Bedaquiline resistance in drug-resistant tuberculosis HIV co-infected patients

Nimmo, Camus; Millard, James; Brien, Kayleen; Moodley, Sashen; Dorp, Lucy van; Lutchminarain, Keeren; Wolf, Allison; Grant, Alison D.; Balloux, François; Pym, Alexander S.; Padayatchi, Nesri; O’Donnell, Max R

doi:10.1183/13993003.02383-2019

Cited by 66 publications

(80 citation statements)

References 11 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

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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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“…In the phenotypic analysis, we included all M tuberculosis isolates from patients with Rv0678 variants in the PRAXIS study (registered with ClinicalTrials.gov , NCT03162107 ) 11 and in three other cohort studies of drug-resistant tuberculosis. We also included sequential isolates from one persistently culture-positive patient with extensively drug-resistant tuberculosis with Rv0678 variants at the KwaZulu-Natal provincial referral laboratory ( table 1 ).…”

Section: Methodsmentioning

confidence: 99%

“…In a clinical report published in February, 2020, that investigated the clinical course and treatment outcomes in a cohort of patients with drug-resistant tuberculosis who were due to start bedaquiline-based therapy in KwaZulu-Natal, we found baseline and emergent Rv0678 resistance-associated variants (RAVs). 11 Among sequenced isolates, five (5%) of 92 had baseline Rv0678 variants. Although none had bedaquiline MICs above the critical concentration, three of five had MICs at the top of the wild-type range and patients with baseline Rv0678 variants had worse outcomes than those without.…”

Section: Introductionmentioning

confidence: 99%

“…Reports describing the presence of bedaquiline and clofazimine resistance in southern Africa (defined as the countries of the Southern African Development Community) have been scarce. 12 , 13 In this study, we present genotypic and phenotypic data for M tuberculosis isolates with RAVs identified from our clinical report 11 and other unpublished (to date) cohort studies at the Africa Health Research Institute, and report a more extensive microbiological investigation of bedaquiline and clofazimine MICs to investigate the extent of cross-resistance. To better understand the phylogenetic and geographical distribution of bedaquiline and clofazimine RAVs in southern Africa, we then analysed a comprehensive collection of our own and publicly available whole-genome sequencing data.…”

Section: Introductionmentioning

confidence: 99%

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Population-level emergence of bedaquiline and clofazimine resistance-associated variants among patients with drug-resistant tuberculosis in southern Africa: a phenotypic and phylogenetic analysis

et al. 2020

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Summary Background Bedaquiline and clofazimine are important drugs in the treatment of drug-resistant tuberculosis and are commonly used across southern Africa, although drug susceptibility testing is not routinely performed. In this study, we did a genotypic and phenotypic analysis of drug-resistant Mycobacterium tuberculosis isolates from cohort studies in hospitals in KwaZulu-Natal, South Africa, to identify resistance-associated variants (RAVs) and assess the extent of clofazimine and bedaquiline cross-resistance. We also used a comprehensive dataset of whole-genome sequences to investigate the phylogenetic and geographical distribution of bedaquiline and clofazimine RAVs in southern Africa. Methods In this study, we included M tuberculosis isolates reported from the PRAXIS study of patients with drug-resistant tuberculosis treated with bedaquiline (King Dinuzulu Hospital, Durban) and three other cohort studies of drug-resistant tuberculosis in other KwaZulu-Natal hospitals, and sequential isolates from six persistently culture-positive patients with extensively drug-resistant tuberculosis at the KwaZulu-Natal provincial referral laboratory. Samples were collected between 2013 and 2019. Microbiological cultures were done as part of all parent studies. We sequenced whole genomes of included isolates and measured bedaquiline and clofazimine minimum inhibitory concentrations (MICs) for isolates identified as carrying any Rv0678 variant or previously published atpE, pepQ , and Rv1979c RAVs, which were the subject of the phenotypic study. We combined all whole-genome sequences of M tuberculosis obtained in this study with publicly available sequence data from other tuberculosis studies in southern Africa (defined as the countries of the Southern African Development Community), including isolates with Rv0678 variants identified by screening public genomic databases. We used this extended dataset to reconstruct phylogenetic relationships across lineage 2 and 4 M tuberculosis isolates. Findings We sequenced the whole genome of 648 isolates from 385 patients with drug-resistant tuberculosis recruited into cohort studies in KwaZulu-Natal, and 28 isolates from six patients from the KwaZulu-Natal referral laboratory. We identified 30 isolates with Rv0678 RAVs from 16 (4%) of 391 patients. We did not identify any atpE, pepQ , or Rv1979c RAVs. MICs were measured for 21 isolates with Rv0678 RAVs. MICs were above the critical concentration for bedaquiline resistance in nine (43%) of 21 isolates, in the intermediate category in nine (43%) isolates, and within the wild-type range in three (14%) isolates. Clofazimine MICs i...

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Antibacterials/antituberculars Development of drug resistance and treatment failure: 8 case reportsIn a prospective cohort study (NCT03162107; PRAXIS study conducted between November 2016 and January 2019) of 297 adult patients, 8 adult patients [sexes and exact ages not stated] were described, of whom, 7 patients exhibited treatment failure during treatment with linezolid, terizidone, aminosalicylic acid [para-amino salicylic acid], imipenem, pyrazinamide, ethionamide, ethambutol, isoniazid, delamanid, bedaquiline, clofazimine or unspecified fluoroquinolones for extensively drug-resistant tuberculousis (XDR-TB). Additionally, five of these patients and the remaining one patient developed drug resistance during treatment with bedaquiline and clofazimine [routes, dosages and duration of treatments to reaction onsets not stated].Patient-A: The adult patient, who had pre-XDR TB and HIV infection, had been receiving unspecified antiretroviral therapy for HIV infection. Concomitantly, the patient started receiving pyrazinamide, unspecified fluoroquinolones, bedaquiline, clofazimine, ethionamide, linezolid, terizidone and aminosalicylic acid for tuberculosis. At a 6-month follow-up, the patient experienced treatment failure. Subsequently, the patient was lost to follow-up.Patient-B: The adult patient, who had pre-XDR TB and HIV infection, had been receiving unspecified antiretroviral therapy for HIV infection. Concomitantly, the patient started receiving pyrazinamide, unspecified fluoroquinolones, bedaquiline, clofazimine, linezolid, terizidone, aminosalicylic acid and iminipem for tuberculosis. Initially, the patient had a baseline Rv0678 variant (associated with bedaquiline resistance; R109L, R159fs) allele frequency of 72%; however, 2 months following treatment initiation, the patient's Mycobacterium tuberculosis minimum inhibitory concentration (MIC) for bedaquiline increased from 0.03 µg/mL to 0.25 µg/mL due to within-patient evolution of the infecting strain. Further, the frequency of Rv0678 variant allele increased to 96%, indicating drug resistance secondary to bedaquiline and clofazimine. At a 6-month follow-up, the patient exhibited treatment failure with pyrazinamide, unspecified fluoroquinolones, terizidone, aminosalicylic acid and iminipem. Eventually, the patient died [immediate cause of death not stated].Patient-D: The adult patient, who had XDR-TB and HIV infection, had been receiving unspecified antiretroviral therapy for HIV infection. Concomitantly, the patient started receiving isoniazid, pyrazinamide, unspecified fluoroquinolones, bedaquiline, clofazimine, terizidone and aminosalicylic acid for XDR-TB. At a 6-month follow-up, the patient exhibited treatment failure. Eventually, the patient died [immediate cause of death not stated].Patient-F: The adult patient, who had XDR-TB and HIV infection, had been receiving unspecified antiretroviral therapy for HIV infection. Concomitantly, the patient started receiving pyrazinamide, unspecified fluoroquinolones, bedaquiline, clofazimine, linezolid, terizido...

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Bedaquiline resistance in drug-resistant tuberculosis HIV co-infected patients

Cited by 66 publications

References 11 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

Population-level emergence of bedaquiline and clofazimine resistance-associated variants among patients with drug-resistant tuberculosis in southern Africa: a phenotypic and phylogenetic analysis

Antibacterials/antituberculars

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