Section 3. Longer regimens for MDR /RR-TB

Further research is needed in the following areas:

• 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 standardized 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: optimization of the dose – the Opti-Q study will soon provide new information on this (242);
   – bedaquiline: use in children to determine optimal pharmacokinetic properties, revised cost– effectiveness analyses based on the IPD meta-analysis, 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/pharmacodynamics), PLHIV and pregnant women; mechanisms of development of drug resistance; and optimization of the 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 (about 25 mg/kg per day) (84);
• 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.  

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