Effect of bedaquiline on mortality in South African patients with drug-resistant tuberculosis: a retrospective cohort study

Schnippel, Kathryn; Ndjeka, Norbert; Maartens, Gary; Meintjes, Graeme; Master, Iqbal; Ismail, Nazir; Hughes, Jennifer; Ferreira, Héverson Batista; Padanilam, Xavier; Romero, Rodolfo; Riele, Julian Te; Conradie, Francesca

doi:10.1016/s2213-2600(18)30235-2

Cited by 202 publications

(172 citation statements)

References 16 publications

(17 reference statements)

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“…Since 2013, BDQ has been recommended for the treatment of multidrug‐resistant (MDR) TB by the World Health Organization and is currently being implemented at the programme level . Emerging results from the use of BDQ around the world show that sputum culture conversion rates are improved when BDQ is added to a background regimen …”

Section: Introductionmentioning

confidence: 99%

Understanding the drug exposure–response relationship of bedaquiline to predict efficacy for novel dosing regimens in the treatment of multidrug‐resistant tuberculosis

Tanneau

Karlsson

Svensson

2020

Brit J Clinical Pharma

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Aims:To externally validate an earlier characterized relationship between bedaquiline exposure and decline in bacterial load in a more difficult-to-treat patient population, and to explore the performances of alternative dosing regimens through simulations. Methods: The bedaquiline exposure-response relationship was validated using timeto-positivity data from 233 newly diagnosed or treatment-experienced patients with drug-resistant tuberculosis from the C209 open-label study. The significance of the exposure-response relationship on the bacterial clearance was compared to a constant drug effect model. Tuberculosis resistance type and the presence and duration of antituberculosis pre-treatment were evaluated as additional covariates. Alternative dosing regimens were simulated for tuberculosis patients with different types of drug resistance.Results: High bedaquiline concentrations were confirmed to be associated with faster bacterial load decline in patients, given that the exposure-effect relationship provided a significantly better fit than the constant drug effect (relative likelihood = 0.0003). The half-life of bacterial clearance was identified to be 22% longer in patients with pre-extensively drug-resistant (pre-XDR) tuberculosis (TB) and 86% longer in patients with extensively drug-resistant (XDR) TB, compared to patients with multidrug-resistant (MDR) TB. Achievement of the same treatment response for (pre-)XDR TB patients as for MDR TB patients would be possible by adjusting the dose and dosing frequency. Furthermore, daily bedaquiline administration as in the ZeNix regimen, was predicted to be as effective as the approved regimen. Conclusion:The confirmed bedaquiline exposure-response relationship offers the possibility to predict efficacy under alternative dosing regimens, and provides a useful tool for potential treatment optimization. K E Y W O R D Sbedaquiline, modelling, multidrug-resistance, nonlinear mixed-effect, sputum culture conversion, time-to-positivity, tuberculosisThe principal investigator of C209 clinical trial is not 1 of the authors since anonymized data from the study were obtained while shared through the European PreDiCT-TB consortium (http://www.predict-tb.eu/). Results and outcomes from the C209 clinical trial have already been published (

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Section: Introductionmentioning

confidence: 99%

Understanding the drug exposure–response relationship of bedaquiline to predict efficacy for novel dosing regimens in the treatment of multidrug‐resistant tuberculosis

Tanneau

Karlsson

Svensson

2020

Brit J Clinical Pharma

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“…This was despite the investigators within the study not attributing the increased number of deaths to the use of Bdq. In support of this, a large retrospective cohort study of individuals with MDR/XDR-TB in South Africa, found that adding Bdq to a treatment regimen was associated with a reduction in all-cause patient mortality (Schnippel et al, 2018). Having a pill-only regimen would be a considerable additional advantage for patients, when taken together with the reduced treatment time.…”

Section: Stream Trial Stagementioning

confidence: 80%

The changing treatment landscape for MDR/XDR-TB — Can current clinical trials revolutionise and inform a brave new world?

Honeyborne

Lipman

Zumla

et al. 2019

International Journal of Infectious Diseases

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“…As a result, the number of patients eligible to receive bedaquiline-containing regimens would significantly increase. Encouraging results from studies currently underway on the use of bedaquiline in all-oral, shorter-course regimens for the treatment of rifampicin-resistant TB could result in an even greater use of bedaquiline in TB control programmes globally (2,3). However, solid surveillance of drug-resistance is needed to monitor the emergence of resistance to bedaquiline in patients during therapy.…”

Section: Manuscriptmentioning

confidence: 99%

Acquisition of cross-resistance to Bedaquiline and Clofazimine following treatment for Tuberculosis in Pakistan

Ghodousi

Rizvi²,

Baloch

et al. 2019

Preprint

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20We report on the first six cases of acquired resistance to bedaquiline in Pakistan. Seventy sequential 21 culture isolates from 30 drug-resistant tuberculosis patients on bedaquiline-containing regimen were 22 tested for minimum inhibitory concentration (MIC) and whole genome sequencing. An increase in MICs 23 associated with cross-resistance to clofazimine and appearance of specific mutations was documented in 24 six cases. The study underlines that appropriate monitoring is mandatory for the introduction of new drugs. 25 26 27 93 strains collected from two patients reported as "failure" at the end of treatment (patient-4 MIC 0.25 94 mg·L −1 , eight fold higher than baseline and patient-5 MIC 0.125 mg·L −1 , four fold higher than baseline) 95 would have been categorised as susceptible. This finding indicates that monitoring MICs during treatment 96 could be a better predictor for failure than single testing at critical concentration. The genetic basis of 97 4 resistance to bedaquiline is still the subject of much uncertainty. WGS analysis in different studies showed 98 that bedaquiline-clofazimine cross resistance arises through mutations in Rv0678 (6,7,8) and pepQ (9). In 99 this study, we show that the increase of MIC to bedaquiline and clofazimine could be explained by 100 mutations emerging during therapy in Rv0678. As reported in table 1 we observed four different mutations 101 and three of these were previously reported as associated 102 to bedaquiline resistance in MTB clinical strains (8). We show that the same mutations are associated to 103 Clofazimine resistance. As a result, regimens that contain both drugs might have to be reconsidered when 104 these mutations are identified, to reduce the risk of failure for the patients and transmission of such strains 105 in the community. Altogether, these data show that resistance to bedaquiline emerges during treatment 106 and emphasize the importance of using MIC and whenever possible molecular based surveillance in 107 national programmes implementing bedaquiline for the treatment of MDR/XDR-TB to monitor the 108 emergence of resistance. Moreover, a classification of mutations associated to bedaquiline and clofazimine 109 resistance is crucial to lead future development of tools for fast detection of resistance. Introducing drugs 110 without proper diagnostics to monitor drug resistance may lead to amplification of hardly treatable cases. 111 112 Ethics approval 113 Ethical clearance was approved by the Institutional review board for HIV, TB and Malaria programme, 114 Pakistan.

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Effect of bedaquiline on mortality in South African patients with drug-resistant tuberculosis: a retrospective cohort study

Cited by 202 publications

References 16 publications

Understanding the drug exposure–response relationship of bedaquiline to predict efficacy for novel dosing regimens in the treatment of multidrug‐resistant tuberculosis

Understanding the drug exposure–response relationship of bedaquiline to predict efficacy for novel dosing regimens in the treatment of multidrug‐resistant tuberculosis

The changing treatment landscape for MDR/XDR-TB — Can current clinical trials revolutionise and inform a brave new world?

Acquisition of cross-resistance to Bedaquiline and Clofazimine following treatment for Tuberculosis in Pakistan

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