Early safety and efficacy of the combination of bedaquiline and delamanid for the treatment of patients with drug-resistant tuberculosis in Armenia, India, and South Africa: a retrospective cohort study

Ferlazzo, Gabriella; Mohr-Holland, Erika; Laxmeshwar, Chinmay; Hewison, Catherine; Hughes, Jennifer; Jonckheere, Sylvie; Khachatryan, Naira; Avezedo, Virginia De; Egazaryan, Lusine; Shroufi, Amir; Kalon, Stobdan; Cox, Helen; Furin, Jennifer; Isaakidis, Petros

doi:10.1016/s1473-3099(18)30100-2

Cited by 120 publications

(77 citation statements)

References 21 publications

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“…One study was conducted in China (Zhang 2014), another in India (Udwadia 2010), and two in South Africa (Seddon 2014; Olayanju 2018); these three countries have high tuberculosis, tuberculosis/HIV and MDR‐TB burden. Ferlazzo 2018 recruited from Armenia (former Soviet Union country, previously on the high MDR‐TB burden list), India and South Africa.…”

Section: Resultsmentioning

confidence: 99%

“…Two RCTs (Lee 2012; Tang 2015), one prospective cohort study (Olayanju 2018), and one retrospective cohort (Zhang 2014), included only XDR‐TB cases, and Jo 2014 and Jeong 2015 included MDR cases with at least fluoroquinolone resistance (including XDR). Half (14/28) of the cases in Ferlazzo 2018 were XDR. The remaining studies included a minority of cases with XDR.…”

Section: Resultsmentioning

confidence: 99%

“…Where reported, ATT was said to be administered on an inpatient basis, at least initially, with some describing continuation of therapy as an outpatient. An exception, Ferlazzo 2018 described some participants receiving outpatient therapy from the outset.…”

Section: Resultsmentioning

confidence: 99%

“…Jeong 2015 followed participants until the end of treatment. Guglielmetti 2017 aimed to follow‐up until 24 months after ATT completion, Ferlazzo 2018 until six months from commencement, and Olayanju 2018 reported monthly follow‐up for the duration of hospital stay. Follow‐up duration and frequency were unclear for the remaining studies (Migliori 2009; Udwadia 2010; Jo 2014; Seddon 2014; Kwak 2015; Van Altena 2015; Galli 2016; Jensenius 2016; Tiberi 2016).…”

Section: Resultsmentioning

confidence: 99%

“…Disaggregated data were available from 12 studies (639 participants), on total number of ‘any' or ‘serious' adverse events or linezolid discontinuation, amongst participants receiving linezolid (Migliori 2009; Jo 2014; Seddon 2014; Zhang 2014; Kwak 2015; Van Altena 2015; Galli 2016; Jensenius 2016; Tiberi 2016; Guglielmetti 2017; Ferlazzo 2018; Olayanju 2018). Six studies (487 participants), provided data for total number of ‘any' or ‘serious' adverse events amongst participants who did not receive linezolid (Seddon 2014; Kwak 2015; Galli 2016; Guglielmetti 2017; Ferlazzo 2018; Olayanju 2018).…”

Section: Resultsmentioning

confidence: 99%

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Linezolid for drug-resistant pulmonary tuberculosis

Singh

Cocker

Ryan

et al. 2019

Cochrane Database of Systematic Reviews

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BackgroundLinezolid was recently re‐classified as a Group A drug by the World Health Organization (WHO) for treatment of multi‐drug resistant tuberculosis (MDR‐TB) and extensively drug‐resistant tuberculosis (XDR‐TB), suggesting that it should be included in the regimen for all patients unless contraindicated. Linezolid use carries a considerable risk of toxicity, with the optimal dose and duration remaining unclear. Current guidelines are mainly based on evidence from observational non‐comparative studies.ObjectivesTo assess the efficacy of linezolid when used as part of a second‐line regimen for treating people with MDR and XDR pulmonary tuberculosis, and to assess the prevalence and severity of adverse events associated with linezolid use in this patient group.Search methodsWe searched the following databases: the Cochrane Infectious Diseases Specialized Register; CENTRAL; MEDLINE; Embase; and LILACS up to 13 July 2018. We also checked article reference lists and contacted researchers in the field.Selection criteriaWe included studies in which some participants received linezolid, and others did not. We included randomized controlled trials (RCTs) of linezolid for MDR and XDR pulmonary tuberculosis to evaluate efficacy outcomes. We added non‐randomized cohort studies to evaluate adverse events.Primary outcomes were all‐cause and tuberculosis‐associated death, treatment failure, and cure. Secondary outcomes were treatment interrupted, treatment completed, and time to sputum culture conversion. We recorded frequency of all and serious adverse events, adverse events leading to drug discontinuation or dose reduction, and adverse events attributed to linezolid, particularly neuropathy, anaemia, and thrombocytopenia.Data collection and analysisTwo review authors (BS and DC) independently assessed the search results for eligibility and extracted data from included studies. All review authors assessed risk of bias using the Cochrane ‘Risk of bias' tool for RCTs and the ROBINS‐I tool for non‐randomized studies. We contacted study authors for clarification and additional data when necessary.We were unable to perform a meta‐analysis as one of the RCTs adopted a study design where participants in the study group received linezolid immediately and participants in the control group received linezolid after two months, and therefore there were no comparable data from this trial. We deemed meta‐analysis of non‐randomized study data inappropriate.Main resultsWe identified three RCTs for inclusion. One of these studies had serious problems with allocation of the study drug and placebo, so we could not analyse data for intervention effect from it. The remaining two RCTs recruited 104 participants. One randomized 65 participants to receive linezolid or not, in addition to a background regimen; the other randomized 39 participants to addition of linezolid to a background regimen immediately, or after a delay of two months. We included 14 non‐randomized cohort studies (two prospective, 12 retrospective), with a total of 1678 partici...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Linezolid for drug-resistant pulmonary tuberculosis

Singh

Cocker

Ryan

et al. 2019

Cochrane Database of Systematic Reviews

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Validation of a Handheld 6-Lead Device for QT Interval Monitoring in Resource-Limited Settings

Metcalfe,

Economou,

Naufal

et al. 2024

JAMA Netw Open

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ImportanceRifampin-resistant tuberculosis treatment regimens require electrocardiographic (ECG) monitoring due to the use of multiple QTc-prolonging agents. Formal 12-lead ECG devices represent a significant burden in resource-constrained clinics worldwide and a potential barrier to treatment scale-up in some settings.ObjectiveTo evaluate the diagnostic accuracy of a handheld 6-lead ECG device within resource-constrained clinics.Design, Setting, and ParticipantsThis diagnostic study was performed within a multicenter, pragmatic (broad eligibility criteria with no exclusions for randomized participants), phase 3 rifampin-resistant tuberculosis treatment trial (BEAT Tuberculosis [Building Evidence for Advancing New Treatment for Tuberculosis]) in South Africa. A total of 192 consecutive trial participants were assessed, and 191 were recruited for this substudy between January 21, 2021, and March 27, 2023. A low proportion (3 of 432 [0.7%]) of all screened trial participants were excluded due to a QTc interval greater than 450 milliseconds. Triplicate reference standard 12-lead ECG results were human calibrated with readers blinded to 6-lead ECG results.Main Outcomes and MeasuresDiagnostic accuracy, repeatability, and feasibility of a 6-lead ECG device.ResultsA total of 191 participants (median age, 36 years [IQR, 28-45 years]; 81 female participants [42.4%]; 91 participants [47.6%] living with HIV) with a median of 4 clinic visits (IQR, 3-4 visits) contributed 2070 and 2015 12-lead and 6-lead ECG assessments, respectively. Across 170 participants attending 489 total clinic visits where valid triplicate QTc measurements were available for both devices, the mean 12-lead QTc measurement was 418 milliseconds (range, 321-519 milliseconds), and the mean 6-lead QTc measurement was 422 milliseconds (range, 288-574 milliseconds; proportion of variation explained, R2 = 0.4; P &lt; .001). At a QTc interval threshold of 500 milliseconds, the 6-lead ECG device had a negative predictive value of 99.8% (95% CI, 98.8%-99.9%) and a positive predictive value of 16.7% (95% CI, 0.4%-64.1%). The normal expected range of within-individual variability of the 6-lead ECG device was high (±50.2 milliseconds [coefficient of variation, 6.0%]) relative to the 12-lead ECG device (±22.0 milliseconds [coefficient of variation, 2.7%]). The mean (SD) increase in the 12-lead QTc measurement during treatment was 10.1 (25.8) milliseconds, with 0.8% of clinic visits (4 of 489) having a QTc interval of 500 milliseconds or more.Conclusions and RelevanceThis study suggests that simplified, handheld 6-lead ECG devices are effective triage tests that could reduce the need to perform 12-lead ECG monitoring in resource-constrained settings.

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Assessing Prolongation of the Corrected QT Interval with Bedaquiline and Delamanid Coadministration to Predict the Cardiac Safety of Simplified Dosing Regimens

Tanneau

Karlsson

Rosenkranz

et al. 2022

Clin Pharma and Therapeutics

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Delamanid and bedaquiline are two drugs approved to treat drug-resistant tuberculosis, and each have been associated with corrected QT interval (QTc) prolongation. We aimed to investigate the relationships between the drugs' plasma concentrations and the prolongation of observed QT interval corrected using Fridericia's formula (QTcF) and to evaluate their combined effects on QTcF, using a model-based population approach. Furthermore, we predicted the safety profiles of once daily regimens. Data were obtained from a trial where participants were randomized 1:1:1 to receive delamanid, bedaquiline, or delamanid + bedaquiline. The effect on QTcF of delamanid and/or its metabolite (DM-6705) and the pharmacodynamic interactions under coadministration were explored based on a published model between bedaquiline's metabolite (M2) and QTcF. The metabolites of each drug were found to be responsible for the drug-related QTcF prolongation. The final drug-effect model included a competitive interaction between M2 and DM-6705 acting on the same cardiac receptor and thereby reducing each other's apparent potency, by 28% (95% confidence interval (CI), 22-40%) for M2 and 33% (95% CI, 24-54%) for DM-6705. The generated combined effect was not greater but close to "additivity" in the analyzed concentration range. Predictions with the final model suggested a similar QT prolonging potential with simplified, once-daily dosing regimens compared with the approved regimens, with a maximum median change from baseline QTcF increase of 20 milliseconds in both regimens. The concentrations-QTcF relationship of the combination of bedaquiline and delamanid was best described by a competitive binding model involving the two main metabolites. Model predictions demonstrated that QTcF prolongation with simplified once daily regimens would be comparable to currently used dosing regimens.

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Early safety and efficacy of the combination of bedaquiline and delamanid for the treatment of patients with drug-resistant tuberculosis in Armenia, India, and South Africa: a retrospective cohort study

Abstract: Médecins Sans Frontières (MSF).

Cited by 120 publications

References 21 publications

Linezolid for drug-resistant pulmonary tuberculosis

Linezolid for drug-resistant pulmonary tuberculosis

Validation of a Handheld 6-Lead Device for QT Interval Monitoring in Resource-Limited Settings

Assessing Prolongation of the Corrected QT Interval with Bedaquiline and Delamanid Coadministration to Predict the Cardiac Safety of Simplified Dosing Regimens

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