Research gaps

In addition to summarizing the available evidence, the reviews undertaken for these consolidated guidelines revealed several gaps in current knowledge about critical areas in DR-TB treatment and care. The estimates of effect for patient studies were commonly assigned a low or very low certainty rating, which explains why most of the recommendations in these guidelines are conditional. Some gaps identified in previous TB treatment guidelines (2, 16) persist. When completing the GRADE EtD tables, studies were lacking on how patients, caregivers and other stakeholders value different treatment options and outcomes (e.g. time to sputum conversion, cure, treatment failure and relapse, death and serious AEs). Areas that would be relevant to many priority questions in the programmatic management of DR-TB include implementation research; studies of resource use; incremental cost, acceptability, feasibility and equity; values and preferences of patients and health care workers; and the inclusion of indicators of quality of life.

The research gaps that were identified by successive GDGs are grouped by the respective sections of these guidelines, although some are interlinked.

The 6-month BPaLM regimen for treatment of MDR/RR-TB or pre-XDR-TB

Further research is needed in the following areas:

  • the efficacy, safety and tolerability of the BPaLM/BPaL regimen for subpopulations for whom current data are limited or missing; that is, children aged below 14 years, patients with extrapulmonary TB, PLHIV with CD4 counts below 100, and pregnant and breastfeeding women;
  • data from other regions and countries (beyond countries with sites included in recent studies);
  • description of the mechanism and molecular markers of pretomanid resistance, allowing development of the DST, clinical implications of the lineage 1 effect on efficacy of pretomanid,⁶¹ cross-resistance with delamanid and surveillance for the development of resistance, with adequate consideration paid to the impact of selected mutations;
  • documenting of the full AE profile of pretomanid and the frequency of relevant AEs, with a focus on hepatotoxicity and reproductive toxicity in humans (studies ongoing);
  • exploring the relative efficacy (and added value in multidrug regimens) of pretomanid and delamanid;
  • studies capturing outcomes for which currently evidence is scarce (e.g. acquisition of drug resistance and quality of life);
  • research on geographical differences in the frequency and severity of linezolid-related AEs and the underlying cause (north–south differences were observed in post-hoc analyses of large and unexplained differences in linezolid-related AEs between sites);
  • exploring the possibility of replacing moxifloxacin with levofloxacin;
  • exploring the extent of cross-resistance between bedaquiline and clofazimine;
  • monitoring of resistance to new and repurposed medicines;
  • exploring methods to ensure treatment adherence;
  • exploring regimen composition when the new generation of component medicines are available; and
  • exploring the efficacy of other 6-month regimens.

The 6-month bedaquiline, delamanid, linezolid, levofloxacin and clofazimine (BDLLfxC) regimen

Further research is needed in the following areas:

  • research on choice of quinolones for 6-month regimens and treatment outcomes (e.g. moxifloxacin/levofloxacin); and
  • cost–effectiveness studies.

The 9-month all-oral regimen for MDR/RR-TB

Further research is needed in the following areas:

  • the effectiveness and safety of variants of the shorter MDR-TB treatment regimen, in which the injectable agent is replaced by an oral agent (e.g. bedaquiline) and the total duration is reduced to 6 months or less;
  • comparison of the effectiveness of these variants of the shorter regimen in:
    • patient subgroups that have often been systematically excluded from studies or country programme cohorts (e.g. children, patients with additional resistance, those with extrapulmonary TB, and pregnant or breastfeeding women);
    • settings where background resistance to drugs other than FQ and second-line injectable agents is high (e.g. PZA or high-level isoniazid resistance);
  • additional RCTs and odds ratios on all-oral shorter MDR-TB treatment regimens, also allowing comparison of all-oral shorter regimens with all-oral longer regimens;
  • programmatic data from countries other than South Africa;
  • data from children, pregnant women, older people, patients with diabetes and other special populations;
  • data on patients presenting with extensive TB disease;
  • information on the frequency and mechanisms of bedaquiline resistance acquisition, and the genetic markers that indicate probable resistance; and
  • identification of optimal companion drugs that protect bedaquiline and limit the acquisition of bedaquiline resistance, including consideration of the need to protect the long “tail” of potential single drug exposure (given its exceptionally long half-life) if bedaquiline is stopped at the same time as companion drugs.

The modified 9-month all-oral regimens for MDR/RR-TB

Further research is needed in the following areas:

  • the role of PZA resistance and the requirement for its use in the regimens;
  • information on bedaquiline resistance in countries through surveillance research;
  • the effect of the regimens in other patient groups, e.g. in children or those with diabetes;
  • research on the acceptability of the regimens; and
  • for the 9BDLLFxZ regimen, research about patient support and adherence to delamanid.

Longer regimens for MDR/RR-TB

Further research is needed in the following areas:

  • the optimal combination of medicines and the approach to regimen design for adults and children with MDR/RR-TB, with or without additional resistance to key agents;
  • RCTs, which are lacking, especially those involving new drugs and regimens – the release of results from the first Phase 3 trials for MDR-TB has led to debate about the clinical relevance of the design and endpoints chosen for these studies, requiring at times additional, off-protocol analysis of data to explore the potential added value of the experimental interventions;
  • inclusion and separate reporting of outcomes for key subgroups in RCTs, especially children, pregnant and breastfeeding women and PLHIV on treatment;
  • studies of pharmacokinetics and safety to determine optimal drug dosing (especially in pregnancy), and the effect of extemporaneous manipulation of existing dosing forms;
  • complete recording of AEs and standardized data on organ class, seriousness, severity and certainty of association, to allow meaningful comparison of the association between AEs and exposure to different medicines between studies, patient subgroups and different regimens;
  • determination of the minimum number of drugs and treatment duration (especially in patients previously treated for MDR-TB);
  • improved diagnostics and DST methods (e.g. which test to use for resistance to PZA) especially for medicines for which no rapid molecular methods are currently available in the field;
  • further research and development would be particularly helpful for the following agents:
    • levofloxacin: optimization of the dose – the Opti-Q study will soon provide new information on this (155);
    • bedaquiline: optimization of the duration in both adults and children, and use during pregnancy;
    • linezolid: optimization of the dose and duration in both adults and children, and patient predictors for adverse reactions;
    • clofazimine: optimization of the dose (especially in children), any added value in using a loading dose and availability of DST methods;
    • cycloserine and terizidone: differences in efficacy between the two medicines, approaches to test for susceptibility to them, and best practices in psychiatric care for people on these medicines;
    • delamanid: better understanding of its role in MDR-TB regimens, including in children (pharmacokinetics and pharmacodynamics), PLHIV and pregnant women; mechanisms of development of drug resistance; and optimization of the duration in both adults and children;
    • PZA: molecular testing for resistance (pursuing either LPA or other approaches);
    • carbapenems: given their effectiveness in the evidence reviews, further research on their role in MDR-TB regimens is important, including the potential role and cost–effectiveness of ertapenem (which can be given intramuscularly) as a substitute for meropenem and imipenem–cilastatin;
    • amikacin: the safety and effectiveness of thrice-weekly administration at a higher dose (about 25 mg/kg per day) (92);
  • identification of factors that determine the optimal duration of treatment (e.g. previous treatment history, baseline resistance patterns, site of disease and age); and
  • exploration of strategies to optimize the balance of benefits versus harms of regimen duration through risk-stratification approaches.

Regimens for rifampicin-susceptible, isoniazid-resistant TB (Hr-TB)

The development of the current recommendations was made possible by the availability of a global Hr-TB IPD. As in other IPD analyses conducted to inform WHO treatment guidelines in recent years, the Hr-TB IPD analysis facilitated the comparison of different patient groups, some adjustment for covariates and better interpretation of the results (72). It is important for researchers and national programmes to continue contributing patient records to the Hr-TB IPD, to increase its value as a source of information for future treatment policy.

All the recommendations were conditional and were based on very low certainty in the estimates of effect; thus, further research is needed to inform the refinement of policies to optimize the treatment of Hr-TB. The GDG identified various research priorities, including the following:

  • the need for RCTs evaluating the efficacy, safety and tolerability of regimens for Hr-TB, and for cases with additional resistance to other medicines such as ethambutol or PZA (e.g. polydrug resistance);
  • research to clarify the potential benefits and risks of treatment with high-dose isoniazid;
  • high-quality studies on optimizing the composition and duration of regimens in children and adults, particularly of high-dose isoniazid, FQ and other second-line medicines, and of reducing the duration of PZA;
  • modelling studies to estimate the number-needed-to-treat for empirical use of an Hr-TB regimen, balancing risks and benefits;
  • high-quality studies on treatment prolongation among PLHIV;
  • high-quality studies evaluating regimens for extrapulmonary or disseminated TB;
  • feasibility of developing FDCs for REZ alone (with or without integrating levofloxacin);
  • monitoring patient response by isoniazid resistance genotype (e.g. katG vs inhA mutations), either in an individual patient or in a population;
  • cost–effectiveness of different approaches to DST, including rapid testing of all TB patients for both isoniazid and rifampicin resistance before the start of treatment;
  • participatory action research within communities and with other stakeholders (e.g. field practitioners and community workers) to explore sociocultural factors that can facilitate treatment adherence and influence outcomes; and
  • effect of underlying FQ and isoniazid polydrug resistance on treatment outcomes.

Monitoring patient response to MDR/RR-TB treatment using culture

Further research is needed in the following areas:

  • analysis of the predictors and biomarkers of treatment failure (related to strain, regimen and host), and of the bacteriological response, in the following important subgroups, which would help to identify more resource-saving options and reduce the time needed to make decisions:
    • patients aged below 15 years;
    • patients with extrapulmonary disease (different forms);
    • patients on shorter MDR-TB regimens (standardized or all-oral variants);
  • continuing to assess the potential role of future-generation rapid molecular testing beyond diagnostic testing, to also monitor the treatment response; and
  • evaluation of the engineering challenges to implementing more affordable liquid culture systems.

Starting antiretroviral therapy in patients on MDR/RR-TB regimens

No research gaps were identified.

Surgery for patients on MDR/RR-TB treatment

Further research is needed in the following areas:

  • the role of surgery – that is, decisions about when to operate and the type of surgical intervention to use, and drug-resistance patterns; and
  • improved collection, reporting and standardization of data on surgery, including long-term survival post-surgery.

HCV and MDR/RR-TB treatment co-administration

The co-administration of treatments for HCV and MDR-TB presents a complex challenge. Prioritizing research is essential to address critical knowledge gaps and enhance treatment outcomes. The GDG outlined several research priorities:

  • conducting high-quality observational studies to evaluate the efficacy and safety of combined HCV and MDR-TB treatments, with a focus on patient adherence and final treatment outcomes;
  • establishing a global and more comprehensive dataset to assess the effectiveness of modern HCV treatment regimens in young children;
  • developing tailored approaches for co-administering HCV and MDR-TB treatments for high-risk populations, including intravenous drug users, children, pregnant women and PLHIV;
  • collecting comprehensive DDI data to better understand the potential interactions between HCV medicines and bedaquiline, a crucial component of the MDR/RR-TB treatment regimen; and
  • defining the optimal treatment approach that permits the concurrent administration of MDR-TB and HCV treatments, refining combinations, dosages and treatment duration to ensure both effectiveness and safety.

Cross-cutting research priorities

Cross-cutting research priorities are as follows:

  • dose reduction strategies of linezolid within 6-month regimens and treatment outcomes;
  • early and practical markers of linezolid toxicity;
  • bedaquiline concentrations in breast milk and its effects on newborns;
  • component drug interactions with a view on drugs used for other frequent comorbidities;
  • values people place on outcomes;
  • quality of life outcomes in TB treatment trials;
  • operational research including strategies on testing;
  • the efficacy of the regimen in patients with disseminated forms of TB;
  • clinically significant effects of QT-prolonging drugs in elderly patients; and
  • cost–effectiveness research, including comparisons of cost per QALY.


61 A lineage effect is observed for lineage 1 strains that are shown to exhibit higher MICs than other lineages in vitro. The in vivo clinical significance of such an effect is unknown (154).

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