Category Archives: Evidence Informed Healthcare

WHO issues update on the use of nucleic acid amplification tests to detect TB and drug-resistant TB (17 February 2021)

Recently, the World Health Organization (WHO) released updated guidance on Nucleic Acid Amplification Tests for Tuberculosis (TB).

Background information:

In 2019, 3 million of an estimated 10 million individuals with TB were not reported to have been diagnosed and notified. This gap is proportionately wider for drug-resistant TB, with only 44% of the estimated 465000 patients with rifampicin-resistant and multi-drug resistant TB (RR/MDR-TB) diagnosed and notified.

Among people with TB and rifampicin-resistant TB, additional testing for resistance to at least isoniazid and fluoroquinolones respectively, should be performed promptly to guide treatment decisions. WHO currently recommends using commercially available molecular line probe assays as the initial test to detect resistance to fluoroquinolones for people with rifampicin resistant TB. Nevertheless, more automated, accessible, accurate diagnostics for the detection of resistance to first- and second-line anti-TB drugs are urgently needed. Monitoring of resistance to pyrazinamide, another important antibiotic for the treatment of both drug-susceptible and drug-resistant TB, remains very limited.

In 2020, WHO commissioned a systematic review of published and unpublished data on three classes of nucleic acid amplification tests (NAATs) not previously reviewed by WHO. The systematic review included data on diagnostic accuracy, economic information, and qualitative evidence on feasibility, acceptability, equity, end-user values and preferences. A Guideline Development Group (GDG) was convened by WHO on 7-18 December 2020 to discuss the findings of the systematic reviews and to make recommendations on these three classes of technologies.

The three classes of technologies that were evaluated include:

  • Low complexity automated NAATs for detection of resistance to isoniazid and second-line anti-TB agents;
  • Moderate complexity automated NAATs for detection of TB and resistance to rifampicin and isoniazid;
  • High complexity hybridization-based NAATs for detection of resistance to pyrazinamide.
Technology classProducts included in evaluation
Low complexity automated NAATs for detection of resistance to isoniazid and second- line anti-TB agents Xpert MTB/XDR (Cepheid)
Moderate complexity automated NNATs for detection of TB and resistance to rifampicin and isoniazidAbbott RealTime MTB and Abbott RealTime MTB RIF/INH (Abbott)
FluoroType MTBDR and FluoroType MTB (Hain Lifescience
BD MAX MDR-TB (Becton-Dickinson)
cobas MTB and cobas MTB-RIF/INH (Roche)
High complexity hybridization-based NAATs for detection of resistance to pyrazinamideGenoscholar PZA-TB II (Nipro)
Table 1. Classes of technologies and associated products evaluated

Key Messages:

Low complexity automated NAATs for the detection of resistance to isoniazid, fluoroquinolones, ethionamide and amikacin in sputum were found to be highly accurate.

What was done?

Three studies involving 1605 participants were studied. Low complexity automated NAATs performed on sputum from people with microbiologically diagnosed pulmonary TB, for detection of resistance to isoniazid, fluoroquinolones, ethionamide and amikacin were compared with

  • phenotypic Drug Susceptibility Testing (DST) (for detection of resistance to isoniazid, fluoroquinolones and amikacin) or
  • gene sequencing of inhA promoter region (for detection of resistance to ethionamide).

Results

High diagnostic accuracy of low complexity automated NAATs was confirmed in people with microbiologically diagnosed pulmonary TB.

Phenotypic DST used as the reference standard:

  • Isoniazid resistance detection: Overall pooled sensitivity (95% CI) was 94.2% (89.3 to 97.0) and specificity was 98.0% (95.2 to 99.2).
  • Fluoroquinolone resistance detection: Overall pooled sensitivity (95% CI) was 93.1% (88.0 to 96.1) and specificity was 98.3% (94.5 to 99.5).
  • Amikacin resistance detection: Overall pooled sensitivity (95% CI)was 89.1% (80.9 to 94.1) and specificity was 99.5% (96.9 to 99.9).

Gene sequencing of inhA promoter region used as the reference:

  • Ethionamide resistance detection: Overall sensitivity (95% CI) was 96.4% (92.2 to 98.3) and specificity was 100.0% (82.5 to 100.0).

Moderate complexity automated NAATs for the detection of TB, rifampicin and isoniazid resistance on respiratory samples were found to be highly accurate.

What was done?

32 studies involving 16726 samples were included in the systematic review.

Moderate complexity automated NAATs performed on respiratory samples from people with signs and symptoms of pulmonary TB for detection of TB and resistance to isoniazid and rifampicin, were compared with culture and phenotypic drug susceptibility testing (DST).

Results

High diagnostic accuracy of moderate complexity automated NAATs was confirmed in people with signs and symptoms of pulmonary TB.

Culture and phenotypic DST as the reference standard

  • TB detection: Overall pooled sensitivity (95% CI) was 93.0% (90.9 to 94.7) and specificity was 97.7% (95.6 to 98.8).
  • Rifampicin resistance detection: Overall pooled sensitivity (95% CI) was 96.7% (93.1 to 98.4) and specificity was 98.9% (97.5 to 99.5).
  • Isoniazid resistance detection: Overall pooled sensitivity (95% CI) was 86.4% (82.8 to 89.3) and specificity was 99.2% (98.1 to 99.7).

High complexity hybridization-based NAATs for the detection of pyrazinamide resistance in M. tuberculosis isolates were found to be highly accurate

What was done?

Seven studies involving 964 participants were included in the systematic review.

Hybridization-based NAATs performed in isolates retrieved from patients with bacteriologically confirmed pulmonary TB, for detection of resistance to pyrazinamide were compared with phenotypic DST.

Results

High diagnostic accuracy of high complexity hybridization-based NAATs was confirmed on isolates retrieved from patients with bacteriologically confirmed PTB.

Phenotypic DST as the reference standard

  • Pyrazinamide resistance detection: Overall pooled sensitivity (95% CI) was 81.2% (75.4 to 85.8) and specificity was 97.8% (96.5 to 98.6).

Overall conclusions

Available evidence supports the use of:

  • low complexity automated NAATs for the detection of resistance to isoniazid and second-line anti-TB agents;
  • moderate complexity automated NAATs for the detection of TB and resistance to rifampicin and isoniazid; and
  • high complexity hybridization-based NAATs for the detection of resistance to pyrazinamide.

Precaution:

These findings were based on evaluation of data for the assays that met the class definition (Table 1).

Extrapolation to other brand-specific tests cannot be made and any new in-class technologies will need to be specifically evaluated.

Useful Link:

Link to the updated guidance from WHO:

https://www.who.int/news/item/17-02-2021-who-announces-updates-on-new-molecular-assays-for-the-diagnosis-of-tuberculosis-(tb)-and-drug-resistance