End TB: WHO makes key changes to Multi-Drug Resistant TB treatment

The bacteria that cause tuberculosis (TB) can develop resistance to the antimicrobial drugs used to cure the disease. Multidrug-resistant TB (MDR-TB) is TB that does not respond to at least isoniazid and rifampicin, the 2 most powerful anti-TB drugs

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This Rapid Communication aims to inform TB programme managers and other stakeholders of WHO Member States about the key implications for MDR-TB treatment regimens arising from the new evidence assessment.

It highlights the immediate steps to be taken to ensure that MDR/RR-TB patients receive treatment in accordance with the latest evidence on effectiveness and safety.

While understanding that it would not be immediately possible to achieve the new standards of care in every individual MDR-TB patient, strategic planning should start immediately to enable rapid transition to the upcoming new WHO guidelines.

Longer MDR-TB regimens

The revised grouping of TB medicines recommended for use in longer MDR-TB regimens is presented in

Table 1. Medicines have been regrouped into three categories and ranked based on the latest evidence

About the balance of effectiveness to safety:

  • Group A: Medicines to be prioritised: levofloxacin/moxifloxacin, bedaquiline and linezolid
  • Group B: Medicines to be added next: clofazimine, cycloserine/terizidone
  • Group C: Medicines to be included to complete the regimens and when agents from Groups A and B cannot be used: ethambutol, delamanidiii, pyrazinamide, imipenem-cilastatin, meropenem, amikacin (streptomycin), ethionamide/prothionamide, p-aminosalicylic acid;

Medicines no longer recommended are kanamycin and capreomycin, given increased risk of treatment failure and relapse associated with their use in longer MDR-TB regimens. Use of amikacin did not show a similar association, although the same safety concerns as for the other injectables apply. Amoxicillinclavulanic acid is only to be used to accompany the carbapenems.

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Table 1 also indicates the overall approach to designing longer MDR-TB regimens for adults and children based on the revised grouping. The regimen is designed by adding medicines sequentially going down the three groups.

Apart from the ranking by balance of effectiveness and harms, choice is also determined by: a preference for oral over injectable agents; the results of drug-susceptibility testing (DST); the reliability of existing DST methods; population drug resistance levels; history of previous use of the medicine in a patient; drug tolerability; and potential drug-drug interactions. Consultation on how best to optimise these aspects of MDR-TB treatment is ongoing.

This includes the minimum number of medicines required in designing MDR-TB regimens based on the revised grouping, while maximising regimen efficacy in the presence of resistance to or tolerability of individual agents.

Options for the choice of agents for the intensive and continuation phases, more detailed guidance on patient selection criteria, number of medicines and duration of treatment, adult and paediatric dosing, treatment of extensively drug resistant disease (XDR-TB), and the use of DST results will be provided at the time of release of the final WHO guidelines.

Shorter MDR-TB regimen

The STREAM Stage 1 trial showed that, in eligible patients, treatment success was similar between patients receiving a shorter MDR-TB regimen and longer regimens conforming to prior WHO recommendations.

  • In observational studies, shorter MDR-TB regimens similar to the one studied in the STREAM Stage 1 trial showed an overall comparable likelihood of treatment success with longer regimens, with a lower risk of treatment interruption.
  • However, shorter regimens were associated with higher risk of treatment failure and relapse compared to longer regimens, especially when resistance to key medicines in the shorter regimen was present or when longer regimens included one or more of the

Group A medicines listed above in Table 1.

Evidence is lacking for the performance of shorter MDR-TB regimens modified from the standardised form recommended in 2016 (e.g. bedaquiline or linezolid replacing the injectable agent or levofloxacin replacing moxifloxacin).

Choice of a MDR-TB regimen

Treatment options for MDR-TB are increasingly becoming more individualised as a result of innovations in diagnostics and growing scientific understanding of the molecular basis for drug resistance and the pharmacokinetics and pharmacodynamics of TB medicines.

Three signals are clear from the current scientific evidence assessment:

The feasibility of effective and fully oral treatment regimens for most patients;

the need to ensure that drug resistance is excluded (at least to the fluoroquinolones and injectables) before starting patients on treatment, especially for the shorter MDR-TB regimen;

The need for close monitoring of patient safety and treatment response and a low threshold for switching non-responding patients or those experiencing drug intolerance to alternative medicines and/or new regimens based on the regrouping of agents in Table 1.