Bedaquiline safety, efficacy, utilization and emergence of resistance following treatment of multidrug-resistant tuberculosis patients in South Africa: a retrospective cohort analysis.

BACKGROUND: This retrospective cohort study assessed benefits and risks of bedaquiline treatment in multidrug-resistant-tuberculosis (MDR-TB) combination therapy by evaluating safety, effectiveness, drug utilization and emergence of resistance to bedaquiline. METHODS: Data were extracted from a register of South African drug-resistant-tuberculosis (DR-TB) patients (Electronic DR-TB Register [EDRWeb]) for newly diagnosed patients with MDR-TB (including pre-extensively drug-resistant [XDR]-TB and XDR-TB and excluding rifampicin-mono-resistant [RR]-TB, as these patients are by definition not multidrug-resistant), receiving either a bedaquiline-containing or non-bedaquiline-containing regimen, at 14 sites in South Africa. Total duration of treatment and follow-up was up to 30 months, including 6 months' bedaquiline treatment. WHO treatment outcomes within 6 months after end-of-treatment were assessed in both patient groups. Longer term mortality (up to 30 months from treatment start) was evaluated through matching to the South African National Vital Statistics Register. Multivariable Cox proportional hazards analyses were used to predict association between receiving a bedaquiline-containing regimen and treatment outcome. RESULTS: Data were extracted from EDRWeb for 5981 MDR-TB patients (N = 3747 bedaquiline-treated; N = 2234 non-bedaquiline-treated) who initiated treatment between 2015 and 2017, of whom 40.7% versus 80.6% had MDR-TB. More bedaquiline-treated than non-bedaquiline-treated patients had pre-XDR-TB (27.7% versus 9.5%) and XDR-TB (31.5% versus 9.9%) per pre-2021 WHO definitions. Most patients with treatment duration data (94.3%) received bedaquiline for 6 months. Treatment success (per pre-2021 WHO definitions) was achieved in 66.9% of bedaquiline-treated and 49.4% of non-bedaquiline-treated patients. Death was reported in fewer bedaquiline-treated (15.4%) than non-bedaquiline-treated (25.6%) patients. Bedaquiline-treated patients had increased likelihood of treatment success and decreased risk of mortality versus non-bedaquiline-treated patients. In patients with evaluable drug susceptibility testing data, 3.5% of bedaquiline-susceptible isolates at baseline acquired phenotypic resistance. Few patients reported bedaquiline-related treatment-emergent adverse events (TEAEs) (1.8%), TEAE-related bedaquiline discontinuations (1.4%) and QTcF values > 500 ms (2.5%) during treatment. CONCLUSION: Data from this large cohort of South African patients with MDR-TB showed treatment with bedaquiline-containing regimens was associated with survival and effectiveness benefit compared with non-bedaquiline-containing regimens. No new safety signals were detected. These data are consistent with the positive risk-benefit profile of bedaquiline and warrant continued implementation in combination therapy for MDR-TB treatment.

Defining Bedaquiline Susceptibility, Resistance, Cross-Resistance and Associated Genetic Determinants: A Retrospective Cohort Study.

BACKGROUND: Bedaquiline (BDQ) is a novel agent approved for use in combination treatment of multi-drug resistant tuberculosis (MDR-TB). We sought to determine BDQ epidemiological cut-off values (ECVs), define and assess interpretive criteria against putative resistance associated variants (RAVs), microbiological outcomes and cross resistance with clofazimine (CFZ). METHODS: A retrospective cohort study was conducted. Minimal inhibitory concentrations (MIC) to BDQ were determined using 7H9 broth microdilution (BMD) and MGIT960. RAVs were genetically characterised using whole genome sequencing. BDQ ECVs were determined using ECOFFinder and compared with 6-month culture conversion status and CFZ MICs. FINDINGS: A total of 391 isolates were analysed. Susceptible and intermediate categories were determined to have MICs of ≤0.125µg/ml and 0.25µg/ml using BMD and ≤1µg/ml and 2µg/ml using MGIT960 respectively. Microbiological failures occurred among BDQ exposed patients with a non-susceptible BDQ MIC, an Rv0678 mutation and ≤2 active drug classes. The Rv0678 RAVs were not the dominant mechanism of CFZ resistance and cross resistance was limited to isolates with an Rv0678 mutation. INTERPRETATION: Criteria for BDQ susceptibility are defined and will facilitate improved early detection of resistance. Cross- resistance between BDQ and CFZ is an emerging concern but in this study was primarily among those with an Rv0678 mutation.