- A new test, the low complexity automated NAAT, is recommended and is an alternative to SL-LPA:
- It can be used in PLHIV, children and people with extrapulmonary TB.
- The first in class test, the Xpert MTB-XDR test, provides results in under 2 hours, requires minimal hands-on time, can be used at the peripheral level and provides results simultaneously for FQ, INH, ETO and AMK. This test requires a 10-colour GeneXpert instrument unlike the current Xpert MTB/RIF and Xpert Ultra test that use the 6-colour GeneXpert instruments. The new instruments can be linked to existing 6-colour GeneXpert systems through a common computer.
- The use of low complexity automated NAAT to detect FQ resistance does not eliminate the need for conventional culture-based phenotypic DST, which will be necessary for determining resistance to other anti-TB agents and monitoring the emergence of additional drug resistance.
- The SL-LPA is still recommended and used where available. The following should, however, be noted:
- The diagnostic accuracy of SL-LPA is similar when it is performed directly on sputum or on cultured isolates. SL-LPA can be used on smear-positive or smear-negative specimens, although a higher indeterminate rate will occur with smear-negative specimens.
- SL-LPA is only recommended for use with sputum specimens or MTBC isolates. The laboratory testing of other specimen types should rely on culture and phenotypic DST.
- SL-LPA is suitable for use at the central or national reference laboratory level. It may also be used at the regional level if the appropriate infrastructure, human resources and QA systems are available. Implementation of SL-LPA testing depends on the availability of a reliable specimen transport system and an efficient mechanism for reporting results.
- The use of SL-LPA to detect FQ resistance does not eliminate the need for conventional culture-based phenotypic DST, which will be necessary for determining resistance to other anti-TB agents and monitoring the emergence of additional drug resistance.
- A shorter all-oral BDQ-containing treatment regimen of 9-12 months in duration is the preferred option for eligible MDR/RR-TB patients (7).
- The preferred regimen contains BDQ, LFX or moxifloxacin (MFX), ETO, EMB, INH (high-dose), PZA and CFZ (4-6 months of BDQ-LFX-ETO-EMB-PZA-high dose INH-CFZ / 5 months of LFX -CFZ-PZA-EMB).
- Individualized all-oral longer regimens, designed using the WHO priority grouping of medicines, may still be used for MDR/RR-TB patients who do not meet the eligibility criteria for an all-oral shorter BDQ-containing regimen.
- Injectable medicines (e.g. AMK) should be phased out as a matter of priority in all treatment regimens and replaced by BDQ. If AMK is still used in the country, WHO recommends that, for patients being considered for the shorter AMK-containing MDR-TB regimen, FQ and AMK susceptibility (e.g. no mutations detected by low complexity automated NAAT or SL-LPA) should be demonstrated before initiating the shorter AMK-containing MDR-TB regimen - see Algorithm 3 of the GLI model diagnostics algorithms for recommended testing (59).
- WHO guidelines stress the importance of DST before treatment, especially for medicines for which mWRDs are available.
- WHO-approved rapid molecular tests are available for RIF, INH and FQs. Genetic tests, including targeted NGS, are being developed for some of the other drugs (e.g. BDQ and LZD) included in MDR-TB regimens.
- WHO recommends a new molecular test for PZA resistance detection belonging to the class high complexity reverse hybridization NAAT. Its use is limited to culture isolates. Alternatively, pncA sequencing should be performed when available. In a quality-assured laboratory, with careful attention to inoculum preparation, a susceptible phenotypic DST result using MGIT960 for PZA can be used to guide the inclusion of PZA in a DR-TB treatment regimen (20).
- Reliable phenotypic DST methods are available for RIF, INH, FQs, BDQ, CFZ, LZD, AMK and DLM. Testing algorithms that rely on culture and phenotypic DST are described in the relevant WHO policy framework (60) and technical manual (20). Member States should ensure there is capacity for DST for drugs used for treatment and for which reliable testing is available.
- No reliable phenotypic DST methods are available for EMB, ETO/prothionamide, cycloserine/terizidone or imipenem-cilastatin/meropenem; hence, results should not be used for clinical decision-making.
- If phenotypic DST to second-line drugs is not available in-country, specimens or isolates may be shipped to an external laboratory for testing (e.g. a WHO supranational reference laboratory [SRL]). Material transfer agreements and import/export permits may be needed.
- Currently, availability of phenotypic DST for BDQ and LZD is limited in many settings, and resistance levels are likely to be low. There is, however, increasing evidence that BDQ resistance even in unexposed patients 1.4-3.4% (61). BDQ is a core drug for DR-TB treatment and included in the revised XDR-TB definition. Thus, building testing capacity to this drug and other drugs used in treatment (e.g. LZD, CFZ and DLM) is essential. If resistance is suspected during treatment and DST is not available, the strains should be referred to an SRL for further testing.
- Do not delay initiation of treatment while waiting for the results of DST.
Decision pathway for Algorithm 3
1. Promptly initiate the patient on an MDR-TB regimen, in accordance with national guidelines. The most recent WHO recommendations is for the use of a shorter all-oral BDQ-containing treatment regimen of 9-12 months in duration (57, 58).
2. If molecular and phenotypic testing are performed in the same laboratory, collecting one specimen may be sufficient. If testing is performed in two laboratories, collect two specimens and conduct the molecular and phenotypic testing in parallel. Transport sputum specimens or isolates to the appropriate testing laboratory, if necessary.
3. Conduct the low complexity automated NAAT or SL-LPA to detect mutations associated with FQ resistance.
4. If the low complexity automated NAAT or SL-LPA detects one or more mutations associated with resistance to FQs:3A
a. Place MDR/RR-TB patients with resistance to FQs on an individualized longer regimen, designed using the WHO priority grouping of medicines recommended in 2018.
b. The first in class low complexity automated NAAT (Xpert MTB-XDR) provides results for INH, ETO and AMK and can be used to inform individualized regimen selection. Collect a specimen and submit for phenotypic DST to the WHO Group A, B and C drugs (e.g. DST for BDQ, DLM and LZD), if phenotypic DST is not already being done as described in Step 6. Testing moxifloxacin at the clinical breakpoint should be performed to determine the potential use of high-dose (800 mg) moxifloxacin for treatment (19).
5. If the low complexity automated NAAT or SL-LPA is negative for mutations associated with resistance to FQs:
a. Continue patients on the all-oral BDQ-containing shorter MDR-TB regimen, while awaiting the results of the phenotypic DST (Step 6).
b. In settings with high underlying prevalence of resistance to FQs or for patients considered at high risk of resistance, refer a specimen for culture and phenotypic DST for FQs, because the sensitivity of the low complexity automated NAAT and SL-LPA to detect mutations associated with FQ resistance is about 93% and 86%, respectively. The phenotypic DST should include testing for resistance to the FQs used in the country. The phenotypic DST should also include testing moxifloxacin at the clinical breakpoint to inform individualized drug selection. Modify the regimen as necessary, based on the phenotypic DST results.
6. Perform culture and phenotypic DST for each of the drugs included in the treatment regimen for which there are accurate and reproducible methods 3B. For the preferred regimens, reliable phenotypic DST methods when performed in a quality-assured laboratory are available for BDQ, FQs, CFZ, PZA and INH. A WHO-approved molecular test for PZA resistance detection is available (high complexity reverse hybridization NAAT) but currently is limited to use on culture isolates.
a. If the isolate is susceptible to all drugs, continue the patient on the preferred MDR-TB regimen.
b. If resistance is detected to any drug, place the patient on an individualized longer MDR-TB regimen, designed using the WHO priority grouping of medicines recommended in 2018. As results for phenotypic DST are slow, reassess patient response when these results are available. The decision to change from a shorter to the longer MDR-TB regimen should consider the phenotypic DST result and clinical response. Monthly monitoring is important, and the patient should be closely followed up.
7. For all patients, ensure that treatment monitoring includes the collection of samples for culturing as described in the WHO consolidated guidelines (58). Any positive culture suggestive of treatment failure should undergo phenotypic DST. Modify the regimen as necessary, based on the phenotypic DST results.
a. WHO recommends that all patients being treated with an MDR-TB regimen be monitored for treatment response using sputum culture and sputum-smear microscopy. It is desirable for sputum culture to be repeated at monthly intervals.
b. Although the risk of treatment failure increases with each additional month without bacteriological conversion, no discrete cut-off point has been defined that could serve as a reliable marker of a failing regimen. The choice of cut-off point will depend on the clinician's desire to minimize the risk of failure and, in particular, to limit the risk of prolonging a failing regimen.
For footnotes please see page 92