Treatment outcomes of bedaquiline-resistant tuberculosis: a retrospective and matched cohort study
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Background
Rising prevalence of bedaquiline resistance undermines benefits from this life-saving drug for rifampicin-resistant tuberculosis (RR-TB). Despite increasing awareness, patient-level outcomes for bedaquiline-resistant TB have not been well-characterised and case management poorly defined.
Methods
We conducted a retrospective cohort study with matched controls at a TB referral hospital in South Africa. Cases included patients ≥13 years with a phenotypic bedaquiline-resistant Mycobacterium tuberculosis isolate identified between January 2018 and June 2023. Matched controls (1:1) with bedaquiline-susceptible RR-TB were selected from a prospective observational study conducted at the same facility. Primary outcomes included time to sputum culture conversion (SCC), a modified WHO-defined unfavourable outcome, and TB-free survival (alive, with SCC, and in care or treatment completed) through 18 months. Adjusted analyses used Cox proportional hazards models.
Findings
Eighty-two patients with bedaquiline-resistant TB were included; 57 (70%) were HIV-positive and 17 (21%) had no prior exposure to bedaquiline or clofazimine. Bedaquiline was prescribed for 72 (88%) and meropenem (plus amoxicillin-clavulanate) for 32 (39%) after submission of the sputum sample with the first bedaquiline-resistant Mycobacterium tuberculosis isolate. At 18 months, 43 (52%) patients achieved TB-free survival; 17 (20%) failed to achieve sustained SCC, there were 19 (23%) deaths, and 50 (80%) survivors (n=63) were still on treatment. WHO treatment outcomes following treatment initiation were unfavourable in 54 (67%) patients, driven by treatment failure in 35 (43%). Median time to SCC after treatment initiation was 175 (IQR 100–254) days in the bedaquiline resistant cohort and 32 days (IQR 30–42 days) in the matched bedaquiline susceptible cohort. Baseline smear microscopy grade (HR 0·41, 95% CI 0·23–0·73, p=0·003) and bedaquiline resistance (HR 0·06, 95% CI 0·02–0·23, p<0·001) were associated with reduced SCC.
Interpretation
Current treatment options for bedaquiline-resistant TB result in prolonged therapy, delayed microbiological responses, and poor clinical outcomes.
Funding
This work was partially supported by the South African Medical Research Council (grant number MRC-RFA-SHIP 02–2018). JK was funded by Swedish Heart & Lung Foundation (20220859 and 20240774) Swedish Society of Medicine (SLS-985976). SW was supported by the National Institutes of Health (U01AI170426) and the Bill & Melinda Gates Foundation. GM was supported by the Wellcome Trust (214321/Z/18/Z, and 203135/Z/16/Z), and the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa (Grant No 64787).
