Treatment

If a patient starts the 9-month all-oral MDR/RR-TB regimen but is later found to be ineligible following detection of M. tuberculosis resistance to fluoroquinolones, the patient must switch to a different regimen. Such patients might be eligible for a 6-month BPaL regimen if their prior exposure to bedaquiline and linezolid was for less than 1 month and there is no demonstrated resistance to any components of the BPaL regimen. The BPaL regimen may only be considered if the patient meets the eligibility criteria and the regimen is available and feasible in the setting.

The 9-month all-oral MDR/RR-TB regimen should be implemented as a standardized package. It is not advisable to change the composition of the regimen or the duration of either the initial or continuation phase, with a few exceptions, as follows:

The dosages of all drugs included in both variations of the 9-month all-oral regimen are outlined in the Annex. Most drugs, except for bedaquiline, are administered once a day, 7 days per week. In the 9-month regimen, bedaquiline is initially administered daily, with a higher loading dose for the first 2 weeks, followed by a lower maintenance dose on 3 days a week (with at least 48 hours between doses) thereafter.

In terms of choice of fluoroquinolone, either levofloxacin or moxifloxacin may be used in the 9-month all-oral regimen, because they have shown similar efficacy for treating MDR/RR-TB. Although levofloxacin results in a higher pill burden, it is often preferred because moxifloxacin is associated with a higher risk of QT interval prolongation (49). Clinically significant, severe QT interval prolongation is relatively uncommon among patients treated with the 9-month all-oral regimens. However, the additive effect of co-administration of other QT-prolonging drugs (i.e.

The linezolid variation involves initiation of bedaquiline, linezolid, levofloxacin/moxifloxacin, clofazimine, ethambutol, isoniazid (high dose) and pyrazinamide. Linezolid is only given for the first 2 months of treatment. Clinical and haematological monitoring are crucial to detect early linezolid-associated adverse events, particularly haematological events (sudden or significant drop in haemoglobin, neutrophils or platelets).

The ethionamide variation involves the initiation of bedaquiline, levofloxacin/moxifloxacin, clofazimine, ethionamide, ethambutol, isoniazid (high dose) and pyrazinamide. All seven drugs are given for 4 months, with the possibility of extending to 6 months if the patient’s sputum remains bacteriologically positive at the end of the fourth month on treatment. Ethionamide and high-dose isoniazid are dropped after 4 or 6 months, depending on the decision to extend treatment based on smear status at month 4 of treatment.

Due to the risk of myelosuppression associated with even relatively short exposures to linezolid, pretreatment assessment of haemoglobin, neutrophils and platelets is crucial in patients considering treatment with a linezolid-containing regimen. Severe anaemia in patients with TB is a significant risk factor for poor treatment outcomes (48), and patients with a low baseline haemoglobin may be at risk of severe linezolid-induced haematological toxicity.

The 9-month all-oral regimen is not adequate for the treatment of patients with pre-XDR-TB or XDR-TB; it is also not adequate to treat MDR/RR-TB that has both inhA and katG mutations. It is recommended that samples be submitted for susceptibility testing to at least fluoroquinolones before the start of this regimen. In settings without access to the Xpert MTB-XDR cartridge, a line probe assay (LPA: MTBDRplus) can be used to detect the two most common mutations that confer resistance to isoniazid.

The extent of a patient’s TB disease is important in determining appropriate regimen options, in addition to the drug susceptibility of the M. tuberculosis and other considerations mentioned above. Patients with extensive disease are not eligible for the 9-month all-oral regimen with either linezolid or ethionamide.

While there have been no cost–effectiveness studies looking at the BPaLM regimen, cost–effectiveness studies for the BPaL regimen have demonstrated lower costs, should the regimen be programmatically implemented. Owing to the substantially shorter treatment duration and reduced need for hospitalization (36, 37), the implementation of a national programme using BPaL for MDR/RR-TB was estimated to cost 57–78% less than conventional longer regimens, when including all costs (e.g. investigations, drugs and hospitalization) (36).