Treatment

Modified all-oral shorter MDR-TB regimens (i.e. regimens that differ from the recommended 9-month shorter regimens) should only be implemented under “operational research conditions”. The main conditions are:

At present, there is little evidence to support modified all-oral shorter MDR-TB regimens that are designed using the hierarchy of TB medicines (Table 6.1). NTPs that intend to pilot such types of shorter MDR-TB regimens are advised to do so under operational research conditions.

The South African NTP implemented the 9-month all-oral MDR/RR-TB regimen as a standardized course of treatment, with little room for variation. Some changes to the prescribed regimen were considered acceptable in the South African context and may be appropriate in other settings (as described in Section 5.2).

Some patients who start treatment with the 9-month all-oral regimen are unable to continue or complete the course of treatment, and may have to restart or switch to a different regimen; for example, in the following situations:

Although the 9-month all-oral MDR/RR-TB regimen is taken for much less time than the longer regimens, this regimen still has a high pill burden and includes medications with multiple overlapping toxicities. The most common adverse events associated with the 9-month all-oral regimen are anaemia (among patients receiving the linezolid-containing regimen), hepatotoxicity, QT prolongation, nausea and vomiting (59).

Response to treatment is monitored by monthly sputum smear microscopy and culture. Older children who had microbiological confirmation of TB disease should also be encouraged to produce respiratory samples for monitoring whenever possible. Treatment response can also be monitored through regular clinical assessment of signs and symptoms of TB disease, and children should be monitored for changes in weight, height and BMI using age-appropriate growth charts.

The dataset evaluated for the 2022 WHO guidelines included patients with uncomplicated extrapulmonary MDR/RR-TB disease. No evidence was available to discern the impact of the 9-month all-oral regimen with either linezolid or ethionamide in patients with severe extrapulmonary TB (defined in this document as the presence of miliary TB or TB meningitis).

Extensive (or advanced) TB disease in adults is defined as the presence of bilateral cavitary disease or extensive parenchymal damage on chest radiography. In children aged below 15 years, extensive (or advanced) disease is usually defined by the presence of cavities or bilateral disease on chest radiography (see above regarding severe and nonsevere TB disease in children). This highlights the importance of chest radiography as part of the diagnostic work-up for patients, along with the usual patient–clinician interaction.

Dosing and safety data to support the optimal use of second-line TB medicines during pregnancy are generally sparse. There have been case reports and observational data reporting successful treatment and pregnancy outcomes among women who received treatment (including bedaquiline-containing regimens) for MDR/RR-TB during pregnancy and postpartum, but pregnant and breastfeeding women are usually excluded from clinical drug trials and early access programmes.

Aside from bedaquiline, the medicines that compose the 9-month all-oral regimen have been part of MDR/RR-TB regimens for many years, in similar combinations, for both adults and children. The associated adverse drug reactions have been widely described and the drug dosages established (Annex). Child-friendly formulations are now available for all second-line drugs and should be provided to children whenever possible.

The 9-month all-oral MDR/RR-TB regimen was evaluated in a setting with a high HIV prevalence. In the dataset analysed for the 2022 WHO guidelines, over 70% of patients starting a shorter regimen were also living with HIV, and among those, more than 90% were receiving ART. There is no reason to believe that a 9-month all-oral regimen would perform any differently in People with HIV who initiate ART early, in accordance with WHO recommendations.