for rifampicin and isoniazid resistance, and data stratified by HIV status were not available.
The recommendation applies to adolescents and children based on the generalization of data from adults; an increased rate of indeterminate results may be found with paucibacillary TB disease in children.
The review did not consider extrapolation of the finding for use in people with extrapulmonary TB and testing on non-sputum samples because data on diagnostic accuracy of technologies in the class for non-sputum samples were limited.