Bedaquiline-Resistant Tuberculosis: Dark Clouds on the Horizon

Andres, Sönke; Merker, Matthias; Heyckendorf, Jan; Kalsdorf, Barbara; Rumetshofer, Rudolf; Indra, Alexander; Hofmann-Thiel, Sabine; Hoffmann, Harald; Lange, Christoph; Niemann, Stefan; Maurer, Florian P.

doi:10.1164/rccm.201909-1819le

Cited by 65 publications

(72 citation statements)

References 8 publications

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“…Another study shows that bedaquiline can also be used to replace Km [ 23 ]. However, bedaquiline resistance is acquired in up to 5% of patients [ 24 , 25 ], which is used as an argument to save this drug for patients with FQ-resistant-TB [ 26 ]. All 17 patients with a Km dose reduction or withdrawal of Km from the regimen, which occurred after a median of two months on treatment, were cured relapse-free.…”

Section: Discussionmentioning

confidence: 99%

“…Whereas resistance acquisition after treatment with injectable-containing regimens has been reported for most shorter treatment regimen studies [ 2 ], this feature was not considered in the ranking of second-line TB drugs shown in the 2019 WHO guidelines [ 9 ]. The potential of acquiring bedaquiline resistance in regimen with at least four likely active drugs [ 24 , 25 ] shows that prevention of resistance acquisition requires more attention as all-oral regimens are being investigated.…”

Section: Discussionmentioning

confidence: 99%

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Course of Adverse Events during Short Treatment Regimen in Patients with Rifampicin-Resistant Tuberculosis in Burundi

Ciza

Gils

Sawadogo

et al. 2020

JCM

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The introduction of the nine-month short-treatment regimen (STR) has drastically improved outcomes of rifampicin-resistant tuberculosis (RR-TB) treatment. Adverse events (AE) commonly occur, including injectable-induced hearing loss. In Burundi we retrospectively assessed the frequency of adverse events and treatment modifications in all patients who initiated the STR between 2013–2017. Among 225 included patients, 93% were successfully treated without relapse, 5% died, 1% was lost-to-follow-up, 0.4% had treatment failure and 0.4% relapsed after completion. AE were reported in 53%, with grade 3 or 4 AE in 4% of patients. AE occurred after a median of two months. Hepatotoxicity (31%), gastro-intestinal toxicity (22%) and ototoxicity (10%) were most commonly reported. One patient suffered severe hearing loss. Following AE, 7% of patients had a dose reduction and 1% a drug interruption. Kanamycin-induced ototoxicity led to 94% of modifications. All 18 patients with a modified regimen were cured relapse-free. In this exhaustive national RR-TB cohort, RR-TB was treated successfully with the STR. Adverse events were infrequent. To replace the present STR, all-oral regimens should be at least as effective and also less toxic. During and after transition, monitoring, management, and documentation of AE will remain essential.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Course of Adverse Events during Short Treatment Regimen in Patients with Rifampicin-Resistant Tuberculosis in Burundi

Ciza

Gils

Sawadogo

et al. 2020

JCM

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“…Bedaquiline resistance can also be conferred by other RAVs including in pepQ (bedaquiline and clofazimine), atpE (bedaquiline only) 44 and Rv1979c (clofazimine only). We only found atpE RAVs at low allele frequency in one patient who also had Rv0678 variants (sample accession ERR2677436), which is in line with other evidence suggesting they rarely occur in clinical isolates, likely due to a high fitness cost.…”

Section: Discussionmentioning

confidence: 99%

Detection of a historic reservoir of bedaquiline / clofazimine resistance associated variants inMycobacterium tuberculosis

Dorp

Nimmo

Ortiz

et al. 2020

Preprint

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Drug resistance in tuberculosis (TB) poses a major ongoing challenge to public health. The recent inclusion of bedaquiline into TB drug regimens has improved treatment outcomes, but this advance is threatened by the emergence of strains of Mycobacterium tuberculosis (Mtb) resistant to bedaquiline. Clinical bedaquiline resistance is most frequently conferred by resistance-associated variants (RAVs) in the Rv0678 gene which can also confer cross-resistance to clofazimine, another TB drug. We compiled a dataset of 3,682 Mtb genomes, including 223 carrying Rv0678 bedaquiline RAVs. We identified at least 15 cases where RAVs were present in the genomes of strains collected prior to the use of bedaquiline in TB treatment regimes. Phylogenetic analyses point to multiple emergence events and in some cases widespread circulation of RAVs in Rv0678, often prior to the introduction of bedaquiline or clofazimine. Strikingly, this included three cases predating the antibiotic era. The presence of a pre-existing reservoir of bedaquiline-resistant Mtb strains necessitates the urgent implementation of rapid drug susceptibility testing and individualised regimen selection to safeguard the use of bedaquiline in TB care and control.

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“…Moreover, phenotypic methods are too slow to provide early indication of susceptibility status at the time of treatment initiation. An accurate classification of SNPs according to their association with drug resistance is therefore essential to allow the use of WGS to guide the composition of treatment regimens ( 7, 53 ). The fact that accurate databases with catalogued mutations are currently lacking for these drugs, represent a serious limitation for molecular DST for BDQ and DLM.…”

Section: Discussionmentioning

confidence: 99%

“…Based on WHO priority grouping of medicines, Delamanid (DLM) compound is recommended when an effective regimen cannot be established by group A agents, containing BDQ, fluoroquinolones (FQs), linezolid (LZD) and B agents group, composed by clofazimine (CLF) and cycloserine (CS) ( 2 ). Previous studies have shown that MDR/XDR-TB patients treated with BDQ and DLM rapidly develop resistance due to fixed mutations in candidate genes which often appear as previously undescribed novel variants ( 3, 4, 5, 6, 7 ). Additionally, resistance to BDQ can arise in naïve populations of MTBc strains as a consequence of a clofazimine-containing regimen, or by random mutations affecting the drug targets ( 8, 9, 10, 11, 12, 13, 14 ).…”

Section: Introductionmentioning

confidence: 99%

Characterization of genomic variants associated with resistance to bedaquiline and delamanid in naïve Mycobacterium tuberculosis clinical strains

Battaglia¹,

Spitaleri

Cabibbe³

et al. 2020

Preprint

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The role of genetic mutations in genes associated to phenotypic resistance to bedaquiline (BDQ) and delamanid (DLM) in Mycobacterium tuberculosis complex (MTBc) strains is poorly understood. However, a clear understanding of the role of each genetic variant is crucial to guide the development of molecular-based drug susceptibility testing (DST). In this work, we analysed all mutations in candidate genomic regions associated with BDQ- and DLM-resistant phenotypes using a whole genome sequencing (WGS) dataset from a collection of 4795 MTBc clinical isolates from six high-burden countries of tuberculosis (TB). From WGS analysis, we identified 61 and 158 unique mutations in genomic regions potentially involved in BDQ- and DLM-resistant phenotypes, respectively. Importantly, all strains were isolated from patients who likely have never been exposed to the medicines. In order to characterize the role of mutations, we performed an energetic in silico analysis to evaluate their effect in the available protein structures Ddn (DLM), Fgd1 (DLM) and Rv0678 (BDQ), and minimum inhibitory concentration (MIC) assays on a subset of MTBc strains carrying mutations to assess their phenotypic effect. The combination of structural protein information and phenotypic data allowed for cataloging the mutations clearly associated with resistance to BDQ (n= 4) and DLM (n= 35), as well as about a hundred genetic variants without any correlation with resistance. Importantly, these results show that both BDQ and DLM resistance-related mutations are diverse and distributed across the entire region of each gene target, which is of critical importance to the development of comprehensive molecular diagnostic tools.ImportancePhenotypic drug susceptibility tests (DST) are too slow to provide an early indication of drug susceptibility status at the time of treatment initiation and very demanding in terms of specimens handling and biosafety. The development of molecular assays to detect resistance to bedaquiline (BDQ) and delamanid (DLM) requires accurate categorization of genetic variants according to their association with phenotypic resistance. We have evaluated a large multi-country set of clinical isolates to identify mutations associated with increased minimum inhibitory concentrations (MICs) and used an in silico protein structure analysis to further unravel the potential role of these mutations in drug resistance mechanisms. The results of this study are an important source of information for the development of molecular diagnostic tests to improve the provision of appropriate treatment and care to TB patients.

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Bedaquiline-Resistant Tuberculosis: Dark Clouds on the Horizon

Cited by 65 publications

References 8 publications

Course of Adverse Events during Short Treatment Regimen in Patients with Rifampicin-Resistant Tuberculosis in Burundi

Course of Adverse Events during Short Treatment Regimen in Patients with Rifampicin-Resistant Tuberculosis in Burundi

Detection of a historic reservoir of bedaquiline / clofazimine resistance associated variants inMycobacterium tuberculosis

Characterization of genomic variants associated with resistance to bedaquiline and delamanid in naïve Mycobacterium tuberculosis clinical strains

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