This section refers to a treatment regimen for MDR/RR-TB that has a duration of at least 9 months and uses oral agents. The recommendation in the updated 2022 guideline (1) states:
Recommendation 2.1. WHO suggests the use of the 9-month all-oral regimen rather than longer (18-month) regimens in patients with MDR/RR-TB and in whom resistance to fluoroquinolones has been excluded.
(Conditional recommendation, very low certainty of evidence)
The 9-month all-oral regimen comprises bedaquiline (used for 6 months), in combination with levofloxacin/moxifloxacin, ethionamide, ethambutol, isoniazid (high dose), pyrazinamide and clofazimine (for 4 months, with the possibility of extending to 6 months if the patient remains sputum smear positive at the end of 4 months); followed by treatment with levofloxacin/moxifloxacin, clofazimine, ethambutol and pyrazinamide (for 5 months). Ethionamide can be replaced by 2 months of linezolid (600 mg daily).
The last consolidated guidelines for the treatment of DR-TB were released in June 2020. In 2019, for the WHO guideline update, the South African Department of Health provided WHO with access to programmatic data on injectable-free regimens that had been used in South Africa since 2017, when most eligible patients were enrolled on a shorter regimen, with bedaquiline replacing the injectable. Since then, new data from patients receiving WHO-recommended shorter and longer MDR/RR-TB regimens have been incorporated into an individual patient dataset (IPD) in 2021; these data were presented to the GDG in 2022 to help inform the development of the updated WHO guidelines on DR-TB. In addition, routine data from the South African NTP were available to assess the modified 9-month all-oral regimen containing linezolid (600 mg daily) instead of ethionamide, for treatment of patients with fluoroquinolone-susceptible MDR/RR-TB and without previous exposure to secondline TB drugs. The South African routine dataset of patients receiving the modified 9-month all-oral regimen would also have excluded children aged below 6 years, as well as patients with extensive pulmonary TB disease and severe forms of extrapulmonary TB, because these patients were not considered eligible for this regimen under current national DR-TB guidelines (41). For the updated 2022 WHO guidelines, the modified 9-month regimen used in South Africa was compared with the earlier dataset and the 2021 IPD from patients meeting the same eligibility criteria and who received the WHO-recommended 9-month all-oral regimen containing ethionamide instead of linezolid, or the longer regimens designed based on the 2020 WHO recommendations.
Following review of the data presented, the GDG judged the benefits of the 9-month regimen with linezolid to be small and the undesirable effects to be moderate compared with the 9-month regimen with ethionamide. The certainty of evidence was judged to be very low. Based on this, the GDG judged that the balance of health effects does not favour either the 9-month regimen with linezolid or the 9-month regimen with ethionamide. Therefore, WHO has updated its conditional recommendation that, in eligible patients with MDR/RR-TB, the 9-month all-oral regimen may be used, and that 2 months of linezolid can be used as an alternative to 4 months of ethionamide within this shorter regimen (1).
The implementation of these two variations of the 9-month all-oral MDR/RR-TB regimen (i.e. including either linezolid for 2 months or ethionamide for 4 months) is expected to provide more flexible and effective treatment options for a wider range of patients requiring treatment for MDR/RR-TB.
This regimen still requires combined use of seven agents (some with considerable toxicity), most of which will be continued for at least 9 months. Patients will need support to overcome the hardships associated with TB and its treatment, including daily adherence challenges, adverse drug reactions, indirect costs and stigma.