Bedaquiline Microheteroresistance after Cessation of Tuberculosis Treatment

Vos, Margaretha de; Ley, Serej D.; Wiggins, Kristin; Derendinger, Brigitta; Dippenaar, Anzaan; Grobbelaar, Melanie; Reuter, Anja; Dolby, Tania; Burns, Scott; Schito, Marco; Engelthaler, David M.; Metcalfe, John; Theron, Grant; Rie, Annelies Van; Posey, James E.; Warren, Robin M.; Cox, Helen

doi:10.1056/nejmc1815121

Cited by 53 publications

(44 citation statements)

References 5 publications

(5 reference statements)

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“…Eight publications presented longitudinal studies where BDQ or DLM resistance was developed after (in vivo or in vitro) drug exposure [5,6,[25][26][27][28][29][30]. Some of these longitudinal studies evaluated two to eight isolates from the same patient.…”

Section: Description Of Collected Articlesmentioning

confidence: 99%

“…Heteroresistance occurs when a subpopulation of apparently isogenic bacteria exhibits drug-resistance within a population of drug-susceptible strains [61]. We identified three studies that reported heteroresistance for BDQ [29,30,36], one for DLM [30], and one to other drugs [6]. WGS is currently the finest approach to detect heteroresistance and, to some extent, can predict the selection of resistant strains within a patient.…”

Section: Other Findings: Mutations In Drug-susceptible Strains Crossmentioning

confidence: 99%

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Whole Genome Sequencing for the Analysis of Drug Resistant Strains of Mycobacterium tuberculosis: A Systematic Review for Bedaquiline and Delamanid

2020

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Tuberculosis (TB) remains the deadliest Infectious disease worldwide, partially due to the increasing dissemination of multidrug and extensively drug-resistant (MDR/XDR) strains. Drug regimens containing the new anti-TB drugs bedaquiline (BDQ) and delamanid (DLM) appear as a last resort for the treatment of MDR or XDR-TB. Unfortunately, resistant cases to these drugs emerged just one year after their introduction in clinical practice. Early detection of resistant strains to BDQ and DLM is crucial to preserving the effectiveness of these drugs. Here, we present a systematic review aiming to define all available genotypic variants linked to different levels of resistance to BDQ and DLM that have been described through whole genomic sequencing (WGS) and the available drug susceptibility testing methods. During the review, we performed a thorough analysis of 18 articles. BDQ resistance was associated with genetic variants in Rv0678 and atpE, while mutations in pepQ were linked to a low-level of resistance for BDQ. For DLM, mutations in the genes ddn, fgd1, fbiA, and fbiC were found in phenotypically resistant cases, while all the mutations in fbiB were reported only in DLM-susceptible strains. Additionally, WGS analysis allowed the detection of heteroresistance to both drugs. In conclusion, we present a comprehensive panel of gene mutations linked to different levels of drug resistance to BDQ and DLM.

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Section: Description Of Collected Articlesmentioning

confidence: 99%

Section: Other Findings: Mutations In Drug-susceptible Strains Crossmentioning

confidence: 99%

Whole Genome Sequencing for the Analysis of Drug Resistant Strains of Mycobacterium tuberculosis: A Systematic Review for Bedaquiline and Delamanid

2020

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“…Such mixed populations of wild type alleles and RAVs have been termed macroheteroresistance when RAVs are present at 5% frequency, a threshold above which they would be identified by most standard WGS pipelines, and microheteroresistance when RAVs are at <5% frequency (21). Several case reports have identified heterozygous RAVs (hetRAVs) that have increased in frequency over the course of treatment (22)(23)(24) leading to fixed resistance, including variants originally identified at <1% frequency (25), and genetic microheteroresistance has been identified predating acquired phenotypic resistance (26). However, due to high levels of turnover of low-frequency variants, it may be difficult to predict which hetRAVs are likely to persist or become fixed and which ones will disappear.…”

Section: Introductionmentioning

confidence: 99%

Dynamics of within-hostMycobacterium tuberculosisdiversity and heteroresistance during treatment

Nimmo

Brien

Millard

et al. 2020

Preprint

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“…Still, the specific role of low-frequency variants during treatment failure is not completely understood, and only few papers confirm the clinical importance [36][37][38] . This is partially due to the lack of valid detection methods.…”

Section: Discussionmentioning

confidence: 99%

Detection of low-frequency resistance-mediating SNPs in next-generation sequencing data of Mycobacterium tuberculosis complex strains with binoSNP

Dreyer

Utpatel

Kohl

et al. 2020

Sci Rep

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Accurate drug resistance detection is key for guiding effective tuberculosis treatment. While genotypic resistance can be rapidly detected by molecular methods, their application is challenged by mixed mycobacterial populations comprising both susceptible and resistant cells (heteroresistance). for this, next-generation sequencing (nGS) based approaches promise the determination of variants even at low frequencies. However, accurate methods for a valid detection of low-frequency variants in nGS data are currently lacking. to tackle this problem, we developed the variant detection tool binoSnp which allows the determination of low-frequency single nucleotide polymorphisms (Snps) in nGS datasets from Mycobacterium tuberculosis complex (MtBc) strains. By taking a reference-mapped file as input, binoSNP evaluates each genomic position of interest using a binomial test procedure. binoSnp was validated using in-silico, in-vitro, and serial patient isolates datasets comprising varying genomic coverage depths (100-500×) and SNP allele frequencies (1-30%). Overall, the detection limit for low-frequency Snps depends on the combination of coverage depth and allele frequency of the resistance-associated mutation. binoSnp allows for valid detection of resistance associated Snps at a 1% frequency with a coverage ≥400×. in conclusion, binoSnp provides a valid approach to detect lowfrequency resistance-mediating Snps in nGS data from clinical MtBc strains. it can be implemented in automated, end-user friendly analysis tools for nGS data and is a step forward towards individualized tB therapy. Globally, tuberculosis (TB) is the leading cause of death from a single infectious agent with an estimated 1.3 million deaths and 10 million new TB cases in 2017 1. The emergence of drug-resistance challenges global TB control efforts with 558 000 estimated cases in 2017 being resistant to the frontline drug rifampicin (RMP); 82% of those were classified as multidrug resistant (MDR) strains, defined as showing additional resistance against isoniazid (INH) 1 and even 10% of those were estimated to be extremely drug resistant (XDR) which means carrying further resistances to a quinolone and one injectable drug 1. Early case detection, rapid drug susceptibility testing (DST), and effective treatment are core elements of global TB programs to control the spread, emergence, and transmission of resistant strains 2. Resistance of Mycobacterium tuberculosis complex (MTBC) strains is caused by spontaneous mutations, mainly single nucleotide polymorphisms (SNPs), in specific regions of the pathogen's genome. In general, mutations appear by chance with a probability of between 10-6 and 10-8 per generation depending on the observed locus 3. Normally, mutations in resistance associated genes are associated with a fitness cost, however, under a selection pressure such as antibiotic treatment resistant cells are selected and fixed in the population 4. The current gold standard to determine drug resistance in clinical MTBC strains is broth-based phenotypic...

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Bedaquiline Microheteroresistance after Cessation of Tuberculosis Treatment

Cited by 53 publications

References 5 publications

Whole Genome Sequencing for the Analysis of Drug Resistant Strains of Mycobacterium tuberculosis: A Systematic Review for Bedaquiline and Delamanid

Whole Genome Sequencing for the Analysis of Drug Resistant Strains of Mycobacterium tuberculosis: A Systematic Review for Bedaquiline and Delamanid

Dynamics of within-hostMycobacterium tuberculosisdiversity and heteroresistance during treatment

Detection of low-frequency resistance-mediating SNPs in next-generation sequencing data of Mycobacterium tuberculosis complex strains with binoSNP

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