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Long-term outcome and safety of prolonged bedaquiline treatment for multidrug-resistant tuberculosis

Lorenzo Guglielmetti, Marie Jaspard, Damien Le Dû, Marie Lachâtre, Dhiba Marigot-Outtandy, Christine Bernard, Nicolas Veziris, Jérôme Robert, Yazdan Yazdanpanah, Eric Caumes, Mathilde Fréchet-Jachym for the French MDR-TB Management Group
European Respiratory Journal 2017 49: 1601799; DOI: 10.1183/13993003.01799-2016
Lorenzo Guglielmetti
1Sanatorium, Centre Hospitalier de Bligny, Briis-sous-Forges, France
2Sorbonne Université, UPMC Université Paris 06, CR7, INSERM, U1135, Centre d'Immunologie et des Maladies Infectieuses, CIMI, Team E13 (Bactériologie), Paris, France
7Both authors contributed equally to this work
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  • For correspondence: lorenzo.guglielmetti@gmail.com
Marie Jaspard
3AP-HP, Service des Maladies Infectieuses et Tropicales, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Paris, France
7Both authors contributed equally to this work
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Damien Le Dû
1Sanatorium, Centre Hospitalier de Bligny, Briis-sous-Forges, France
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Marie Lachâtre
4AP-HP, Service des Maladies Infectieuses et Tropicales, Hôpital Bichat Claude Bernard, Paris, France
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Dhiba Marigot-Outtandy
1Sanatorium, Centre Hospitalier de Bligny, Briis-sous-Forges, France
5AP-HP, Service de Médecine Aigue Spécialisée, Hôpital Raymond Poincaré, Garches, France
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Christine Bernard
2Sorbonne Université, UPMC Université Paris 06, CR7, INSERM, U1135, Centre d'Immunologie et des Maladies Infectieuses, CIMI, Team E13 (Bactériologie), Paris, France
6AP-HP, Centre National de Référence des Mycobactéries et de la Résistance des Mycobactéries aux Antituberculeux (CNR-MyRMA), Bactériologie-Hygiène, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Paris, France
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Nicolas Veziris
2Sorbonne Université, UPMC Université Paris 06, CR7, INSERM, U1135, Centre d'Immunologie et des Maladies Infectieuses, CIMI, Team E13 (Bactériologie), Paris, France
6AP-HP, Centre National de Référence des Mycobactéries et de la Résistance des Mycobactéries aux Antituberculeux (CNR-MyRMA), Bactériologie-Hygiène, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Paris, France
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Jérôme Robert
2Sorbonne Université, UPMC Université Paris 06, CR7, INSERM, U1135, Centre d'Immunologie et des Maladies Infectieuses, CIMI, Team E13 (Bactériologie), Paris, France
6AP-HP, Centre National de Référence des Mycobactéries et de la Résistance des Mycobactéries aux Antituberculeux (CNR-MyRMA), Bactériologie-Hygiène, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Paris, France
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Yazdan Yazdanpanah
4AP-HP, Service des Maladies Infectieuses et Tropicales, Hôpital Bichat Claude Bernard, Paris, France
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Eric Caumes
3AP-HP, Service des Maladies Infectieuses et Tropicales, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Paris, France
8Joint senior authors
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Mathilde Fréchet-Jachym
1Sanatorium, Centre Hospitalier de Bligny, Briis-sous-Forges, France
8Joint senior authors
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  • FIGURE 1
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    FIGURE 1

    Box plot of the Fridericia-corrected QT (QTcF) values of the 45 patients at treatment start, at week 2 of treatment (W2), at month 1, 2, 3, 4, 5, 6, 9, 12 and 15 of treatment (M1, M2, M3, M4, M5, M6, M9, M12 and M15), and at the end of treatment. Data are presented as median and interquartile range; minimum and maximum values are shown by whiskers; outliers are indicated by circles.

  • FIGURE 2
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    FIGURE 2

    Kaplan–Meier analysis of time to sputum culture conversion of patients with positive sputum cultures at the beginning of treatment (n=41) according to whether they received standard (n=9) or prolonged (n=32) bedaquiline treatment. Prolonged bedaquiline treatment was defined as >190 days.

Tables

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  • TABLE 1

    Prerequisites and criteria used in this cohort for bedaquiline prolongation beyond 24 weeks

    Prerequisites
     Good tolerabilityNo serious side-effects linked to bedaquiline during the first 24 weeks of treatment
     Informed consentPatient should be correctly informed about the potential risks and benefits, as well as about the available evidence on prolonged bedaquiline treatment
     Closely monitored treatmentTreatment should be monitored closely according to available guidance for timely detection and management of adverse events
     Expert opinion by an independent  organisationExpert opinion should be provided by an external organisation (i.e. national or international consilium)
     Pharmacovigilance systemA proper pharmacovigilance system should be in place
    Criteria
     Late microbiological responsePatient still sputum culture-positive after ≥3 months of treatment and not meeting the criteria for treatment failure
     Insufficient number of effective drugs in the  treatment regimenLess than four effective drugs# left in the treatment regimen if bedaquiline is discontinued; the paucity of effective drugs in the treatment regimen may be due to drug resistance pattern, adverse events or any other contraindication
     Presence of risk factors for poor treatment  outcomePresence of risk factor for unfavourable treatment outcome, including low BMI (<18.5 kg·m−2), high sputum smear bacillary load (2+/3+), HIV-positivity, extensive/advanced pulmonary disease and contraindication to surgery
    • BMI: body mass index. #: never used before in a failing regimen and susceptible according to a reliable drug susceptibility testing result.

  • TABLE 2

    Sociodemographic characteristics, disease features and treatment regimens of the patient cohort

    Subjects45
    Foreign-born44 (97.8)
     Eastern Europe and Caucasus region36 (80.0)
     Africa5 (11.1)
     Asia3 (6.7)
    HIV infection2 (4.4)
    HCV infection21 (46.7)
    Intravenous drug use with methadone substitution6 (13.3)
    Pulmonary tuberculosis localisation44 (97.8)
    Bilateral lung involvement#36 (81.8)
    Cavities on chest radiography#39 (88.6)
    Sputum smear positive at treatment start42 (93.3)
    Sputum culture-positive at treatment start41 (91.1)
    Any previous tuberculosis treatment34 (75.6)
    Drugs contained in the treatment regimen
     Ethambutol20 (44.4)
     Pyrazinamide19 (42.2)
     Amikacin32 (71.1)
     Capreomycin3 (6.7)
     Moxifloxacin (400/800 mg daily)14 (31.1)/10 (22.2)
     Levofloxacin (1000 mg daily)8 (17.8)
     Ethionamide11 (24.4)
     p-Aminosalicylic acid40 (88.9)
     Cycloserine32 (71.1)
     Linezolid43 (95.6)
     Clofazimine20 (44.4)
     Imipenem/clavulanic acid28 (62.2)
     Meropenem/clavulanic acid2 (4.4)
    Age at admission years38 (30–42)
    Serum albumin g·dL−132.5 (27.5–36.9)
    BMI kg·m−219.6 (17.8–22.0)
    Drugs included in the treatment regimen7 (6–8)
    • Data are presented as n, n (%) or median (interquartile range). HCV: hepatitis C virus; BMI: body mass index. #: n=44 subjects.

  • TABLE 3

    Baseline phenotypic and genotypic resistance patterns of the isolated strains

    Antibiotic (gene)Phenotypic resistanceGenotypic resistance
    Rifampicin (rpoB)45/45 (100)45/45 (100)
    Isoniazid (inhA promoter, katG)45/45 (100)45/45 (100)
    Pyrazinamide (pncA)17/19 (89.5)32/45 (71.1)
    Ethambutol (embB)33/44 (75.0)18/45 (40.0)
    Streptomycin41/45 (91.1)ND
    Amikacin (rrs)14/45 (31.1)12/45 (26.7)
    Kanamycin (rrs)28/45 (62.2)12/45 (26.7)
    Capreomycin (rrs)17/45 (37.8)12/45 (26.7)
    Ofloxacin (gyrA, gyrB)35/45 (77.8)33/45 (73.3)
    Moxifloxacin# (gyrA, gyrB)24/45 (53.3)33/45 (73.3)
    Ethionamide (inhA promoter, ethA, ethR)38/44 (86.4)38/44 (86.4)
    p-Aminosalicylic acid14/45 (31.1)ND
    Cycloserine24/45 (54.5)ND
    Linezolid0/45ND
    Bedaquiline0/22ND
    • Data are presented as n resistant strains/n tested strains (%) for each drug. ND: not done. Sequenced genes and promoters are specified for each drug. #: moxifloxacin was tested at 2 mg·L−1 in order to distinguish between low- and high-level resistance; strains that were ofloxacin resistant but moxifloxacin susceptible were considered low-level resistant to moxifloxacin.

  • TABLE 4

    Treatment safety in the whole cohort and comparison between patients receiving standard (≤190 days) or prolonged (>190 days) bedaquiline treatment

    Whole cohortStandard bedaquiline treatmentProlonged bedaquiline treatmentp-value#
    Subjects451233
    Any adverse event44 (97.8)12 (100)32 (97.0)1.000
    Any severe adverse event28 (62.2)5 (41.7)23 (69.7)0.163
    Any serious adverse event7 (15.6)1 (8.3)6 (18.2)0.655
    At least one drug stopped due to adverse events37 (82.2)8 (66.7)29 (87.9)0.181
    Bedaquiline stopped due to adverse events3 (6.7)1 (8.3)2 (6.1)1.000
    Liver enzyme elevation17 (37.8)6 (50.0)11 (33.3)0.325
    Pancreatitis1 (2.2)1 (8.3)00.267
    QTcF >500 ms5 (11.1)05 (15.2)0.303
    QTcF >60 ms increase13 (28.9)4 (33.3)9 (27.3)0.721
    Maximum QTcF increase during treatment36.2 (17.9–68.5)31.9 (16.0–73.3)41.6 (19.7–63.7)0.437
    • Data are presented as n, n (%) or median (interquartile range), unless otherwise stated. QTcF: Fridericia-corrected QT interval. #: comparison between patients with standard and prolonged bedaquiline treatment, calculated with Wilcoxon's test for continuous variables and Fisher's exact test for categorical variables.

  • TABLE 5

    Treatment outcomes of the whole cohort and comparison between patients receiving standard (≤190 days) or prolonged (>190 days) bedaquiline treatment

    Whole cohortStandard bedaquiline treatmentProlonged bedaquiline treatmentp-value#
    Subjects451233
    Favourable outcomes36 (80.0)9 (75.0)27 (81.8)0.682
     Cured34 (75.6)7 (58.3)27 (81.8)0.131
     Treatment completed2 (4.4)2 (16.7)00.067
    Unfavourable outcomes9 (20.0)3 (25.0)6 (18.2)1.000
     Lost to follow-up5 (11.1)2 (16.7)3 (9.1)0.598
     Died3 (6.7)1 (8.3)2 (6.1)1.000
     Treatment failed1 (2.2)01 (3.0)1.000
    Follow-up at 12 months¶
     No recurrence23 (63.9)4 (44.4)19 (70.4)0.235
     Lost to follow-up9 (25.0)5 (55.6)4 (14.8)0.026
     Died1 (2.8)01 (3.7)1.000
     Censored3 (8.3)03 (11.1)0.558
    Follow-up at 24 months¶
     No recurrence4 (17.4)1 (25.0)3 (15.8)1.000
     Lost to follow-up2 (8.7)02 (10.5)1.000
     Died1 (3.7)1 (25.0)00.174
     Censored16 (69.6)2 (50.0)14 (73.7)0.557
    Time to sputum smear conversion90 (36–173)71 (22–90)110 (47–195)0.002
    Time to sputum culture conversion89 (45–107)71 (53–88)91 (43–114)0.021
    • Data are presented as n, n (%) or median (interquartile range), unless otherwise stated. #: comparison between patients with standard and prolonged bedaquiline treatment, calculated with Wilcoxon's test for continuous variables and Fisher's exact test for categorical variables; ¶: patients eligible for follow-up are those with favourable outcomes at the previous time point (12 months: n=36 whole cohort, n=9 standard treatment and n=27 prolonged treatment; 24 months: n=23 whole cohort, n=4 standard treatment and n=19 prolonged treatment).

  • TABLE 6

    Univariate and multivariate Cox proportional hazards models assessing the association of factors with time to culture conversion

    Univariate HR (95% CI)p-valueMultivariate HR (95% CI)p-value
    Age0.765
    Male0.54 (0.24–1.22)0.1590.611
    HCV-negative2.64 (1.34–5.19)0.0052.35 (1.14–4.88)0.021
    Serum albumin1.11 (1.05–1.18)<0.0011.09 (1.02–1.16)0.010
    Body mass index0.407
    Absence of lung cavities5.35 (1.70–16.87)0.0144.56 (1.41–14.75)0.011
    Bilateral lung involvement0.31 (0.13–0.73)0.0130.270
    Sputum smear positive at treatment start0.16 (0.02–1.34)0.1730.524
    Treatment with ethambutol0.400
    Treatment with pyrazinamide0.52 (0.27–1.02)0.0510.424
    Treatment with any second-line injectable0.892
    Treatment with any fluoroquinolone1.71 (0.89–3.29)0.1050.334
    Treatment with ethionamide2.09 (0.97–4.53)0.0770.051
    Surgery0.877
    Standard bedaquiline treatment duration0.39 (0.17–0.89)0.0350.702
    • HR: hazard ratio; HCV: hepatitis C virus.

  • TABLE 7

    Summary of the characteristics and evolution of patients who died or experienced treatment failure

    PatientOutcomeTB diagnosisInitial treatment regimenDescription
    1Treatment failureExtended pulmonary XDR-TBBDQ, AM, ETO, PAS, LZD, CFZLZD, PAS and AM had to be stopped because of peripheral neuropathy, gastrointestinal intolerance and hearing loss. After achieving initial culture conversion, the patient reverted to sputum culture-positive at 14 months of treatment, acquiring resistance to BDQ.
    2DeathExtended pulmonary MDR-TBAM, MFX, CS, PAS, LZD, CFZThe patient died from dissemination of a pharyngolaryngeal cancer after 9 months of treatment. BDQ was started at month 4 and stopped at month 5 because of QTcF interval prolongation.
    3DeathExtended pulmonary XDR-TBBDQ, CS, PAS, LZD, IPM/CLN, AMX/CLVThe patient achieved sputum culture conversion at month 4 of treatment. At month 15 of treatment, he developed peripheral neuropathy, difficulty swallowing, myositis, myoclonia and psychiatric disorders. He died 1 month later with no obvious diagnosis. No signs of serotonin syndrome were present and the patient did not receive any serotonin-inducing concomitant medication. Autopsy found no explanation for the death.
    4DeathExtended pulmonary XDR-TBBDQ, AM, PAS, LZD, IPM/CLN, AMX/CLVThe patient achieved sputum culture conversion at month 4 of treatment, after performing lung surgery. From month 9 of treatment, he gradually developed peripheral neuropathy and neuropsychiatric disorders. After a septic shock due to catheter infection at month 21, he was diagnosed with polyradiculoneuropathy and brainstem disorder. He died a few days later. No signs of serotonin syndrome were present and the patient did not receive any serotonin-inducing concomitant medication. Autopsy was not performed.
    5Death (during follow-up)Extended pulmonary XDR-TBBDQ, CM, MFX, CFZ, LZD, IPM/CLN, AMX/CLVThe patient underwent lung surgery at month 1 and was declared cured after 19 months of treatment. He died of an overdose of recreational drugs 1 month after the end of treatment.
    6Death (during follow-up)Extended pulmonary XDR-TBBDQ, E, Z, AM, MFX, PAS, LZDThe patient suffered from type 1 diabetes and chronic renal insufficiency. He was declared cured after 18 months of treatment and had no sign of recurrence. He died of terminal renal failure 20 months after the end of treatment.
    • TB: tuberculosis; XDR: extensively drug-resistant; MDR: multidrug-resistant; BDQ: bedaquiline; AM: amikacin; ETO: ethionamide; PAS: p-aminosalicylic acid; LZD: linezolid; CFZ: clofazimine; MFX: moxifloxacin; CS: cycloserine; IPM/CLN: imipenem/cilastatin; AMX/CLV: amoxicillin/clavulanic acid; CM: capreomycin; E: ethambutol; Z: pyrazinamide; QTcF: Fridericia-corrected QT interval.

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    Supplementary materials ERJ-01799-2016_Supplementary_Tables

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    M. Fréchet-Jachym ERJ-01799-2016_Fréchet-Jachym

    M. Jaspard ERJ-01799-2016_Jaspard

    J. Robert ERJ-01799-2016_Robert

    N. Veziris ERJ-01799-2016_Veziris

    Y. Yazdanpanah ERJ-01799-2016_Yazdanpanah

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Long-term outcome and safety of prolonged bedaquiline treatment for multidrug-resistant tuberculosis
Lorenzo Guglielmetti, Marie Jaspard, Damien Le Dû, Marie Lachâtre, Dhiba Marigot-Outtandy, Christine Bernard, Nicolas Veziris, Jérôme Robert, Yazdan Yazdanpanah, Eric Caumes, Mathilde Fréchet-Jachym
European Respiratory Journal Mar 2017, 49 (3) 1601799; DOI: 10.1183/13993003.01799-2016

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Long-term outcome and safety of prolonged bedaquiline treatment for multidrug-resistant tuberculosis
Lorenzo Guglielmetti, Marie Jaspard, Damien Le Dû, Marie Lachâtre, Dhiba Marigot-Outtandy, Christine Bernard, Nicolas Veziris, Jérôme Robert, Yazdan Yazdanpanah, Eric Caumes, Mathilde Fréchet-Jachym
European Respiratory Journal Mar 2017, 49 (3) 1601799; DOI: 10.1183/13993003.01799-2016
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