3.1 Access to DST

The current guidelines for drug-resistant TB treatment stress the need for access to reliable, qualityassured DST, to be provided by national TB programmes (NTPs) and associated laboratories, to inform the use of the WHO-recommended regimens. Rapid molecular testing is making it increasingly feasible for NTPs to detect MDR/RR-TB and other types of resistance, and to use the results to guide treatment decisions (12, 13) (see also Sections 4–7). Hence, rapid molecular testing should be available and accessible, to ensure DST for at least rifampicin and fluoroquinolones, given that DST for both of these agents is essential for selecting the most appropriate initial regimen. While NTPs build capacity to ensure access to DST, they should also build capacity of a surveillance system to determine the local prevalence of drug-resistant TB strains and to guide programmatic management. Such information can only be accurately determined by appropriate surveillance, whether it be based on data from routine diagnostic DST in TB patients (i.e. continuous surveillance) or from special surveys representative of the entire TB patient population (i.e. drug-resistance surveys) (14). Local TB drugresistance surveillance (DRS) data should provide accurate estimates of the frequency of resistance to at least rifampicin and isoniazid in new patients, and to fluoroquinolones among MDR/RR-TB cases, as well as some information about the frequency of resistance in relevant subgroups of re-treatment cases (e.g. recurrence or failure after a first-line anti-TB regimen and return after loss to follow-up). Some drug-resistance surveys are now using rifampicin resistance as the main target indicator, given that all RR-TB cases are eligible for an MDR-TB treatment regimen (1, 15).

WHO recommends the use of the approved rapid molecular DST as the initial test to detect drug resistance before the initiation of appropriate therapy for all TB patients, including new patients and patients with a previous history of TB treatment. The increased recognition of drug resistance and improved access to rapid molecular testing have led more programmes to test for at least rifampicin resistance at the start of TB treatment. In addition to Xpert MTB/RIF® for rifampicin, a line probe assay (LPA) can detect mutations commonly associated with resistance to rifampicin, isoniazid, fluoroquinolones and second-line injectable agents. No rapid molecular testing is currently available for ethambutol or pyrazinamide. Results from LPA typically become available within a few days of testing and can thus be used to decide upon the initial regimen for treatment of Hr-TB, or some other forms of mono-resistant or poly-resistant TB. Apart from its rapidity, LPA can also provide information on the mutation patterns, which can influence the choice of treatment (e.g. if only the inhA mutation is present, it is likely that isoniazid can still be effective at high dose, whereas if the katG mutation alone or both inhA and katG are present, isoniazid is no longer effective, even at high dose). If rifampicin resistance is detected, rapid molecular tests for resistance to isoniazid and fluoroquinolones should be performed promptly, to inform the decision on which regimen to use for the treatment (16). Rapid molecular testing for both rifampicin and fluoroquinolones is widely available; countries have accumulated experience in using these rapid tests, and access is also supported by the main donors where necessary. Commercially available rapid molecular methods (e.g. the second-line LPAs) detect about 85% of fluoroquinolone-resistant isolates (13). Culture-based DST for fluoroquinolones should be considered when the prevalence of resistance to these drugs is high, or when resistance is suspected despite the molecular tests being negative.

Country programmes need to work towards the establishment of DST for all TB medicines for which there are now agreed reliable and reproducible methods (e.g. bedaquiline, linezolid, clofazimine, delamanid and pyrazinamide). The critical concentrations for various drugs were either established for the first time (bedaquiline, delamanid, clofazimine and linezolid) or revised (fluoroquinolones) in a WHO technical consultation in 2017 (17). If available, targeted or whole genome sequencing (or sequencing of the pncA gene) will be used as a reference method to detect pyrazinamide resistance. Susceptibility to ethionamide/prothionamide may in part be inferred from the results of molecular testing for isoniazid resistance (i.e. presence of mutations in the inhA promotor region) using LPA. Phenotypic DST for cycloserine/terizidone, ethambutol, ethionamide/prothionamide, imipenem/meropenem or p-aminosalicylic acid is not routinely recommended because results may be unreliable (16).

The inability to undertake DST routinely in all patients despite all possible efforts should not be a barrier to starting patients on a potentially life-saving MDR-TB regimen, but should always be considered in a context of the potential risk of prescribing ineffective treatment and amplifying drug resistance, with a subsequent decrease in the likelihood of a successful treatment outcome. If DST for second-line TB medicines is not yet available, the clinician or the TB programme manager needs to estimate the likelihood of effectiveness of the medicines used, informed by the patient’s history of use of second-line TB medicines, the drug-resistance pattern of the contact or index case, and recent representative drug-resistance surveillance data. Therefore, a reliable clinical history of exposure to second-line TB medicines should be considered when designing a treatment regimen, but this should not be the primary source of evidence to guide clinical judgement. For paediatric patients, it is not always possible to obtain a DST result, owing to the difficulty of obtaining an adequate specimen or the lack of bacteriological confirmation; hence, the treatment design is usually based on the drugresistance pattern of the index case. In the absence of individual DST, relevant population surveillance data are essential to inform the choice and design of MDR-TB treatment regimens. In addition to TB DRS findings, it is important for practitioners to know which medicines have been in frequent use in a given geographical setting or patient groups. If DST is not routinely available for individual patients, storage of M. tuberculosis isolates collected at baseline or during treatment monitoring can be considered for performing whole genome sequencing in case of treatment failure.

The DST results are generally used to guide the choice of chemotherapy in TB and MDR-TB regimens. When based on externally quality-assured laboratory work, DST to isoniazid, rifampicin and fluoroquinolones is most useful for clinical purposes. Methods for phenotypic DST – on mycobacteria growth indicator tube (MGIT) – for bedaquiline, linezolid, clofazimine, pyrazinamide and delamanid have now also been validated (16, 17). Mutations in the promotor region of the inhA gene are detected by the first-line LPA; these mutations confer resistance to thioamides. Rapid implementation and use of these methods are needed to ensure antimicrobial stewardship, to accompany transition to new regimens. A standardized DST method for pretomanid is being developed and will be made available in the near future. Capacity to test for at least bedaquiline and linezolid should be established as a priority; however, regimen adoption and implementation (in line with recent WHO recommendations) can and should proceed while this DST capacity is being established.

Phenotypic DST for ethambutol, ethionamide and prothionamide may be inaccurate and not reproducible, especially in settings that lack proper external quality assurance. Moreover, no agreed DST methods have been established for some other second-line drugs (e.g. cycloserine/terizidone, imipenem-cilastatin/meropenem and PAS) (16)

Despite some of the uncertainties about DST, NTPs should strive to test for drug resistance and limit empiric treatment to a minimum. The patient’s clinical response to treatment should always be carefully monitored. If there is poor treatment response, undiagnosed resistance should be considered, as should alternative explanations for failure to respond to treatment (e.g. poor or erratic adherence to treatment, immune reconstitution inflammatory syndrome [IRIS] or the presence of comorbidities) (18).

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