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Long-term bedaquiline-related treatment outcomes in patients with extensively drug-resistant tuberculosis from South Africa

Olatunde Olayanju, Jason Limberis, Aliasgar Esmail, Suzette Oelofse, Phindile Gina, Elize Pietersen, Mohammed Fadul, Rob Warren, Keertan Dheda
European Respiratory Journal 2018 51: 1800544; DOI: 10.1183/13993003.00544-2018
Olatunde Olayanju
1Lung Infection and Immunity Unit, Division of Pulmonology, Dept of Medicine, University of Cape Town, Cape Town, South Africa
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Jason Limberis
1Lung Infection and Immunity Unit, Division of Pulmonology, Dept of Medicine, University of Cape Town, Cape Town, South Africa
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Aliasgar Esmail
1Lung Infection and Immunity Unit, Division of Pulmonology, Dept of Medicine, University of Cape Town, Cape Town, South Africa
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Suzette Oelofse
1Lung Infection and Immunity Unit, Division of Pulmonology, Dept of Medicine, University of Cape Town, Cape Town, South Africa
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Phindile Gina
1Lung Infection and Immunity Unit, Division of Pulmonology, Dept of Medicine, University of Cape Town, Cape Town, South Africa
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Elize Pietersen
1Lung Infection and Immunity Unit, Division of Pulmonology, Dept of Medicine, University of Cape Town, Cape Town, South Africa
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Mohammed Fadul
1Lung Infection and Immunity Unit, Division of Pulmonology, Dept of Medicine, University of Cape Town, Cape Town, South Africa
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Rob Warren
2DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, US/SAMRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Depts of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
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Keertan Dheda
1Lung Infection and Immunity Unit, Division of Pulmonology, Dept of Medicine, University of Cape Town, Cape Town, South Africa
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  • FIGURE 1
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    FIGURE 1

    Kaplan–Meier survival estimate for patients in the bedaquiline and the non-bedaquiline groups. Shading indicates the 95% confidence interval and plus signs represent patients censoring events. a) Whole cohort; b) HIV-infected patients; c) HIV-infected patients who received antiretroviral therapy; d, e) HIV-infected patients whose CD4 counts were d) ≥200 cells·µL−1 and e) <200 cells·µL−1.

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  • TABLE 1

    Comparison of demographic data, clinical characteristics and treatment outcomes between the bedaquiline and non-bedaquiline groups

    BedaquilineNon-bedaquilinep-value
    Patients n68204
    Age years34.5 (26–55)33.5 (18–73)0.42
    Male41 (60.3)120 (58.8)0.89
    Body weight at admission kg51.8 (33.3–78.1)51.9 (21.0–89.9)0.76
    Patients weighing >50 kg39 (57.4)115 (56.4)0.89
    Previous TB treatment33 (48.5)171 (83.8)<0.001
    HIV-infected35 (51.5)99 (48.5)0.81
    HIV-infected on ARV therapy35 (100)90 (90.9)0.11
    Median CD4 count at admission µL·mL−1146 (57–271)198 (71–302)0.51
    Anti-TB drugs received# n8 (7–8)9 (8–10)<0.001
    Patients in whom at least one drug was withdrawn due to adverse events40 (58.8)78 (38.2)0.005
    Days of admission n158 (102–221)199 (77–329)0.05
    Outcomes
     Favourable (cured/completed treatment)45 (66.2)27 (13.2)<0.001
     Unfavourable outcome23 (33.8)175 (85.8)
      Deceased10 (14.7)69 (33.8)0.004
      Failed4 (5.9)53 (26)<0.001
      LTFU8 (11.8)22 (10.8)1
      Defaulted1 (1.5)31 (15.2)<0.001
     On treatment0 (0)2 (1)
     Patients with favourable outcome despite drug  withdrawal due to adverse events¶23 (57.5)10 (12.8)<0.001
     HIV-infected patients with a favourable outcome24 (68.6)18 (18.2)<0.001

    Data are presented as median (interquartile range) or n (%), unless otherwise stated. TB: tuberculosis; ARV: antiretroviral; LTFU: lost to follow-up. #: bedaquiline was included in the total number of anti-TB drugs used in the bedaquiline group; ¶: this was to identify the proportion of patients who had a favourable outcome (regardless of adverse events that necessitated the withdrawal of at least one drug in the treatment regimen).

    • TABLE 2

      List of drugs used in the bedaquiline and the non-bedaquiline treatment regimens, the proportion of patients who used them and the frequency of drug withdrawal due to adverse events

      BedaquilineNon-bedaquiline
      DrugsPatients who received drugPatients in whom drug was withdrawn due to adverse events (grade ≥3)Patients who received drugPatients in whom drug was withdrawn due to adverse events (grade ≥3)p-values (comparing proportions of patients who received drug)
      Patients n68204
      Capreomycin7 (10.3)6 (85.7)196 (95.6)43 (21.9)+<0.001
      Kanamycin1 (1.5)1 (100)110 (53.9)12 (10.9)<0.001
      Amikacin002 (1.0)0N/A
      Any aminoglycoside#8 (11.8)0202 (99.0)47 (23.0)<0.001
      Para-amino salicylic acid64 (94.1)10 (15.6)194 (95.1)13 (6.7)0.75
      Pyrazinamide66 (97.1)3 (4.5)201 (98.5)10 (5.0)0.60
      Terizidone61 (89.7)8 (13.1)201 (98.5)10 (5.0)0.003
      Moxifloxacin13 (19.1)1 (7.7)101 (49.5)3 (3.0)<0.001
      Ofloxacin00127 (62.3)3 (2.4)N/A
      Levofloxacin67 (98.5)000N/A
      Ciprofloxacin001 (0.5)0N/A
      Third- or fourth-generation fluoroquinolone¶68 (98.5)0101 (49.5)0<0.001
      Clofazimine67 (98.5)1 (1.5)65 (31.9)2 (3.1)<0.001
      Linezolid55 (80.9)18 (32.7)00N/A
      Ethambutol26 (38.2)5 (19.2)189 (92.7)15 (7.9)<0.001
      Ethionamide15 (22.1)6 (40)198 (97.1)12 (6.1)<0.001
      High-dose isoniazid22 (32.4)3 (13.6)133 (65.2)13 (9.8)<0.001
      Dapsone0034 (16.7)0N/A
      Co-amoxiclavulanate2 (2.9)079 (38.7)0<0.001
      Clarithromycin0043 (21.1)0N/A
      Amoxicillin0013 (6.4)0N/A
      Azithromycin001 (0.5)0N/A
      Meropenem1 (1.5)00 (0.0)0N/A
      Bedaquiline68 (100)00 (0.0)0N/A

      Data are presented as n (%), unless otherwise stated. N/A: not applicable. #: combination of amikacin, kanamycin and capreomycin; kanamycin was replaced by capreomycin in the course of the treatment; ¶: treatment with either moxifloxacin or levofloxacin; +: significant difference between number of patients from whom drugs were withdrawn.

      • TABLE 3

        Sensitivity, specificity, positive predictive values (PPV) and negative predictive values (NPV) of culture negativity at specific time points to predict survival and favourable treatment outcome in each group

        SensitivitySpecificityPPVNPVPatients considered n
        BedaquilineNon-bedaquilineBedaquilineNon-bedaquilineBedaquilineNon-bedaquilineBedaquilineNon-bedaquilineBedaquilineNon-bedaquiline
        A) Survival as dependent variable
         2 months82.550.0079.086.854.1076.245121
         3 months91.566.733.379.595.666.720.079.550134
         6 months97.281.033.383.694.675.650.087.539109
         12 months90.375.084.275.084.23162
         18 months96.278.371.481.866.72637
        B) Favourable treatment outcome as dependent variable
         2 months88.26027.375.278.932.442.990.545121
         3 months94.672.723.168.877.831.460.092.850134
         6 months10094.722.270.081.140.010098.439109
         12 months96.210040.074.589.345.866.71003162
         18 months10093.350.063.69663.610093.32637

        Data are presented as %, unless otherwise stated. Sensitivity: probability that a negative sputum culture will result in patient survival (or in the case of section B, a favourable treatment outcome); specificity: probability that a positive sputum culture will result in patient mortality (or in the case of section B, a favourable treatment outcome); PPV: probability that a patient with a negative sputum culture survived (or in the case of section B, a favourable treatment outcome); NPV: probability a patient with a positive sputum culture died (or in the case of section B, a favourable treatment outcome). A combined analysis is shown in online supplementary table S9.

        • TABLE 4

          Treatment outcomes at specific time points as measured from treatment initiation

          Treatment outcome12 months18 months24 months
          BedaquilineNon-bedaquilineBedaquilineNon-bedaquilineBedaquilineNon-bedaquiline
          FavourableN/AN/AN/AN/A45 (66.2)27 (13.2)#
          Unfavourable21 (30.9)160 (78.4)23 (33.8)173 (84.8)23 (33.8)175 (85.8)#
           Deceased8 (11.8)55 (27)*9 (13.2)60 (29.4)*10 (14.7)69 (33.8)*
           Default2 (2.9)21 (10.3)2 (2.9)26 (12.7)*1 (1.5)31 (15.2)#
           Treatment failed5 (7.4)70 (34.3)#4 (5.9)69 (33.8)#4 (5.9)53 (26.0)#
           LTFU6 (8.8)14 (6.9)8 (11.8)18 (8.8)8 (11.8)22 (10.8)
          On treatment47 (69.1)44 (21.6)45 (66.2)31 (15.2)0 (0)2 (1.0)

          Data are presented as n (%). Outcomes were assigned as described in online supplementary table S2 for the bedaquiline (n=68) and non-bedaquiline (n=204) groups. LTFU: lost to follow-up; N/A: not applicable. p-values were *: <0.05 or #: <0.005 when comparing time-specific treatment outcomes between patients in the bedaquiline and non-bedaquiline groups.

          • TABLE 5

            List of all adverse events reported in the bedaquiline and the non-bedaquiline groups

            Bedaquiline groupNon-bedaquiline groupp-value
            Subjects n68204
            Peripheral neuropathy15 (22.1)13 (6.4)<0.001
            Dizziness/disorientation11 (16.2)35 (17.2)0.85
            Depression2 (2.9)27 (13.2)0.02
            Headache2 (2.9)12 (5.9)0.53
            Psychosis3 (4.4)17 (8.3)0.42
            Blurred vision5 (7.4)5 (2.5)0.14
            Hearing impairment29 (42.7)31 (15.2)<0.001
            Tinnitus1 (1.5)4 (2.0)1
            Abdominal pain15 (22.1)34 (16.7)0.41
            Vomiting16 (23.5)58 (28.4)0.71
            Nausea16 (23.5)59 (28.9)0.65
            Diarrhoea6 (8.8)21 (10.3)0.91
            Acute liver failure1 (1.5)6 (2.9)0.68
            Dyspepsia3 (4.4)5 (2.5)0.42
            Skin reaction20 (29.4)40 (19.6)0.13
            Arthralgia13 (19.1)15 (7.4)0.011
            Body pains19 (27.9)32 (15.7)0.04
            Anaemia14 (20.6)2 (1.0)<0.001
            Deranged renal function14 (20.6)41 (20.1)0.93
            Pruritus3 (4.4)12 (5.9)0.77
            Hypothyroidism6 (8.8)10 (4.9)0.37
            Haematological disorders2 (2.9)2 (1.0)0.26
            Oedema1 (1.4)1 (0.5)0.44
            Anxiety1 (1.5)N/AN/A
            Sore throat1 (1.5)N/AN/A
            Insomnia0 (0)4 (2.0)N/A
            Prolonged QT interval7 (10.3)N/AN/A

            Data are presented as n (%), unless otherwise stated. N/A: not applicable.

            • TABLE 6

              Multivariate Cox proportional hazard model for risk of death in the bedaquiline and the non-bedaquiline groups

              Hazard ratio (95% CI)p-value
              All XDR-TB patients (n=271)#
               Weight <50 kg at admission1.96 (1.38–2.78)<0.001
               Male1.08 (0.76–1.52)0.67
               HIV-infected#1.51 (1.06–2.15)0.02
               Previous TB treatment1.08 (0.69–1.68)0.73
               Number of anti-TB drugs received0.83 (0.72–0.96)0.01
               Bedaquiline¶0.24 (0.06–0.98)0.05
               Linezolid¶0.43 (0.11–1.61)0.21
               Clofazimine0.80 (0.47–1.37)0.42
               Third- and fourth-generation fluoroquinolones+1.10 (0.68–1.76)0.70
               Any aminoglycoside§0.95 (0.24–3.69)0.94
              HIV-infected patients (n=132)ƒ
               Weight <50 kg at admission2.06 (1.26–3.36)0.004
               Male0.73 (0.43–1.23)0.24
               Number of anti-TB drugs received0.87 (0.67–1.11)0.26
               Any aminoglycoside0.06 (0.01–0.67)0.02
               On ARV treatment1.13 (0.44–2.91)0.80
               CD4 count <200 cells·µL−11.4 (0.85–2.32)0.19
               Bedaquiline##0.01 (0–0.33)0.01
               Linezolid0.87 (0.1–7.82)0.90
               Clofazimine0.62 (0.3–1.31)0.21
               Previous TB treatment1.29 (0.65–2.54)0.47

              Univariate analyses are shown in online supplementary tables S3 and S4 for the whole cohort and the HIV-infected subgroups, respectively. XDR-TB: extensively drug-resistant tuberculosis; ARV: antiretroviral. #: one patient refused testing. ¶: 55 (80.9%) out of the 68 patients who received bedaquiline also received linezolid. We performed subanalyses to investigate the effect of linezolid treatment, and to investigate collinear variables (online supplementary table S5). +: moxifloxacin and levofloxacin. §: amikacin, capreomycin and kanamycin. ƒ: two patients did not have CD4 count done at admission (n=132). ##: 31 (88.6%) out of the 35 patients who received bedaquiline also received linezolid.

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              Long-term bedaquiline-related treatment outcomes in patients with extensively drug-resistant tuberculosis from South Africa
              Olatunde Olayanju, Jason Limberis, Aliasgar Esmail, Suzette Oelofse, Phindile Gina, Elize Pietersen, Mohammed Fadul, Rob Warren, Keertan Dheda
              European Respiratory Journal May 2018, 51 (5) 1800544; DOI: 10.1183/13993003.00544-2018

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              Long-term bedaquiline-related treatment outcomes in patients with extensively drug-resistant tuberculosis from South Africa
              Olatunde Olayanju, Jason Limberis, Aliasgar Esmail, Suzette Oelofse, Phindile Gina, Elize Pietersen, Mohammed Fadul, Rob Warren, Keertan Dheda
              European Respiratory Journal May 2018, 51 (5) 1800544; DOI: 10.1183/13993003.00544-2018
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