Algorithm 4 is a follow-on algorithm, the purpose of which is to detect resistance in individuals with RIF-susceptible TB at risk of having DR-TB and individuals with Hr-TB. 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 known person with 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 may 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).
Tests
- The 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. People 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 INH resistance for those with only RIF results.
- The low complexity automated NAAT (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.
- Targeted NGS tests, such as the Deeplex® Myc-TB test (GenoScreen), which is recommended for detecting resistance to RIF, INH, PZA, EMB, FQ, BDQ, LZD, CFZ, AMK and STR; and the AmPORE TB test (Oxford Nanopore Technologies), which is recommended for detecting resistance to RIF, INH, FQ, LZD, AMK and STR.
- The use of targeted NGS tests to detect resistance does not eliminate the need for conventional phenotypic DST, which will be necessary for determining resistance to anti-TB agents not assessed by the targeted NGS test (or suboptimal by that test) and for monitoring the emergence of additional drug resistance.
- Targeted NGS tests are suitable for use at the central laboratory or NTRL level. They may also be used at the regional level if the appropriate infrastructure, human resources and QA systems are available. Implementation of targeted NGS testing depends on the availability of a reliable specimen transport system and an efficient mechanism for reporting results.
- 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 people with Hr-TB, to ensure that an effective treatment is offered and to prevent amplification of resistance to RIF or FQ.
- Phenotypic DST to PZA is desirable if a quality-assured reliable phenotypic 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 gene is another option, if available.