The Hr-TB regimen is recommended once isoniazid resistance has been confirmed and rifampicin resistance excluded. Rifampicin resistance needs to be excluded using rapid molecular tests (e.g. Xpert MTB/RIF) before levofloxacin is used, to avoid the inadvertent treatment of MDR/RR-TB with an inadequate regimen. Ideally, rapid DST for fluoroquinolones and pyrazinamide is also performed.
It is not advisable to give a regimen for Hr-TB unless isoniazid resistance is confirmed or highly suspected (e.g. confirmed TB patient who is the close contact of a documented Hr-TB case). This will avert the unnecessary use of levofloxacin and prolonged pyrazinamide exposure in TB patients who may be cured with 2HRZE/4HR. Once the Hr-TB regimen has been started, if the results of initial DST reveal isoniazid susceptibility, the regimen may be modified so that the patient effectively completes a course of first-line TB treatment.
The recommendations apply to both adults and children, including People with HIV. Thus, HIV testing and treatment of People with HIV with ART is important, and the aim is to start ART within 8 weeks of TB treatment initiation (regardless of CD4 count), or within the first 2 weeks in patients with profound immunosuppression (e.g. CD4 counts <50 cells/mm3) (115). The regimen is also likely to be effective in patients with extrapulmonary Hr-TB; however, consultation with appropriate specialists is advised.
Hr-TB treatment is expected to be started if either of the following circumstances apply:
- Hr-TB is confirmed and rifampicin resistance is ruled out before TB treatment is started – in such cases, the 6(H)RZE-Lfx regimen is started immediately. If the diagnosis is strongly presumed (e.g. close contact of a confirmed Hr-TB source case) but results of DST are still pending, the regimen may be introduced. Should DST results taken at the start eventually show susceptibility to isoniazid, then levofloxacin is stopped and the patient continues treatment to complete a 2HRZE/4HR regimen.
- Hr-TB is discovered after the start of treatment with the 2HRZE/4HR regimen (this includes patients who had undiagnosed isoniazid resistance at the start or who developed isoniazid resistance while on first-line treatment) – in such cases, rapid molecular testing for rifampicin resistance must be undertaken (or repeated). Once rifampicin resistance has been excluded, a full 6-month course of (H)RZE-Lfx is given. The duration is driven by the need to give levofloxacin for 6 months, which usually implies that the companion first-line medicines are taken for longer than 6 months. A report of resistance during treatment presents the clinician with a challenge, because the results may no longer reflect the drug susceptibility of the current bacterial population, given that an inadequate regimen – at times a functional monotherapy – may have favoured the acquisition of additional resistance in the interval. The unexpected discovery of resistance to one agent should prompt the clinician to repeat DST for other agents in the regimen. The example in Box 7.1 illustrates a typical situation that could arise.