The new recommendations signal an important departure from previous approaches to treating MDR/RR-TB. The implementation of MDR/RR-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 half-life 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 (76).38
Concurrent bedaquiline and delamanid use
The GDG 2019 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 regarding 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.
The 2021 WHO model list of essential medicines (77) 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 would help clinicians to decide whether the patient is eligible for a specific MDR/RR-TB regimen, and what agents to include in a longer MDR-TB regimen. The 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 once DST results 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 several 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 consider the relative benefits and harms to the individual patient, including drug–drug interactions.
Dosage and duration
The guidelines update in 2018 revised the weight-based dosage schedules for medicines used in MDR-TB regimens for both children and adults (see the Operational handbook on tuberculosis (3)). 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 (78). 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.39
It is important to prevent treatment interruption, to increase the likelihood of treatment success. One measure that can help to increase retention is 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 (37).
38 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 (76).
39 This is particularly problematic with the delamanid tablet, the contents of which are most unpalatable (see summaries of unpublished data for the 2018 guidelines update in Web Annex 5).