6.5 Algorithm 3 – Follow-on testing for individuals with RIF-susceptible TB at risk of resistance to other drugs

Algorithm 3 is a follow-on algorithm, the purpose of which is to detect resistance in individuals with RIF-susceptible TB who are at risk of having DR-TB and individuals with Hr-TB (Fig. 6.6). People at high risk for having DR-TB include those who have prior drug exposure; reside in settings where the probability of resistance to RIF, INH or FQs is high (≥5%), or belong to subgroups where the probability of such resistance is high; or have a history of contact with a person known to have DR-TB. Individuals not responding to first-line treatment include those who continue to be smear or culture positive after 2 months or more of treatment, and those who experience treatment failure.

Decentralized molecular testing is preferred, and can make use of any of the existing WHO-recommended tests that detect resistance to INH and FQ. However, the ability of targeted NGS tests to detect mutations associated with resistance to many anti-TB medicines could be particularly useful for people at high risk of having DR-TB (e.g. people in whom therapy has failed).

6.5.1 General considerations

WHO guidelines stress the importance of DST before treatment, especially for medicines for which genotypic DST is available.
People with TB that is RIF susceptible, INH susceptible or unknown should be started on a first-line regimen for drug-susceptible TB (7).
Globally, 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 people who were treated previously (98). The prevalence in some settings can exceed 25% (98). Contacts of a person known to have Hr-TB 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 undetected in many settings but is clinically important. Compared with people with drug-susceptible TB, people 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%) (98).
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 people with Hr-TB and placing them on effective treatment regimens. The LC-aNAATs for follow-up detection of INH resistance can be valuable tools because they are easy to use and can be implemented in the lower levels of the health system.
The recommended Hr-TB treatment regimen is RIF, EMB, PZA and LFX for 6 months (7, 99).
Targeted NGS tests report results for many medicines not used for treatment of drug-susceptible TB (e.g. BDQ, LZD, CFZ, AMK and STR). These results should not be released for people with RIF-susceptible TB; however, if the results are released, it should be made clear that these medicines are only to be used for individualized regimens in specialized circumstances.
Reliable phenotypic DST methods are available for RIF, INH, FQs, BDQ, CFZ, Pa, CS, LZD, AMK and DLM. Testing algorithms that rely on culture and phenotypic DST are described in the WHO policy framework (96) and technical manual (Web Annex C). Member States should ensure there is capacity for DST for drugs that are used for treatment and for which reliable testing is available.
No reliable phenotypic DST methods are available for EMB, ETO/prothionamide, or imipenem-cilastatin/MPM; hence, results for these medicines should not be used for clinical decision-making.
Initiation of treatment should not be delayed while waiting for the results of DST.

Fig. 6.6. Algorithm 3: Follow-on testing for people with RIF-susceptible TB at risk of resistance to other drugs

DR-TB: drug-resistant TB; DST: drug susceptibility testing; FL-LPA: line probe assay for first-line drugs; Hr-TB: isoniazidresistant, rifampicin-susceptible TB; MC-aNAAT: moderate-complexity automated nucleic acid amplification test; mWRD: molecular WHO-recommended rapid diagnostic test; NGS: next-generation sequencing; SL-LPA: line probe assay for second-line drugs; SRL: supranational reference laboratory; TB: tuberculosis; WHO: World Health Organization.

Drugs: AMK: amikacin; BDQ: bedaquiline; CFZ: clofazimine; CS: cycloserine; DLM: delamanid; EMB: ethambutol; FQ: fluoroquinolone; INH: isoniazid; LZD: linezolid; Pa: pretomanid; PZA: pyrazinamide; RIF: rifampicin; STR: streptomycin.

^a People diagnosed with TB should be promptly initiated on a regimen for drug-susceptible TB or Hr-TB in accordance with national guidelines and WHO recommendations (7, 100). People at high risk for having DR-TB include those who have prior drug exposure; reside in settings where the probability of resistance to RIF, INH or FQs is high (≥5%), or belong to subgroups in which the probability of such resistance is high; or have a history of contact with a person with known DR-TB or not responding to first-line treatment, including those who continue to be smear or culture positive after 2 months or more of treatment or experience treatment failure.

^b If molecular and phenotypic testing are performed in the same laboratory, one specimen may be sufficient. If testing is performed in two laboratories, two specimens should be collected, and the molecular and phenotypic testing conducted in parallel.

^cWHO recommends getting the rapid DST results before the start of treatment, although this testing should not delay the start of treatment. Rapid mWRDs for detecting FQ resistance include Xpert MTB/XDR and SL-LPAs; for detecting INH resistance include Xpert MTB/XDR, FL-LPAs and MC-aNAATs, and for detecting PZA resistance include the Genoscholar PZA-TB II test. Targeted NGS tests can provide results for BDQ, FQ, LZD, INH, PZA, EMB, CFZ, AMK, STR and RIF.

^d Phenotypic DST should be conducted for each of the drugs included in the treatment regimen for which there are accurate and reproducible methods. Reliable phenotypic DST methods are available for RIF, INH, PZA, FQs, BDQ, CFZ, Pa, CS, LZD, AMK and DLM (Web Annex C). The initiation of treatment should not be delayed while awaiting the results of the phenotypic DST.

^eFor more information regarding modified treatment regimens, see the WHO consolidated guidelines on treatment of DR-TB (7) and drug-susceptible TB (100).

^fFor DR-TB, a specimen should be collected and submitted for phenotypic DST, if not already being done as described in Note 4. If targeted NGS tests are available, a sample should be submitted for testing for resistance to additional medicines for specified risk groups in accordance with national guidelines.

^g If resistance to an individual drug is suspected and DST for these drugs is not available in the country, laboratories should establish mechanisms to store the isolate and ship it to a WHO SRL for DST.

Decision pathway for Algorithm 3 – Follow-on testing for individuals with RIF-susceptible TB at risk of resistance to other drugs

The person should be promptly initiated on a regimen for the treatment of RIF-susceptible TB in accordance with national guidelines (100). Individuals with Hr-TB should be started on an Hr-TB regimen (99, 100).
If molecular and phenotypic testing are performed in the same laboratory, collecting one specimen may be sufficient. If testing is performed in two laboratories, two specimens should be collected and the molecular and phenotypic testing conducted in parallel. Sputum specimens or isolates should be transported to the appropriate testing laboratory, if necessary.
Molecular testing and culture should be performed in parallel.
1. If targeted NGS tests are used:
  1. The treatment should be modified if appropriate, and phenotypic DST performed when the culture is positive based on Table 6.1. Note: the results from sequencing produce information on multiple drugs simultaneously; however, for simplicity, Table 6.1 takes a single-drug approach for interpreting targeted NGS test results, although all results should be taken into consideration when designing a treatment regimen.
  2. If the targeted NGS test result is indeterminate, the test should be repeated with a fresh sample, and treatment decisions should be based on clinical assessments, the epidemiological situation and the results of phenotypic DST.
2. If a WHO-recommended follow-on molecular test other than a targeted NGS test is used:
  1. For a person with RR-TB detected by either a molecular (e.g. Xpert Ultra or Truenat) or phenotypic DST, but for whom no results are available for INH and who is at high risk for Hr-TB, the process should start at Step 1 below.
  2. For a person who had an initial TB test that included RIF and INH results (e.g. an MC-a NAAT was used) in Algorithm 1, the process should start at Step 4 below.
    1. A good-quality specimen should be collected and transported to the testing laboratory for molecular or phenotypic testing for INH resistance:
      - Testing could follow a two-step process: detection of INH resistance followed by detection of FQ resistance. The two-step process is applicable when an MC-aNAAT or FL-LPA is used for Hr-TB detection, followed by the LC-aNAAT or SL-LPA for detection of FQ resistance. A single-step option is now available using the first-in-class LC-aNAAT, which detects both INH and FQ resistance simultaneously.
      - Phenotypic DST may be required for INH resistance determination because of the sensitivity; depending on the test used, it may miss about 15% of resistant samples (Table 3.3). Phenotypic DST will be relevant when the person is at high risk for Hr-TB. If both molecular and phenotypic tests are performed, the tests should be initiated in parallel; it is important to not wait for the results of one test before initiating the other test.
      - Culture-based phenotypic DST for INH requires 3–8 weeks to produce a result. Phenotypic DST may be useful for evaluating people with results from an mWRD showing susceptibility to INH, particularly in populations with a high pretest probability for resistance to INH.

Table 6.1. Treatment modifications and follow-on DST for Hr-TB based on results from targeted NGS

If INH resistance is not detected, treatment should be continued with a first-line regimen in accordance with national guidelines:
- Additional DST should be conducted in accordance with national guidelines.
- Consideration should be given to requesting additional molecular or phenotypic DST for resistance to INH if the person is thought to be at risk of having Hr-TB, despite the mWRD result.
If INH resistance is detected:
1. The LC-aNAAT will provide simultaneous detection of resistance to INH and FQ. If FQ resistance is not detected, Steps 3b and 5 should be followed; if FQ resistance is detected, Steps 3d(ii) and 5 should be followed; and if the FQ result is unknown or unsuccessful, Step 3c should be followed.
2. Treatment with an Hr-TB regimen should be initiated (7):
  1. There is no clear evidence showing that adding INH at the usual doses benefits or harms people. For the convenience of the people being treated and for ease of administration, the four-drug INH/RIF/EMB/PZA (HREZ) fixed-dose combination tablets may be used to deliver the Hr-TB regimen, alongside LFX.
  2. Emerging evidence suggests that people infected with strains with only inhA promoter mutations and corresponding modest increases in minimal inhibitory concentration (MIC) may benefit from high-dose INH therapy. Thus, additional INH – up to a maximum dose of 15 mg/kg per day – may be considered for use with the Hr-TB regimen for such isolates. The added value of INH in the regimen, even when used at the higher dose, declines as MICs increase further.
3. A specimen should be referred from a person with laboratory-confirmed Hr-TB for molecular (e.g. LC-aNAAT or SL-LPA) or phenotypic DST for FQs and PZA. Note: if the Xpert MTB/XDR test was used in Step 1, the FQ result will already be available and Step 6d applies.
  1. Rapid molecular testing for FQ resistance is preferred. When used for direct testing of sputum specimens, the LC-aNAAT and SL-LPA detect 93% and 86% of people with FQ resistance, respectively (Table 3.4):
    - LC-aNAATs provide rapid results and are suitable for use at the peripheral level. The first-in-class test, Xpert MTB/XDR, reports low-level FQ resistance when the mutations gyrA A90V, gyrA S91P and gyrA D94A are detected from the probe melting temperature (92). Phenotypic DST at the clinical breakpoint for MFX should be performed to confirm the potential value of high-dose MFX treatment for such people.
    - The diagnostic accuracy of SL-LPA is similar when it is performed directly on sputum or cultured isolates. SL-LPA can be used with smear-positive or smear-negative specimens, although the indeterminate rate will be higher when testing smear-negative specimens.
    - Despite the good specificity and sensitivity of LC-aNAATs and SL-LPA for the detection of FQ resistance, phenotypic DST is required to completely exclude resistance to individual FQs. In particular, phenotypic DST may be needed in settings with a high pretest probability for resistance to FQ, to exclude resistance when the SL-LPA does not detect mutations associated with resistance.
4. FQ resistance results should be reviewed:
  1. If FQ resistance is not detected, treatment should be continued with the LFX-containing Hr-TB regimen.
  2. If FQ resistance is detected:
    - Use of LFX should be discontinued and instead a 6-month regimen of (INH)/ RIF/EMB/ PZA should be used; that is, 6(H)REZ, where the “(H)” indicates that the INH is optional, or an individualized Hr-TB regimen.
    - A specimen should be referred for PZA DST if reliable PZA DST is available in the country. Options include the HC-rNAAT, phenotypic DST in the MGIT system and pncA sequencing. Further details are given in the WHO technical manual for drug susceptibility testing of medicines used in TB treatment (Web Annex C).
    - If PZA resistance is not detected, or if PZA DST is not available, therapy should be continued with the regimen that was designed based on the previous DST results.
    - If PZA resistance is detected, it may be necessary to design individualized treatment regimens, especially if resistance to both FQs and PZA is detected.
If the INH result cannot be interpreted or is invalid, the LC-aNAAT or MC-aNAAT or FL-LPA should be repeated with a fresh specimen. Consideration should be given to conducting culture and molecular or phenotypic DST for INH on the isolate, if the person is considered to be at risk of having Hr-TB.
For all people with TB, treatment monitoring should include collection of samples for culturing, as described in WHO guidelines. Any positive culture suggestive of treatment failure should undergo phenotypic and molecular DST, if available. At a minimum, DST should include testing for resistance to INH and RIF for people on first-line regimens, and for RIF, FQs and PZA (if available) for people on Hr-TB regimens. The treatment regimen should be modified as necessary, based on the results of the DST.

6.5 Algorithm 3 – Follow-on testing for individuals with RIF-susceptible TB at risk of resistance to other drugs

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