The new recommendations signal an important departure from previous approaches to treating MDR/ RR-TB. The implementation of MDR-TB treatment on a large scale is feasible under programmatic conditions, as has been shown by the global expansion in the use of standardized and individualized MDR-TB regimens in low-, middle- and high-income countries worldwide, particularly in the past decade (1). The 2018 revision of the guidelines brought important changes to the grouping of medicines, the composition of longer MDR-TB regimens and the duration of medicine use, but it is expected that implementation of these changes will be feasible. The rapidity with which the new recommendations are applied in (or to) programmes may be influenced by a range of factors, but these should not stand in the way of increased access to life-saving treatment for patients who need it.
All of the agents recommended for use are available via the GDF, and most are also available in quality-assured, affordable generic formulations from other sources. Bedaquiline was available via a donation programme until March 2019; it is now available via the GDF, and a decrease in price has been negotiated with the manufacturer for low-resource settings. The evidence assessed during the GDG meeting in November 2019 did not allow the group to make any judgements about the efficacy or effectiveness of bedaquiline when used for longer than 6 months; however, it did allow the GDG to determine that the safety profile of bedaquiline use for longer than 6 months is becoming clearer. The group concluded that bedaquiline can be safely used in patients beyond 6 months, if decided by the programme or treating clinician, and if appropriate schedules of baseline testing and monitoring are in place. In addition, the treating clinician should be aware of the use of other potentially QT-prolonging medications in any MDR/RR-TB regimen, and the comparatively long halflife of bedaquiline, which means that bedaquiline will remain in human tissue beyond the duration of its use. The half-life of bedaquiline is about 6 months, and the half-life of the N-monodesmethyl metabolite (M2) is about 5.5 months (82).⁴⁴
Concurrent bedaquiline and delamanid use. The GDG felt that there was insufficient evidence to assess the efficacy or effectiveness of the concurrent use of bedaquiline and delamanid. However, the group concluded that the safety data assessed in 2019 suggest there are no additional safety concerns with regard to the concurrent use of bedaquiline and delamanid. Therefore, bedaquiline and delamanid may be used in patients who have limited options for other treatment; that is, for patients with a small number of other effective drugs included in their regimen, probably due to an extensive drug-resistance profile or intolerance to other second-line TB medications. Appropriate schedules of safety monitoring (at baseline and throughout treatment) should be in place for these patients, including ECG and electrolyte monitoring, and clinicians should be cognizant of other medicines in the regimen that can either prolong the QT interval or cause other potential adverse events.
With the exception of the carbapenems and bedaquiline in children, the latest WHO model list of essential medicines (83) includes all agents required for longer regimens.
Drug susceptibility testing. These guidelines stress past advice that a patient’s MDR/RR-TB strain should be tested for susceptibility to medicines planned for inclusion in the regimen, so that effectiveness can be maximized. Access to rapid diagnostic testing, which could reliably identify resistance to fluoroquinolones, would help clinicians to decide whether the patient is eligible for the shorter MDR-TB regimen, and what agents to include in a longer MDR-TB regimen (the GenoType MTBDRsl LPA may be used for this purpose). GenoType MTBDRsl can be used in both children and adults for testing sputum specimens (direct testing) and cultured isolates of M. tuberculosis complex (indirect testing). The latter can be performed on culture isolates from both pulmonary and extrapulmonary sites. Direct testing on sputum specimens allows for the earlier initiation of appropriate treatment, and it can be applied irrespective of the smear status, although the indeterminate rate is higher when testing smear-negative sputum specimens than it is with smear-positive sputum specimens. Conventional phenotypic DST can still be used in the evaluation of patients with a negative GenoType MTBDRsl result, particularly in populations with a high pretest probability for resistance to fluoroquinolones or if the patient is at high risk for fluoroquinolone resistance (or both). The new recommendations on regimen design need to be accompanied by continued efforts to increase access to DST for medicines for which there are reliable methods, and by the development and roll-out of DST for the newer medicines. However, potentially life-saving treatment should not be withheld until all DST results become available, and empirical treatment with a regimen that is likely to be effective may need to be started, then adjusted based on DST results once they become available.
An important observation in the 2018 IPD meta-analysis for longer regimens is that when a DST result indicates resistance to an agent, it is better to replace that agent. This also applies to medicines for which DST or the DST method used is known to be unreliable for clinical decision-making. Although DST is important for guiding effective treatment, DST results present uncertainties for a number of regimen components (e.g. cycloserine, streptomycin and ethambutol). “Likelihood of effectiveness” is generally assessed in the programmatic setting 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 medicine in an area (possibly supported by low drug-resistance levels from surveillance activities), and no previous use of the medicine in a regimen that failed to cure that same patient. When there is uncertainty about the effectiveness of a certain agent, that agent may still be included in the regimen, but it should not be considered as one of the target number of medicines needed; clinical judgement should be used to decide whether the benefit from its inclusion outweighs any added toxicity, pill burden or other disadvantages. The design of the regimen must take into account the relative benefits and harms to the individual patient, including drug–drug interactions.
Bedaquiline use beyond 6 months. It is generally agreed that most patients can be treated with four effective agents at the start of the therapy, one of which – usually bedaquiline – can usually be stopped at month 6. However, evidence assessed by the GDG in November 2019 supports the safety of using bedaquiline beyond 6 months in patients who receive appropriate schedules of baseline and follow-up monitoring. The GDG was not able to assess the relative effectiveness of prolonged bedaquiline use, owing to the limited evidence and to potential residual confounding in the data. The regimen needs to have at least three effective agents if bedaquiline is stopped at 6 months; thus, if another agent needs to be stopped because of toxicity, then that medicine would need to be replaced by another one.⁴⁵ The replacement medicine would be chosen from either Group B (unless both clofazimine and cycloserine or terizidone are already included) or Group C. The choice from Group C is determined by the order in which the medicines are ranked, and the individual circumstances of the patient and setting. Starting with five agents instead of four may be preferred in certain situations, to avoid the need to replace a medicine after treatment has started. Such situations include the following: two of the four agents are likely to be stopped before the end of treatment (e.g. if bedaquiline is stopped at month 6 and linezolid is stopped early because of toxicity); reliable DST is not available for one or more of the agents on the regimen, but background resistance to the agent is known to be high; and the agents included in the regimen are unlikely to cure the patient (e.g. a total of only two of the agents from Group A and Group B are included in the regimen).
Longer versus shorter regimens. The conditionality of the recommendation for the use of the shorter MDR-TB regimen may require the patient and health care provider to decide on longer treatment in patients who are otherwise eligible for the shorter MDR-TB regimen, based on the individual circumstances. Such circumstances include uncertainty about DST results or lack of access to second-line LPA, unavailability of clofazimine or another component medicine, or the patient’s condition requiring immediate start of treatment before all baseline testing can be completed. If the shorter MDR-TB regimen cannot be used, the patient needs to be reassessed with a view to starting a longer MDR-TB treatment regimen. Usually, a patient started on the shorter MDR-TB regimen can later be transferred to a longer regimen should the need arise. However, in general, patients who are placed on a longer regimen for at least 4 weeks can no longer be switched to the shorter regimen.
Dosage and duration. The guidelines update in 2018 concurrently revised the weight-based dosage schedules for medicines used in MDR-TB regimens for both children and adults (see the Operational handbook on tuberculosis). The update to the dosages benefited from the expertise of the GDG members, and from an extensive consultation with other specialists in different fields. It was based on the latest knowledge available about the optimal use of the medicines involved (84). Adherence to the schedules is advised as far as possible. Manipulation of tablets (e.g. splitting, crushing or dissolving in water) outside their indications is to be avoided because this may interfere with the bioavailability of the drugs.⁴⁶
In patients taking amikacin or streptomycin who are culture positive at the start of treatment, all three recommendations on the duration of treatment apply. For patients on an all-oral MDR-TB regimen, the length of treatment is determined by the recommendations on total duration and time after culture conversion (Recommendations 3.15 and 3.16, respectively). In patients with bacteriologically negative TB or most forms of extrapulmonary disease, Recommendation 3.15 on total duration is the only applicable recommendation.
The 6-month duration of use of bedaquiline and delamanid generally recommended in these guidelines reflects how these medicines have been used in most of the patient data reviewed, which is aligned to the prescribing recommendations that their manufacturers filed with regulatory authorities (e.g. (85–87). New evidence on the safety profile of bedaquiline use beyond 6 months suggests that it is safe in patients who receive appropriate baseline and follow-up monitoring. However, in contrast to bedaquiline and delamanid, several of the other medicines included in MDR-TB regimens (e.g. fluoroquinolones and clofazimine) are used outside their licensed indication, and the recommended duration of use in MDR-TB regimens is often much longer than the one proposed for their original licensed purpose. Other medicines may need to be used for shorter durations because of toxicity associated with their long-term administration (particularly linezolid).
It is important to prevent treatment interruption, to increase the likelihood of treatment success. Measures that can help to increase retention include supporting patient adherence, either by facilitating patient visits to health care facilities or home visits by health care staff, or by using digital technologies for daily communication (29).
⁴⁴ This is the mean terminal half-life of bedaquiline and the M2 metabolite; this longer terminal elimination phase probably reflects the slow release of bedaquiline and M2 from peripheral tissues (83).
⁴⁵ While replacement of one agent by another one because of toxicity may be acceptable, this should not be done if there are signs that the patient is not responding (e.g. persistent culture positivity or reversion to positive after culture has become negative). A need to replace two or more agents because of toxicity fulfils the definition of treatment failure (41).
⁴⁶ This is particularly problematic with the delamanid tablet, the contents of which are very unpalatable (see summaries of unpublished data for the 2018 guidelines update in Annex 5).