4.4 Algorithm 4 – mWRD as the initial or follow-on test to detect Hr-TB

Algorithm 4 is for either detection of Hr-TB or follow-on testing for those with Hr-TB already identified. Detection of Hr-TB would be applicable in patients or settings with a high risk for Hr-TB and with RIF-susceptible TB (e.g. those with a molecular WRD result of "MTB detected, RIF resistance not detected") and isoniazid unknown. All patients with RIF-susceptible TB and INH susceptible/unknown should be started on an appropriate first-line regimen, in accordance with national guidelines, while awaiting the results of follow-up testing. The successful treatment of Hr-TB, prevention of the spread of Hr-TB and acquisition of resistance to additional drugs such as RIF rely on rapidly detecting patients with Hr-TB and placing them on effective treatment regimens.


  • The new moderate complexity automated NAAT class of initial tests for TB detection that simultaneously detects resistance to RIF and INH is recommended and should improve rapid identification of Hr-TB. Patients from Algorithm 1, where this class of test was used and Hr-TB was identified, would enter this algorithm for further investigation and management. This test could also be used for detection of isoniazid resistance for those with only rifampicin results.
  • The new first in class low complexity automated NAAT class (Xpert MTB-XDR) is recommended as a follow-on test that simultaneously detects resistance to INH and FQ, is suited to the peripheral level and complements existing WRDs that detect only RIF resistance.
  • The FL-LPA and SL-LPA are useful alternatives where these tests are already available and can detect INH and FQ resistance, respectively.
  • The use of molecular tests to detect INH resistance does not eliminate the need for conventional culture-based phenotypic DST, which will be necessary to determine resistance to other anti-TB agents and to monitor the emergence of additional drug resistance.
  • Detection of FQ resistance, along with PZA resistance, is important for patients with Hr-TB to ensure that an effective treatment is offered and prevent amplification of resistance to RIF or FQ.
  • Phenotypic DST to PZA is desirable if a quality-assured reliable DST for PZA has been established in the country. An alternative is the new high complexity reverse hybridization NAAT which is recommended for use on culture isolates for PZA resistance detection. Sequencing of the pncA if available is another option.

General considerations

  • Hr-TB prevalence is 7.4% (95% CI: 6.5-8.4%) in new cases and 11.4% (95% CI: 9.4-13.4%) in previously treated patients (62). The prevalence in some settings can exceed 25%. Contacts of a known Hr-TB patient are also at increased risk. The prevalence of any INH resistance is particularly high in some parts of the WHO European Region and Western Pacific Region.
  • Hr-TB is currently largely undetected but clinically relevant. Compared with patients with drug-susceptible TB, patients with Hr-TB who are treated with the recommended regimen for drug-susceptible TB have a much higher risk of treatment failure (11% versus 2%), relapse (10% versus 5%) and acquiring additional drug resistance (8% versus 1%) (63).
  • The successful treatment of Hr-TB, prevention of the spread of Hr-TB and acquisition of resistance to additional drugs such as RIF rely on rapidly detecting patients with Hr-TB and placing them on effective treatment regimens.
  • The recommended Hr-TB treatment regimen is :RIF, EMB, PZA and LFX for 6 months (63).

 Molecular WRD as the initial test to detect Hr-TB in patients with RIF-susceptible TB

DST: drug-susceptibility testing; EMB: ethambutol; FL-LPA: line-probe assay for first-line drugs; FQ: fluoroquinolone; HC-rNAAT: high complexity reverse hybridization NAAT; HREZ: isoniazid (H), rifampicin (R), ethambutol (E) and pyrazinamide (Z); Hr-TB: isoniazid-resistant, rifampicin-susceptible tuberculosis; INH: isoniazid; LC-aNAAT: low complexity automated NAAT; LFX: levofloxacin; MC-aNAAT: moderate complexity automated NAAT; MTB: Mycobacterium tuberculosis; MTBC: Mycobacterium tuberculosis complex bacteria; NAAT: nucleic acid amplification test; PZA: pyrazinamide; REZ: rifampicin (R), ethambutol (E) and pyrazinamide (Z); RIF: rifampicin; SL-LPA: line-probe assay for second-line drugs; TB: tuberculosis; WHO: World Health Organization; WRD: WHO-recommended rapid diagnostic test.

¹ All patients with MTBC detected, RIF resistance not detected and INH resistance unknown should be initiated on a first-line regimen according to national guidelines.

² Patients at high risk for Hr-TB should be given priority for molecular testing for INH resistance. Patients at high risk of Hr-TB include previously treated patients such as those who had been lost to follow-up, relapsed and failed a treatment regimen; Hr-TB contacts; and any other groups at risk for Hr-TB identified in the country (e.g. from populations with a high prevalence of Hr-TB). Molecular DST is preferred and includes MC-aNAAT, LC-aNAAT or FL-LPA.

³ Patients should be initiated on an Hr-TB regimen in accordance with national guidelines. The preferred regimen is 6 months of RIF-EMB-PZA-LFX (6 REZ-LFX) after confirmation of INH resistance, so long as RIF resistance has been reliably excluded. INH may be included in the regimen to enable the use of an HREZ fixed-dose combination tablet. The use of high doses of INH (up to 15 mg/kg) may be useful for patients whose isolate displays low-level resistance to INH (e.g. isolate with mutations in the inhA promoter region only).

⁴ For each patient with Hr-TB, a specimen should be referred for molecular DST for FQs. The LC-aNAAT can simultaneously detect INH and FQ resistance. The alternative for FQ resistance detection is the SL-LPA. PZA resistance detection should also be performed where this is available and quality assured.

⁵ Despite good sensitivity of LC-aNAAT (93%) and SL-LPA (86%) for detecting FQ resistance, culture and phenotypic DST may be needed for patients with a high pretest probability for FQ resistance (e.g. setting with a high underlying prevalence of resistance to FQs or patient risk factors) when the resistance is not detected by the molecular test.

⁶ Patients with FQ-resistant Hr-TB may be treated with a 6-month regimen of (H)REZ or an individualized Hr-TB regimen.

⁷ For all Hr-TB patients with concurrent resistance to FQ, phenotypic or molecular DST (e.g. HC-rNAAT) for PZA is desirable if a reliable DST for PZA has been established in the country. When resistance to PZA is confirmed, appropriate treatment regimens may have to be designed individually, especially if resistance to both FQ and PZA are detected.

Book navigation