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Clinical Therapeutics

Randomized Pilot Trial of Eight Weeks of Bedaquiline (TMC207) Treatment for Multidrug-Resistant Tuberculosis: Long-Term Outcome, Tolerability, and Effect on Emergence of Drug Resistance

A. H. Diacon, P. R. Donald, A. Pym, M. Grobusch, R. F. Patientia, R. Mahanyele, N. Bantubani, R. Narasimooloo, T. De Marez, R. van Heeswijk, N. Lounis, P. Meyvisch, K. Andries, D. F. McNeeley
A. H. Diacon
aFaculty of Health Sciences, Stellenbosch University, Tygerberg, South Africa
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P. R. Donald
aFaculty of Health Sciences, Stellenbosch University, Tygerberg, South Africa
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A. Pym
bMedical Research Council, Durban, South Africa
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M. Grobusch
cFaculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
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R. F. Patientia
aFaculty of Health Sciences, Stellenbosch University, Tygerberg, South Africa
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R. Mahanyele
bMedical Research Council, Durban, South Africa
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N. Bantubani
cFaculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
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R. Narasimooloo
cFaculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
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T. De Marez
dTibotec, Inc., Yardley, Pennsylvania, USA
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R. van Heeswijk
eTibotec BVBA, Mechelen, Belgium
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N. Lounis
eTibotec BVBA, Mechelen, Belgium
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P. Meyvisch
eTibotec BVBA, Mechelen, Belgium
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K. Andries
eTibotec BVBA, Mechelen, Belgium
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D. F. McNeeley
dTibotec, Inc., Yardley, Pennsylvania, USA
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DOI: 10.1128/AAC.06126-11
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    Fig 1

    Patient disposition and culture status. All 47 randomized patients were analyzed for safety. For the efficacy analysis, 44 patients were available: 2 subjects (one in each group) were diagnosed with XDR TB on a sputum sample submitted before enrollment and were withdrawn within 2 weeks of randomization, and 1 subject in the bedaquiline group remained culture negative at baseline.

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    Fig 2

    Proportion of patients with positive sputum cultures and time to conversion. (A) Culture conversion over 24 weeks among subjects who discontinued during the first 24 weeks carried forward as not converting (hazard ratio, 2.253; 95% CI, 1.08 to 4.71; P = 0.031). In the bedaquiline (orange line, above) and placebo (blue line, below) groups, the times to 50% culture conversion were 78 and 129 days, respectively, and 17/21 (81.0%) and 15/23 (65.2%) of the subjects, respectively, submitted negative sputum samples at week 24. (B) Culture conversion over 24 weeks among subjects who discontinued scored according to their culture status at the time of discontinuation and kept in the analysis (hazard ratio, 3.135; 95% CI, 1.51 to 6.53; P = 0.002). In the bedaquiline (orange line, above) and placebo (blue line, below) groups, the times to 50% culture conversion were 68 and 126 days, respectively, and 19/21 (90.5%) and 16/23 (69.6%) of the subjects, respectively, were culture negative at week 24 or at the time of discontinuation.

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    HIV status, chest radiography findings, drug resistance, and culture status at baseline, 8 weeks, 24 weeks and 104 weeksa

    Treatment group and patientBaseline8 wk24 wk104 wk
    HIVCXRDrug resistance profileBedaquiline MIC (μg/ml)Culture statusAcquired resistanceCulture statusAcquired resistanceCulture statusAcquired resistance
    Bedaquiline + BR group
        1PUCHR0.06C–C––/Dis 24w
        2NUCHRS0.03C+NGC–C–/Com
        3NUCHRZ0.03C–C–C–/Com
        4NUCHRSE0.008C––/Dis 17w–/Dis 17w
        5NUCHRSE0.03C–C–C–/Com
        6NNCHRZS0.01C–C–C+/Com
        7NNCHRZS0.008–/Dis 3w–/Dis 3w–/Dis 3w
        8NBCHRSE0.03C–C––/Dis 36w
        9PUCHRSE0.06C+NGC–C–/Com
        10NUCHRZSE0.06C–C––/Dis 26w
        11NUCHRZSE0.06C+NGC–C–/Com
        12NBCHRSE0.01C–C–C–/Com
        13PBCHRZSEEth0.25C–C–C–/Com
        14NUCHRZSE0.25––/Dis 2w–/Dis 2w
        15NUCHRSEOZ0.01C–C–C–/Com
        16NBCHRZSEEth0.03C+K, CC–C+/Com
        17NBCHRZSEK0.06C–C––/Dis 93w
        18NUCNGNGC+NSC––/Dis 41w
        19NNCNG0.03C+ at 7wNGC–C–/Com
        20NUCNG0.01C+NSC–C–/Com
        21NBCNGNGC––/Dis 14w–/Dis 14w
        22*NUCHRZSEOKC0.01–/Dis 2w–/Dis 2w–/Dis 2w
        23**NUCNGNGC–C–C–/Com
    Placebo + BR group
        1NUCHR0.01C––/Dis 10w–/Dis 10w
        2NUCHR0.03C–C–C–/Com
        3PUCHR0.24C+NoC–C–/Com
        4NUCHRES0.03C+Z, E revertedC–C–/Com
        5NBCHRS0.01C–C–C–/Com
        6NUCHRZ0.03C+NS–/Dis 16w–/Dis 16w
        7NUCHRES0.008C––/Dis 16w–/Dis 16w
        8NBCHRZS0.008C+EC+E, O–/Dis 49w
        9NNCHRZE0.01C+E revertedC––/Dis 63wC+ at 60w: O, S
        10NUCHRZK0.06C+O, E, SC+NG–/Dis 63w
        11NBCHRZS0.01C+NGC––/Dis 47w
        12NUCHRZSE0.12C+OC–C–/Com
        13NBCHRZSE0.03C+NSC–C–/Com
        14NUCHRZSE0.06C+No–/Dis 11w–/Dis 11w
        15NUCHRZSE0.06C+NoC–C–/Com
        16PUCHRZSE0.01C+NGC–C–/Com
        17NUCHRZSE0.06C–C––/Dis 33w
        18NBCHRZSEO0.06C+NGC––/Dis 41w
        19NBCHRZSEO0.12–/Dis 5w–/Dis 5w–/Dis 5w
        20PNCHRZSEKEthC0.25C+NGC–C–/ComC+ at 60w: Eth reverted
        21NBCNG0.03C+NGC–C–/Com
        22NUCNG0.01C––/Dis 18w–/Dis 18w
        23NNCNGNGC–C–C–/Com
        24*NNCHRZSEOKEthC0.03–/Dis 2w–/Dis 2w–/Dis 2w
    • ↵a BR, background regimen; Com, completed; Dis, discontinued; N, negative; NG or NS, no growth or no sample; P, positive; w, week. Chest radiography: BC, bilateral cavitary disease; CXR, chest radiograph; NC, noncavitary disease (no cavity = ≤2-cm diameter); UC, unilateral cavitary disease. Drugs: C, capreomycin; E, ethambutol; Eth, ethionamide; H, isoniazid; K, kanamycin; O, ofloxacin; R, rifampin; S, streptomycin; Z, pyrazinamide. Drug susceptibility tests were performed using the agar proportion method for the background regimen. TMC207 MIC, MIC obtained with a resazurin microtiter assay.

    • ↵* , Subjects withdrawn at 2 weeks because of XDR TB diagnosed from sputum submitted prior to enrollment;

    • ↵** , subject not included in efficacy population because of negative baseline culture.

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Randomized Pilot Trial of Eight Weeks of Bedaquiline (TMC207) Treatment for Multidrug-Resistant Tuberculosis: Long-Term Outcome, Tolerability, and Effect on Emergence of Drug Resistance
A. H. Diacon, P. R. Donald, A. Pym, M. Grobusch, R. F. Patientia, R. Mahanyele, N. Bantubani, R. Narasimooloo, T. De Marez, R. van Heeswijk, N. Lounis, P. Meyvisch, K. Andries, D. F. McNeeley
Antimicrobial Agents and Chemotherapy May 2012, 56 (6) 3271-3276; DOI: 10.1128/AAC.06126-11

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Randomized Pilot Trial of Eight Weeks of Bedaquiline (TMC207) Treatment for Multidrug-Resistant Tuberculosis: Long-Term Outcome, Tolerability, and Effect on Emergence of Drug Resistance
A. H. Diacon, P. R. Donald, A. Pym, M. Grobusch, R. F. Patientia, R. Mahanyele, N. Bantubani, R. Narasimooloo, T. De Marez, R. van Heeswijk, N. Lounis, P. Meyvisch, K. Andries, D. F. McNeeley
Antimicrobial Agents and Chemotherapy May 2012, 56 (6) 3271-3276; DOI: 10.1128/AAC.06126-11
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