New drugs and treatment recommendations - what are the consequences at the TB-laboratory?
Authors: Hoffner Sven 
Published: January 2021

Aims & objectives:
Resistance to TB drugs is a severe obstacle to effective TB control globally. Timely detection of multidrug-resistant TB (MDR-TB) is crucial to avoid poor cure rates and further development and transmission of increasingly drug-resistant strains of M. tuberculosis. Molecular rapid tests are recommended by WHO for the early detection of mutations associated with drug-resistance. When resistance to rifampicin and/or isoniazid is detected, additional DST should be performed for additional drugs. Optimally all drugs used in the therapy of MDR-TB should be tested, and regimens include only drugs to which the patient's isolate has documented susceptibility. The recent introduction of new anti-TB drugs made more effective and shorter treatment of MDR-TB possible. An example is the WHO recommended all-oral bedaquiline-containing MDR-TB regimen (WHO TB treatment handbook 2020) which contains bedaquiline, levofloxacin/moxifloxacin, clofazimine, ethionamide, ethambutol, isoniazid (high dose) and pyrazinamide for 4 months followed by 5 months of treatment with levofloxacin/moxifloxacin, clofazimine, ethambutol and pyrazinamide. The use of rapid diagnostic tests and more effective MDR-TB treatment regimens has the potential to improve treatment outcomes and reduce transmission of MDR-TB.

Results:
The introduction of new drugs and WHO recommendations for the therapy of MDR-TB put increased demands on TB-laboratories around the world to update their diagnostics algorithms to make sure they reflect new treatment regimens. If possible, DST should be performed for all drugs used in modern MDR-TB therapy. It is a challenge for TB laboratories to introduce DST for several compounds not earlier tested. On the other hand, DST of obsolete drugs such as the second line injectables, and especially kanamycin and capreomycin which are no longer recommended for use should be discontinued. Standardized protocols with critical concentrations for solid or liquid culture-based assays are needed to enable a successful re-focusing of DST at clinical TB laboratories. The possible added value of MIC determinations, as an alternative to just testing a single critical drug concentration, should be considered especially for the new drugs where we have more limited experience. Irrespectively of the method, there is a strong need for relevant drug-susceptible and drug-resistant control strains to ensure high quality when a new DST method is introduced. It is also of importance to develop and implement QC/EQA methods for all drugs tested. The need for knowledge transfer and training should not be neglected.

Conclusions:
Extended DST is initially a task of the NRL. In high drug-resistant TB burden areas, there might be a subsequent need for decentralization. To meet the demands of rapid detection of drug resistance there is a need for increased use of molecular tests. Such tests promise to be increasingly useful, but they can not be initiated for new drugs until we have a sufficient understanding of which genetic markers need to be examined to predict clinically relevant drug resistance in a reliable way. Research is ongoing to determine this for the new drugs and I expect to see such tests developed in the not so far future.