Bedaquiline Resistance in Drug-Resistant Tuberculosis in South Africa: A Systematic Review and Meta-Analysis of Emerging Trends

Background : Bedaquiline (BDQ) resistance poses a serious threat to its long-term efficacy, particularly in high-burden settings like South Africa, where data remain scattered and largely non-synthesized. Objective : This study aimed to estimate the trends of BDQ resistance in drug resistant tuberculosis (DR-TB), characterize associated resistance mechanisms, and evaluate implications for treatment outcomes in South Africa. Eligibility criteria : We included primary studies reporting BDQ resistance, resistance mechanisms, minimum inhibitory concentrations (MICs), or treatment outcomes among patients with MDR- or XDR-TB treated with BDQ-containing regimens in South Africa. Information sources : PubMed, Web of Science, and Embase were searched for studies published between January 2016 and July 2024. Risk of bias : Study quality was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist. Synthesis of results: Random-effects meta-analysis with Freeman-Tukey double-arcsine transformation was used to estimate pooled BDQ resistance prevalence. Heterogeneity, sensitivity analyses, and publication bias were assessed. Results: Twenty-eight studies were included. The pooled prevalence of BDQ resistance was 6.0% (95% CI: 4.1-7.9%; I 2 = 62%). Treatment success averaged 63.5%, and culture conversion reached 84.1%. Resistance-associated mutations were most frequently reported in Rv0678 , followed by atpE and pepQ , often associated with elevated MICs (≥2-4 μg/mL). Evidence of small-study effects was observed (Egger's test, p = 0.0012). A pooled prevalence estimate was calculated; however, evidence of small-study effects suggests that estimates should be interpreted cautiously. Limitations: Heterogeneity in study design, outcome definitions, and resistance testing methods limited comparability across studies. Conclusions: Bedaquiline remains effective for DR-TB treatment in South Africa; however, emerging resistance and its molecular drivers pose a growing threat to regimen sustainability, including BPaL. Strengthened surveillance and standardized resistance testing are urgently needed.