Research priorities on treatment regimens for drug-resistant tuberculosis (TB)

Shorter all-oral bedaquiline-containing regimen for MDR/RR-TB
 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
Comparison of the effectiveness of these variants of the shorter regimen would be helpful 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 fluoroquinolones and second-line injectable agents is high (e.g. pyrazinamide 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 to  all-oral longer regimens
Programmatic data from countries other than South Africa
Data from children, pregnant women, the elderly, 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 likely resistance
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
Longer regimens for MDR/RR-TB
 The optimal combination of medicines and approach to regimen design for adults and children with MDR/RR-TB, with or without additional  resistance to key agents
RCTs, which there is a lack of, especially those involving new drugs and regimens: the release of results from the first phase III trials for  MDR-TB has led to debate about the clinical relevance of the design and end-points 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  HIV-positive individuals 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 adverse events and standardised data on organ class, seriousness, severity and certainty of association to allow  meaningful comparison of the association between adverse events 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 pyrazinamide) 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: optimisation of the dose: the Opti-Q study will soon provide new information on this ( identifier number NCT01918397)
  • bedaquiline: use in children to determine optimal pharmacokinetic properties, revised cost–effectiveness analyses based on the IPD meta-analysis, optimisation of duration in both adults and children, and use during pregnancy
  • linezolid: optimisation of the dose and duration in both adults and children, and patient predictors for adverse reactions
  • clofazimine: optimisation 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/pharmacodynamics), pregnant women and people living with HIV; mechanisms of development of drug resistance; and optimisation of duration in both adults and children
  • pyrazinamide: 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 (∼25 mg·kg−1 per day) [56]
 Identification of factors that determine the optimal duration of treatment (e.g. previous treatment history, baseline resistance patterns, site of  disease and age)
Exploration of strategies to optimise the balance of benefits versus harms of regimen duration through risk-stratification approaches
The BPaL regimen for MDR-TB with additional fluoroquinolone resistance
 The efficacy, safety and tolerability of BPaL compared with other all-oral regimens
Description of the mechanism and molecular markers of pretomanid resistance, and surveillance for the development of resistance with  adequate consideration paid to the impact of selected mutations
 Data from other regions and countries (beyond South Africa)
 Documenting the full adverse event profile of pretomanid, and the frequency of relevant adverse events, with a focus on hepatotoxicity and  reproductive toxicity in humans (the reproductive toxicities of pretomanid have been signalled in animal studies, but the potential effects of  this medicine on human fertility have not been adequately evaluated)
Exploring the relative efficacy (and added value in multidrug regimens) of pretomanid and delamanid
Optimal dose and duration of linezolid use in drug-resistant TB regimens (ZeNix study)

MDR: multidrug-resistant; RR: rifampin-resistant; BPaL: bedaquiline, pretomanid and linezolid; RCT: randomised controlled trial; IPD: individual patient dataset; DST: drug susceptibility testing; LPA: line probe assay.