Baseline and treatment-emergent bedaquiline resistance in drug-resistant tuberculosis: a systematic review and meta-analysis

Rationale Bedaquiline is a novel antimycobacterial agent for drug-resistant tuberculosis (DR-TB) and is classified as a World Health Organization (WHO) Group A drug due to its excellent clinical efficacy, high bactericidal activity, and potent sterilizing effect. Baseline and treatment-emergent bedaquiline resistance have been described but prevalence and incidence have not been reported, leading to gaps in the knowledge required to design strategies to optimize MDR-TB clinical outcomes and prevent the amplification of bedaquiline resistance. Methods We performed a systematic review and meta-analysis to estimate the frequency of, and mutations associated with, baseline and acquired (treatment-emergent) bedaquiline resistance in clinical Mtb isolates. Pooled estimates of bedaquiline resistance were generated by proportional meta-analysis in R version 4.2.2 using dmetar, metafor and meta packages. Resistance associated variants associated with prevalent and incident bedaquiline resistance were identified. Results Data from 14 studies were included; 14 and 9 studies reported on pre-treatment and acquired bedaquiline resistance, respectively. The pooled prevalence of pre-treatment bedaquiline resistance was 2.4% (95% CI 1.7 – 3.5), with significant heterogeneity across all studies ( I 2 66%, p<0.01). The pooled prevalence of treatment-emergent bedaquiline resistance was 2.1% (95% CI 1.4 - 3.0), with no significant heterogeneity across the included studies ( I 2 0%, p=0.97). Discussion We found a concerning frequency of bedaquiline resistance present at baseline and acquired during treatment. Urgent strategies are required to mitigate further resistance to this crucial drug. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Protocols ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes