2. Commonly used terms and key definitions in drug-resistant TB treatment

This section briefly describes some of the main terms that are used in this module and elsewhere.

Drug susceptibility testing (DST) refers to in vitro testing using either molecular, genotypic techniques to detect resistance-conferring mutations, or phenotypic methods to determine susceptibility to a medicine (5, 6).

Isoniazid-resistant TB (Hr-TB) is caused by Mycobacterium tuberculosis strains resistant to isoniazid and susceptible to rifampicin.

Rifampicin-resistant TB (RR-TB) is caused by M. tuberculosis strains that are resistant to rifampicin. RR-TB strains may be susceptible to isoniazid or resistant to it (i.e. MDR-TB), or resistant to other firstline or second-line TB medicines.

Multidrug-resistant TB (MDR-TB) is caused by M. tuberculosis strains that are resistant to at least both isoniazid and rifampicin.

Multidrug- or rifampicin-resistant TB (MDR/RR-TB) is the term used in this handbook and elsewhere to group MDR-TB and RR-TB cases together as MDR/RR-TB; both MDR-TB and RR-TB cases are eligible for treatment with MDR-TB regimens. MDR/RR-TB usually refers to all patients affected by either MDR-TB or RR-TB.

MDR-TB treatment refers to treatment options for patients with MDR/RR-TB.

Extensively drug-resistant TB (XDR-TB) is TB that is resistant to any fluoroquinolone and to at least one of three second-line injectable drugs (capreomycin, kanamycin and amikacin), in addition to multidrug resistance.¹

Extensive (or advanced) TB disease refers to the presence of bilateral cavitary disease or extensive parenchymal damage on chest radiography. In children aged under 15 years, advanced disease is usually defined by the presence of cavities or bilateral disease on chest radiography.

Severe extrapulmonary TB refers to the presence of miliary TB or TB meningitis. In children aged under 15 years, extrapulmonary forms of disease other than lymphadenopathy (peripheral nodes or isolated mediastinal mass without compression) are considered as severe (adapted from Wisemanet al., 2012 (7)).

A second-line TB medicine (or drug) is an agent used for the treatment of drug-resistant TB. Some first-line TB medicines that are used to treat drug-susceptible TB (e.g. ethambutol, isoniazid and pyrazinamide) may also be used in MDR-TB regimens. Streptomycin is now considered a secondline TB medicine and is used only as a substitute for amikacin when amikacin is not available, or when there is confirmed resistance to amikacin but confirmed susceptibility to streptomycin, and when an all-oral regimen cannot be constituted.

A shorter MDR-TB regimen refers to a course of treatment for MDR/RR-TB lasting less than 12 months, which is largely standardized.

Longer MDR-TB regimens are used for treatment of MDR/RR-TB, last at least 18 months and are designed using a hierarchy of recommended medicines, to include a minimum number of TB medicines considered to be effective based on drug-resistance patterns or patient history

Empiric treatment refers to the initiation of treatment before laboratory confirmation of the drugresistance pattern. Empiric regimens can be either standardized (in which the composition and duration are to a large extent fixed) or individualized (i.e. adapted to the local epidemiological situation or specific needs of a particular patient or patient group).² In general, the more information available on the drug-resistance pattern, the less a regimen is considered an empiric treatment and the more likely it is that the treatment will be effective without exposing patients to unnecessary medicines that are unlikely to be effective. Hence, having the full range of rapid molecular testing helps in getting patients on a definitive regimen with a high probability of cure.

The likelihood of effectiveness of a medicine is judged on the basis of one or more of the following: confirmed susceptibility in the individual patient; confirmed susceptibility in the presumed source case; no known resistance to another drug that has cross-resistance to the medicine; rare use of the drug in a geographical area or setting (possibly supported by low drug-resistance levels from surveillance activities); and no previous use of the medicine in a regimen that failed to cure the individual patient.³

Off-label use refers to the use of a pharmaceutical agent for an indication, age group, dosage, duration or route of administration that differs from what was approved by a national drug regulatory authority (8). Several agents (e.g. fluoroquinolones, clofazimine and linezolid) have been used off-label for the treatment of MDR-TB. However, because sufficient evidence has been collected on efficacy and safety of their use in TB treatment so far, the current use of these drugs is no longer considered as off-label. The decision to use drugs off-label is usually based on clinical judgement, when clinicians expect better treatment for patients by using the drugs beyond what is prescribed by the national drug regulatory authorities. This has been seen with the use of bedaquiline or delamanid beyond 6 months (see Section 6 of this module).

An adverse event is any untoward medical occurrence that may present in a TB patient during treatment with a pharmaceutical product, but that does not necessarily have a causal relationship with the treatment.

A serious adverse event is an adverse event that leads to death or a life-threatening experience, to hospitalization or prolongation of hospitalization, to persistent or significant disability, or to a congenital anomaly. Serious adverse events that do not immediately result in one of these outcomes but that require an intervention to prevent such an outcome from happening are included. Serious adverse events may require a drastic intervention, such as termination of the drug suspected of having caused the event.

Operational research or implementation research has been defined as “the use of systematic research techniques for programme decision-making to achieve a specific outcome” (9). In the context of this document, such research can also be described as applied research that aims to develop the critical evidence base that informs the effective, sustained and embedded adoption of interventions within a health system, to improve health or patient outcomes. It deals with the knowledge gap between efficacy, effectiveness and current practice to produce the greatest gains in disease control (10). Operational research also provides decision-makers with information to enable them to improve the performance of their health programmes (11).

¹ The current definition of XDR-TB is likely to change, given the phasing out of injectables, the likelihood of patterns of resistance that are more relevant to current and future regimens, and advances in diagnostic methods and DST. Changes to the definition of XDR-TB will be the subject of future expert consultation, and will be included in revised WHO surveillance and reporting guides. Choosing appropriate regimens for patients with strains showing MDR-TB plus additional resistance to fluoroquinolones (so called “pre-XDR”) is becoming more important and feasible thanks to rapid advances in molecular DST.

² For example, an empiric MDR-TB regimen may be used in diagnosed TB patients who are close contacts of an MDR/RR-TB patient and whose diagnosis of MDR/RR-TB is not yet confirmed by a diagnostic test, or in confirmed MDR/RR-TB patients who are still waiting for second-line DST (e.g. line probe assay results for identification of fluoroquinolone resistance). In certain patients (e.g. children or those who are exposed to a confirmed MDR/RR-TB case), a definitive diagnosis is not always possible, and initiation of empiric treatment would be the best option for their prognosis.

³ Where there is uncertainty about the effectiveness of a certain agent, it can still be included in the regimen, but it should be considered supernumerary to the target number of medicines needed (usually a minimum of at least four effective agents at the start of treatment). In the case of uncertainty about effectiveness, clinical judgment is often necessary to decide whether an agent is “likely to be effective” and whether the benefit from its inclusion outweighs any added toxicity, pill burden, or other downsides.

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