Bedaquiline and clofazimine: successes and challenges

Bedaquiline, a novel therapeutic drug, and clofazimine, a re-purposed drug, are front-line therapies recommended by WHO to treat rifampicin-resistant or multidrug-resistant tuberculosis. Both drugs have been in use in South Africa at least 10 years: bedaquiline since 2007 and clofazimine since 2010. The use of bedaquiline in programmatic settings in South Africa has reduced the risk of all-cause mortality threefold (hazard ratio 0·35, 95% CI 0·28–0·46)1Schnippel K Ndjeka N Maartens G et al.Effect of bedaquiline on mortality in South African patients with drug-resistant tuberculosis: a retrospective cohort study.Lancet Respir Med. 2018; 6: 699-706Summary Full Text Full Text PDF PubMed Scopus (122) Google Scholar and achieved treatment success in at least 70% of patients.2Ndjeka N Schnippel K Master I et al.High treatment success rate for multidrug-resistant and extensively drug-resistant tuberculosis using a bedaquiline-containing treatment regimen.Eur Respir J. 2018; 521801528Crossref PubMed Scopus (59) Google Scholar The inclusion of clofazimine in combination therapy has reduced treatment duration from 18–24 months to 9–12 months. South Africa has adopted both drugs extensively in the modified short and long regimens for rifampicin-resistant or multidrug-resistant tuberculosis. According to the electronic drug-resistant tuberculosis register, as of June 1, 2020, 29 193 individuals in South Africa have received bedaquiline, and 30 599 have received clofazimine. Emerging resistance and cross-resistance have been reported.3Andries K Villellas C Coeck N et al.Acquired resistance of Mycobacterium tuberculosis to bedaquiline.PLoS One. 2014; 9e102135Crossref PubMed Scopus (212) Google Scholar, 4Ismail NA Omar SV Joseph L et al.Defining bedaquiline susceptibility, resistance, cross-resistance and associated genetic determinants: a retrospective cohort study.EBioMedicine. 2018; 28: 136-142Summary Full Text Full Text PDF PubMed Scopus (45) Google Scholar In The Lancet Microbe, Camus Nimmo and colleagues5Nimmo C Millard J van Dorp L et al.Population-level emergence of bedaquiline and clofazimine resistance-associated variants among patients with drug-resistant tuberculosis in southern Africa: a phenotypic and phylogenetic analysis.Lancet Microbe. 2020; 1: e165-e174Summary Full Text Full Text PDF PubMed Scopus (16) Google Scholar used whole-genome sequencing of 676 Mycobacterium tuberculosis isolates from 391 patients with drug-resistant tuberculosis in KwaZulu-Natal, South Africa, to identify variants associated with resistance to bedaquiline and clofazimine.5Nimmo C Millard J van Dorp L et al.Population-level emergence of bedaquiline and clofazimine resistance-associated variants among patients with drug-resistant tuberculosis in southern Africa: a phenotypic and phylogenetic analysis.Lancet Microbe. 2020; 1: e165-e174Summary Full Text Full Text PDF PubMed Scopus (16) Google Scholar Their study provides additional evidence of emerging resistance to these drugs. Among the cohorts analysed, 16 (4%) of 391 patients had genotypic resistance; of those who had a resistance pattern defined, 11 (79%) of 14 had pre-extensively drug-resistant or extensively drug-resistant tuberculosis and harboured unique Rv0678 mutations. Interestingly, identical Rv0678 mutations were only observed among patients who developed resistance during treatment, emerging between 2 and 20 months after exposure. Selection of these mutations could reflect adaptive responses requiring further investigation, although the authors noted that primary nosocomial transmission is the most likely reason. Measuring resistance to bedaquiline and clofazimine is a challenge. Two multi-country quality studies showed poorer reproducibility6Kaniga K Cirillo DM Hoffner S et al.A multilaboratory, multicountry study to determine bedaquiline mic quality control ranges for phenotypic drug susceptibility testing.J Clin Microbiol. 2016; 54: 2956-2962Crossref PubMed Scopus (26) Google Scholar and false resistance7Kaniga K Aono A Borroni E et al.Validation of bedaquiline phenotypic drug susceptibility testing methods and breakpoints: a multilaboratory, multicountry study.J Clin Microbiol. 2020; 58: e01677-e01719Crossref PubMed Scopus (10) Google Scholar for the agar method used by Nimmo and colleagues (ie, the 1% proportion method on Middlebrook 7H11 agar)5Nimmo C Millard J van Dorp L et al.Population-level emergence of bedaquiline and clofazimine resistance-associated variants among patients with drug-resistant tuberculosis in southern Africa: a phenotypic and phylogenetic analysis.Lancet Microbe. 2020; 1: e165-e174Summary Full Text Full Text PDF PubMed Scopus (16) Google Scholar Furthermore, clinical trial data did not show a substantial difference in culture conversion at 24 weeks between high and low minimum inhibitory concentrations (MICs) using this method.8US Food and Drug AdministrationSirturo: highlights of prescribing information.https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/204384s000lbl.pdfDate: December, 2012Date accessed: May 26, 2020Google Scholar Determination of genetic resistance is also problematic as not all mutations in the Rv0678 gene confer large increases in MIC, with some mutations having the opposite effect.9Villellas C Coeck N Meehan CJ et al.Unexpected high prevalence of resistance-associated Rv0678 variants in MDR-TB patients without documented prior use of clofazimine or bedaquiline.J Antimicrob Chemother. 2017; 72: 684-690PubMed Google Scholar Population-level analysis of these data is useful, although for individual patient management the evidence base for specific mutations, levels of resistance, and final treatment outcomes is sparse and requires further research. The number of patients with rifampicin-resistant or multidrug-resistant tuberculosis in sub-Saharan Africa was estimated to be 77 000 in 2018 while only 19 730 were reported to have started treatment, and of these patients 9558 (48%) were treated in South Africa. The bold decision in South Africa to use these new and repurposed drugs in shortened treatment regimens was based on operational research data and the ethical need for effective, patient-friendly, injection-free regimens. The introduction of bedaquiline was accompanied by a national surveillance programme to monitor the emergence of drug resistance. Data generated led to the criteria for resistance adopted by WHO in 2018.4Ismail NA Omar SV Joseph L et al.Defining bedaquiline susceptibility, resistance, cross-resistance and associated genetic determinants: a retrospective cohort study.EBioMedicine. 2018; 28: 136-142Summary Full Text Full Text PDF PubMed Scopus (45) Google Scholar Additionally, two crucial changes in South African policy occurred in 2018: the modified short regimen was strengthened with linezolid, and a standardised laboratory testing protocol to detect resistance to bedaquiline, clofazimine, and linezolid was introduced. These interventions overlap in time with the study by Nimmo and colleagues,5Nimmo C Millard J van Dorp L et al.Population-level emergence of bedaquiline and clofazimine resistance-associated variants among patients with drug-resistant tuberculosis in southern Africa: a phenotypic and phylogenetic analysis.Lancet Microbe. 2020; 1: e165-e174Summary Full Text Full Text PDF PubMed Scopus (16) Google Scholar pre-emptively addressing the concerns raised. The approach applied by South Africa should be used as an example for other countries when adopting these new regimens at scale. A rapid assay that can screen for resistance to either bedaquiline or clofazimine at treatment initiation is still urgently needed. Of interest is the phylogenetic analysis by Nimmo and colleagues5Nimmo C Millard J van Dorp L et al.Population-level emergence of bedaquiline and clofazimine resistance-associated variants among patients with drug-resistant tuberculosis in southern Africa: a phenotypic and phylogenetic analysis.Lancet Microbe. 2020; 1: e165-e174Summary Full Text Full Text PDF PubMed Scopus (16) Google Scholar—which included the genome sequences from their study, publicly available sequences from previously published studies in southern Africa, and sequences indexed in the National Center for Biotechnology Information Sequencing Read Archive originating from samples collected in southern African countries—showing emergence of Rv0678 mutations preceding the introduction of bedaquiline, which was also reported in a previous study.10Makhado NA Matabane E Faccin M et al.Outbreak of multidrug-resistant tuberculosis in South Africa undetected by WHO-endorsed commercial tests: an observational study.Lancet Infect Dis. 2018; 18: 1350-1359Summary Full Text Full Text PDF PubMed Scopus (69) Google Scholar The current study highlights the propensity of these mutations to occur in specific strain lineages, and the need for further investigation into the nature of these occurrences. Are these sporadic mutations unrelated to selection pressure and well established among mycobacteria? Alternatively, selection pressure could be due to the azole group of antifungal agents, which would have different implications for control, especially in sub-Saharan Africa, where they are commonly used. The excellent successes achieved with bedaquiline and clofazimine require scale-up if the poor global outcomes for rifampicin-resistant or multidrug-resistant tuberculosis are to be addressed. However, upscaling the use of these drugs comes at the cost of resistance emergence, which needs to be mitigated. Early detection of resistance is essential, requiring development of new rapid technologies combined with strengthening of laboratory capacity to support the introduction of new regimens. Additionally, effective combination therapies and adherence to these regimens are crucial factors in curbing emergence of resistance. Unfortunately, the pipeline for new drug classes for tuberculosis is running at a trickle when compared with HIV, and if not addressed urgently, we will find ourselves in a pre-antibiotic era, which we cannot afford as we set our sights on ending tuberculosis by 2035. We declare no competing interests. Population-level emergence of bedaquiline and clofazimine resistance-associated variants among patients with drug-resistant tuberculosis in southern Africa: a phenotypic and phylogenetic analysisBedaquiline and clofazimine cross-resistance in southern Africa is emerging repeatedly, with evidence of onward transmission largely due to Rv0678 mutations in M tuberculosis. Roll-out of bedaquiline and clofazimine treatment in the setting of limited drug susceptibility testing could allow further spread of resistance. Designing strong regimens would help reduce the emergence of resistance. Drug susceptibility testing is required to identify where resistance does emerge. 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