Figures
- FIGURE 1
Cumulative rates of a) any and b) serious adverse events during treatment, stratified by the duration of bedaquiline (Bdq) exposure.
Tables
- TABLE 1
Characteristics of patients on standard or prolonged treatment with bedaquiline
Standard treatment with bedaquiline Prolonged treatment with bedaquiline Overall p-value# Patients n 83 30 113 – Patient characteristics Median (IQR) age 37 (29–47) 38 (31–51) 38 (30–47) 0.74 Male 60 (72.3) 21 (70) 81 (71.7) 0.99 HIV infection 4 (4.8) 0 (0) 4 (3.5) 0.52 Thyroid disease 3 (3.6) 0 (0) 3 (2.7) 0.69 Alcohol abuse disorder 11 (13.3) 6 (20) 17 (15) 0.56 Diabetes 6 (7.2) 1 (3.3) 7 (6.2) 0.75 Median (IQR) baseline QTcF interval¶ 388 (360–407) 386 (362–416) 387 (360–410) 0.63 Microbiological/radiological findings AFB smear-positive at baseline+ 21 (25.3) 23 (76.7) 44 (38.9) <0.01 Cavitation on chest radiograph 50 (60.2) 22 (73.3) 72 (63.7) 0.29 Previous treatment Never previously treated for TB 9 (10.8) 1 (3.3) 10 (8.8) 0.39 Previously treated with first-line drugs 12 (14.5) 1 (3.3) 13 (11.5) 0.19 Previously treated with second-line drugs 62 (74.7) 28 (93.3) 90 (79.6) 0.06 DST DST performed for fluoroquinolones 78 (94) 30 (100) 108 (95.6) 0.39 If DST performed, fluoroquinolone resistant 67 (85.9) 27 (90) 94 (87) 0.80 DST performed for second-line injectables 79 (95.2) 30 (100) 109 (96.5) 0.52 If DST performed, second-line injectable resistant 60 (75.9) 22 (73.3) 82 (75.2) 0.97 Data reported as n (%) unless otherwise specified. HIV: human immunodeficiency virus; AFB: acid-fast bacilli; TB: tuberculosis; DST: drug susceptibility test. #: the following tests were used to calculate p-value: for medians Kruskal–Wallis Test; for proportions Chi square test; for rates Exact Fisher two-sided test. ¶: missing for five patients (two in the bedaquiline 6 months group and three in the bedaquiline >6 months group). +: missing for one patient (one in the bedaquiline 6 months group).
- TABLE 2
Regimen received and treatment outcomes among patients on standard and prolonged treatment with bedaquiline
Bedaquiline <190 days Bedaquiline >190 days p-value# Patients n 83 30 Regimen duration Median (IQR) total treatment duration, months 23.7 (20.7–24.0) 24.2 (23.8–24.9) <0.01 Median (IQR) treatment duration with bedaquiline, months 5.5 (5.4–5.6) 8.0 (7.3–9.2) <0.01 Median (IQR) treatment duration with linezolid, months¶ 23.5 (20.1–24.0) 24.1 (23.7–24.4) <0.01 Median (IQR) treatment duration with injectables, months+ 5.3 (5.3–21.2) 13.8 (10.7–24.2) 0.02 Treatment outcomes Number with treatment success 77 (92.8) 29 (96.7) 0.75 Number with failure 1 (1.2) 0 (0) 1 Number dying during treatment 3 (3.6) 1 (3.3) 1 Number lost to follow-up 2 (2.4) 0 (0) 0.96 Regimen received Initial Added during treatment Initial Added during treatment Number of drugs in initial regimen, median (IQR) 6 (5–6) – 6 (6–6) – 0.80 Included moxifloxacin or levofloxacin or gatifloxacin 11 (13.3) 43 (51.8) 0 (0) 15 (50) 0.08 Included linezolid 83 (100) 0 (0) 29 (96.7) 1 (3.3) 0.59 Included clofazimine 80 (96.4) 1 (1.2) 27 (90) 2 (6.7) 0.39 Included terizidone 82 (98.8) 0 (0) 28 (93.3) 2 (6.7) 0.35 Included amikacin or capreomycin or kanamycin 32 (38.6) 6 (7.2) 14 (46.7) 10 (33.3) 0.58 Included pyrazinamide 54 (65.1) 2 (2.4) 23 (76.7) 0 (0) 0.35 Included imipenem/cilastatin with amoxicillin and clavulanic acid 42 (50.6) 2 (2.4) 16 (53.3) 7 (23.3) 0.97 Included ethionamide or prothionamide 8 (9.6) 8 (9.6) 2 (6.7) 3 (10) 0.91 Data reported as n (%) unless otherwise specified. #: the following tests were used to calculate p-value: for medians Kruskal–Wallis test; for proportions Chi square test; for rates exact Fisher two-sided test. For the regimen received, p-value only refers to initial regimen. ¶: all patients received linezolid during treatment. +: only if received injectables ever during treatment (n=35 bedaquiline 6 months; n=20 bedaquiline >6 months; n=55 overall).
- TABLE 3
All adverse events registered during the treatment course among patients on standard and prolonged treatment with bedaquiline
Bedaquiline <190 days Bedaquiline >190 days Overall p-value#
between standard and prolongedNumber of patients 83 30 113 – Total treatment duration months 1807.8 722.7 2530.5 – Total treatment with bedaquiline months 440.3 257.2 697.5 – All adverse events Patients experiencing any adverse event 81 (97.6) 28 (93.3) 109 (96.4) – Events during treatment total 1448 585 2033 – Incidence per 100 person-months (95% CI) 80.1 (76.0–84.3) 80.9 (74.5–87.8) 80.3 (76.9–83.9) 0.83 Adverse events during periods of treatment Events with bedaquiline up to day 190 of treatment 783 280 1063 – Incidence per 100 person-months (95% CI) 177.8 (165.6–190.7) 150.1 (133.1–168.8) 169.6 (159.5–180.1) 0.01 Events with bedaquiline from day 190 to cessation N/A 62 62 – Incidence per 100 person-months (95% CI) N/A 87.8 (67.3–112.6) 87.8 (67.3–112.6) – Events after stopping bedaquiline up to 5 months after bedaquiline cessation 288 120 408 – Incidence per 100 person-months (95% CI) 81.5 (67.5–97.4) 72.7 (64.5–81.6) 75.1 (68.0–81.6) 0.31 Events >5 months after stopping bedaquiline, to end of treatment 377 123 500 – Incidence per 100 person-months (95% CI) 38.8 (35.0–42.9) 38.7 (32.1–46.1) 38.8 (35.4–42.3) 0.97 All events during bedaquiline 783 342 1125 – Incidence per 100 person-months (95% CI) 177.8 (165.6–190.7) 133.0 (119.2–147.8) 161.3 (152.0–171.0) <0.001 All events up to 5 months after stopping bedaquiline 1071 462 1533 – Incidence per 100 person-months (95% CI) 128.0 (1120.5–135.9) 114.2 (104.0–125.1) 123.5 (117.4–129.9) 0.04 Bedaquiline-related adverse events Patients with at least one bedaquiline-related adverse event 12 3 15 – Number of bedaquiline-related adverse events up to 5 months after bedaquiline cessation 25 4 29 – Incidence per 100 person-months (95% CI) 3.0 (1.9–4.4) 1.0 (0.3–2.5) 2.3 (1.6–3.4) 0.01 Category of adverse events – QTcF prolongation 18 (72) 4 (100) 22 (75.7) – Liver enzyme elevation 3 (12) 0 (0) 3 (10.3) – Hyperuricaemia 1 (4) 0 (0) 1 (3.4) – Pancreatitis 1 (4) 0 (0) 1 (3.4) – Anxiety 1 (4) 0 (0) 1 (3.4) – Cardiac failure 1 (4) 0 (0) 1 (3.4) Patients stopping treatment due to bedaquiline-related adverse event 6 0 6 – Median (IQR) months to bedaquiline cessation 5.5 (5.1–5.5) N/A 5.5 (5.1–5.5) – Data reported as n (%) unless otherwise specified. #: exact Fisher two-sided test was used to calculate p-value.
- TABLE 4
Serious adverse events registered during the treatment course among patients on standard and prolonged treatment with bedaquiline
Bedaquiline <190 days Bedaquiline>190 days Overall p-value#
between standard and prolongedNumber of patients 83 30 113 – Total treatment duration months 1807.8 722.7 2530.5 – Total treatment with bedaquiline months 440.3 257.2 697.5 – Total treatment up to 5 months after bedaquiline cessation, months 836.5 404.4 1240.9 – Serious adverse events Patients experiencing any serious adverse event 32 (38.6) 16 (53.3) 48 (42.5) – Events during treatment total 50 26 76 – Incidence per 100 person-months (95% CI) 2.8 (2.1–3.6) 3.6 (2.4–5.3) 3.0 (2.4–3.8) 0.30 Serious adverse events during periods of treatment Events with bedaquiline up to day 190 of treatment 37 10 47 – Incidence per 100 person-months (95% CI) 7.5 (5.5–10.0) 5.4 (2.6–9.9) 8.4 (5.9–11.6) 0.07 Events with bedaquiline from day 190 to cessation N/A 0 0 – Incidence per 100 person-months (95% CI) N/A 0 (0–5.2) 0 (0–5.2) – Events after stopping bedaquiline up to 5 months after bedaquiline cessation 8 8 16 – Incidence per 100 person-months (95% CI) 2.0 (0.9–4.0) 5.4 (2.3–10.7) 2.9 (1.7–4.8) 0.10 Events > 5 months after stopping bedaquiline, to end of treatment 5 8 13 – Incidence per 100 person-months (95% CI) 0.5 (0.2–1.2) 2.5 (1.1–5.0) 1.0 (0.5–1.7) 0.03 All events up to 5 months after stopping bedaquiline 45 18 63 – Incidence per 100 person-months (95% CI) 5.4 (3.9–7.2) 4.4 (2.6–7.0) 5.1 (3.9–6.5) 0.48 Bedaquiline-related serious adverse events Patients with at least one bedaquiline-related serious adverse event 5 1 6 – Number of bedaquiline-related serious adverse events up to 5 months after bedaquiline cessation 6¶ 1 7 – Incidence per 100 person-months (95% CI) 0.7 (0.3–1.6) 0.2 (0.1–1.4) 0.6 (0.2–1.2) 0.22 Category of serious adverse events – QTcF prolongation 2 (33.3) 1 (100) 3 (42.8) – Liver enzyme elevation 1 (16.7) 0 (0) 1 (14.3) – Pancreatitis 1 (16.7) 0 (0) 1 (14.3) – Hyperuricaemia 1 (16.7) 0 (0) 1 (14.3) – Cardiac failure 1 (16.7) 0 (0) 1 (14.3) – Patients stopping treatment due to bedaquiline-related serious adverse event 1 0 1 – Months to bedaquiline cessation 1.4 N/A N/A – Data reported as n (%) unless otherwise specified. #: exact Fisher two-sided test was used to calculate p-value; ¶: patient experienced two serious adverse events: the first was hyperuricaemia 21 days into treatment and the second was aspartate aminotransferase elevation 147 days into treatment.
- TABLE 5
Change in mean QTcF interval by month of treatment#
Month Number of patients with measure Mean±sd maximum QTcF measure Mean±sd change in QTcF from baseline Mean±sd change in QTcF from previous month Number of patients (%) with QTcF that is >60 ms from baseline Baseline 108 385.7±33.9 – – – 1 105 402.5±33.1 17.6±24.4 17.6±24.4 6 (5.7) 2 77 414.6±28.7 26.5±33.9 10.1±32.4 12 (15.6) 3 94 416.1±32.1 28.5±36.9 3.2±30.1 21 (22.3) 4 86 420.8±33.4 34.2±37.4 8.2±33.4 22 (25.6) 5 89 422.7±29 33.8±38.5 1.0±33.6 21 (23.6) 6 61 426±29.6 40.2±40.7 4.2±27.0 14 (23) 7 24 418.5±34.6 34.1±57.4 −15±36.8 8 (33.3) 8 12 411.2±32.6 24.8±42.5 1±24.0 3 (25) 9 10 434.1±28.4 61.9±49.1 11.7±31.9 5 (50) 10 4 442±15.6 58.8±35.4 9.5±9.0 1 (25) ECG measures done on the same day were averaged to arrive at an estimate. #: only one patient included in months 11 and beyond.
- TABLE 6
Primary and secondary multivariate analyses
Outcome Events/person-months Events/person-months Multivariate IRR (95% CI) Serious adverse events Standard treatment with bedaquiline# Prolonged treatment with bedaquiline Up to 5 months after bedaquiline cessation 38/767 18/405 0.82 (0.42–1.61) Within the first 190 days of treatment 33/410 10/187 0.73 (0.33–1.61) Serious adverse events Within the first 190 days of treatment From day 190 until 5 months after bedaquiline cessation Among persons receiving prolonged treatment 10/187 8/212 0.75 (0.30–1.88) #: reference group.
Supplementary Material
Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.
Supplementary material 00685-2021.SUPPLEMENT
