Figures
- 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.
Tables
- TABLE 1
Comparison of demographic data, clinical characteristics and treatment outcomes between the bedaquiline and non-bedaquiline groups
Bedaquiline Non-bedaquiline p-value Patients n 68 204 Age years 34.5 (26–55) 33.5 (18–73) 0.42 Male 41 (60.3) 120 (58.8) 0.89 Body weight at admission kg 51.8 (33.3–78.1) 51.9 (21.0–89.9) 0.76 Patients weighing >50 kg 39 (57.4) 115 (56.4) 0.89 Previous TB treatment 33 (48.5) 171 (83.8) <0.001 HIV-infected 35 (51.5) 99 (48.5) 0.81 HIV-infected on ARV therapy 35 (100) 90 (90.9) 0.11 Median CD4 count at admission µL·mL−1 146 (57–271) 198 (71–302) 0.51 Anti-TB drugs received# n 8 (7–8) 9 (8–10) <0.001 Patients in whom at least one drug was withdrawn due to adverse events 40 (58.8) 78 (38.2) 0.005 Days of admission n 158 (102–221) 199 (77–329) 0.05 Outcomes Favourable (cured/completed treatment) 45 (66.2) 27 (13.2) <0.001 Unfavourable outcome 23 (33.8) 175 (85.8) Deceased 10 (14.7) 69 (33.8) 0.004 Failed 4 (5.9) 53 (26) <0.001 LTFU 8 (11.8) 22 (10.8) 1 Defaulted 1 (1.5) 31 (15.2) <0.001 On treatment 0 (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 outcome 24 (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
Bedaquiline Non-bedaquiline Drugs Patients who received drug Patients in whom drug was withdrawn due to adverse events (grade ≥3) Patients who received drug Patients in whom drug was withdrawn due to adverse events (grade ≥3) p-values (comparing proportions of patients who received drug) Patients n 68 204 Capreomycin 7 (10.3) 6 (85.7) 196 (95.6) 43 (21.9)+ <0.001 Kanamycin 1 (1.5) 1 (100) 110 (53.9) 12 (10.9) <0.001 Amikacin 0 0 2 (1.0) 0 N/A Any aminoglycoside# 8 (11.8) 0 202 (99.0) 47 (23.0) <0.001 Para-amino salicylic acid 64 (94.1) 10 (15.6) 194 (95.1) 13 (6.7) 0.75 Pyrazinamide 66 (97.1) 3 (4.5) 201 (98.5) 10 (5.0) 0.60 Terizidone 61 (89.7) 8 (13.1) 201 (98.5) 10 (5.0) 0.003 Moxifloxacin 13 (19.1) 1 (7.7) 101 (49.5) 3 (3.0) <0.001 Ofloxacin 0 0 127 (62.3) 3 (2.4) N/A Levofloxacin 67 (98.5) 0 0 0 N/A Ciprofloxacin 0 0 1 (0.5) 0 N/A Third- or fourth-generation fluoroquinolone¶ 68 (98.5) 0 101 (49.5) 0 <0.001 Clofazimine 67 (98.5) 1 (1.5) 65 (31.9) 2 (3.1) <0.001 Linezolid 55 (80.9) 18 (32.7) 0 0 N/A Ethambutol 26 (38.2) 5 (19.2) 189 (92.7) 15 (7.9) <0.001 Ethionamide 15 (22.1) 6 (40) 198 (97.1) 12 (6.1) <0.001 High-dose isoniazid 22 (32.4) 3 (13.6) 133 (65.2) 13 (9.8) <0.001 Dapsone 0 0 34 (16.7) 0 N/A Co-amoxiclavulanate 2 (2.9) 0 79 (38.7) 0 <0.001 Clarithromycin 0 0 43 (21.1) 0 N/A Amoxicillin 0 0 13 (6.4) 0 N/A Azithromycin 0 0 1 (0.5) 0 N/A Meropenem 1 (1.5) 0 0 (0.0) 0 N/A Bedaquiline 68 (100) 0 0 (0.0) 0 N/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
Sensitivity Specificity PPV NPV Patients considered n Bedaquiline Non-bedaquiline Bedaquiline Non-bedaquiline Bedaquiline Non-bedaquiline Bedaquiline Non-bedaquiline Bedaquiline Non-bedaquiline A) Survival as dependent variable 2 months 82.5 50.0 0 79.0 86.8 54.1 0 76.2 45 121 3 months 91.5 66.7 33.3 79.5 95.6 66.7 20.0 79.5 50 134 6 months 97.2 81.0 33.3 83.6 94.6 75.6 50.0 87.5 39 109 12 months 90.3 75.0 84.2 75.0 84.2 31 62 18 months 96.2 78.3 71.4 81.8 66.7 26 37 B) Favourable treatment outcome as dependent variable 2 months 88.2 60 27.3 75.2 78.9 32.4 42.9 90.5 45 121 3 months 94.6 72.7 23.1 68.8 77.8 31.4 60.0 92.8 50 134 6 months 100 94.7 22.2 70.0 81.1 40.0 100 98.4 39 109 12 months 96.2 100 40.0 74.5 89.3 45.8 66.7 100 31 62 18 months 100 93.3 50.0 63.6 96 63.6 100 93.3 26 37 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 outcome 12 months 18 months 24 months Bedaquiline Non-bedaquiline Bedaquiline Non-bedaquiline Bedaquiline Non-bedaquiline Favourable N/A N/A N/A N/A 45 (66.2) 27 (13.2)# Unfavourable 21 (30.9) 160 (78.4) 23 (33.8) 173 (84.8) 23 (33.8) 175 (85.8)# Deceased 8 (11.8) 55 (27)* 9 (13.2) 60 (29.4)* 10 (14.7) 69 (33.8)* Default 2 (2.9) 21 (10.3) 2 (2.9) 26 (12.7)* 1 (1.5) 31 (15.2)# Treatment failed 5 (7.4) 70 (34.3)# 4 (5.9) 69 (33.8)# 4 (5.9) 53 (26.0)# LTFU 6 (8.8) 14 (6.9) 8 (11.8) 18 (8.8) 8 (11.8) 22 (10.8) On treatment 47 (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 group Non-bedaquiline group p-value Subjects n 68 204 Peripheral neuropathy 15 (22.1) 13 (6.4) <0.001 Dizziness/disorientation 11 (16.2) 35 (17.2) 0.85 Depression 2 (2.9) 27 (13.2) 0.02 Headache 2 (2.9) 12 (5.9) 0.53 Psychosis 3 (4.4) 17 (8.3) 0.42 Blurred vision 5 (7.4) 5 (2.5) 0.14 Hearing impairment 29 (42.7) 31 (15.2) <0.001 Tinnitus 1 (1.5) 4 (2.0) 1 Abdominal pain 15 (22.1) 34 (16.7) 0.41 Vomiting 16 (23.5) 58 (28.4) 0.71 Nausea 16 (23.5) 59 (28.9) 0.65 Diarrhoea 6 (8.8) 21 (10.3) 0.91 Acute liver failure 1 (1.5) 6 (2.9) 0.68 Dyspepsia 3 (4.4) 5 (2.5) 0.42 Skin reaction 20 (29.4) 40 (19.6) 0.13 Arthralgia 13 (19.1) 15 (7.4) 0.011 Body pains 19 (27.9) 32 (15.7) 0.04 Anaemia 14 (20.6) 2 (1.0) <0.001 Deranged renal function 14 (20.6) 41 (20.1) 0.93 Pruritus 3 (4.4) 12 (5.9) 0.77 Hypothyroidism 6 (8.8) 10 (4.9) 0.37 Haematological disorders 2 (2.9) 2 (1.0) 0.26 Oedema 1 (1.4) 1 (0.5) 0.44 Anxiety 1 (1.5) N/A N/A Sore throat 1 (1.5) N/A N/A Insomnia 0 (0) 4 (2.0) N/A Prolonged QT interval 7 (10.3) N/A N/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 admission 1.96 (1.38–2.78) <0.001 Male 1.08 (0.76–1.52) 0.67 HIV-infected# 1.51 (1.06–2.15) 0.02 Previous TB treatment 1.08 (0.69–1.68) 0.73 Number of anti-TB drugs received 0.83 (0.72–0.96) 0.01 Bedaquiline¶ 0.24 (0.06–0.98) 0.05 Linezolid¶ 0.43 (0.11–1.61) 0.21 Clofazimine 0.80 (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 admission 2.06 (1.26–3.36) 0.004 Male 0.73 (0.43–1.23) 0.24 Number of anti-TB drugs received 0.87 (0.67–1.11) 0.26 Any aminoglycoside 0.06 (0.01–0.67) 0.02 On ARV treatment 1.13 (0.44–2.91) 0.80 CD4 count <200 cells·µL−1 1.4 (0.85–2.32) 0.19 Bedaquiline## 0.01 (0–0.33) 0.01 Linezolid 0.87 (0.1–7.82) 0.90 Clofazimine 0.62 (0.3–1.31) 0.21 Previous TB treatment 1.29 (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.
Supplementary Material
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Supplementary tables ERJ-00544-2018_Supplement
