Figures
- 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
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
- TABLE 1
Prerequisites and criteria used in this cohort for bedaquiline prolongation beyond 24 weeks
Prerequisites Good tolerability No serious side-effects linked to bedaquiline during the first 24 weeks of treatment Informed consent Patient should be correctly informed about the potential risks and benefits, as well as about the available evidence on prolonged bedaquiline treatment Closely monitored treatment Treatment should be monitored closely according to available guidance for timely detection and management of adverse events Expert opinion by an independent organisation Expert opinion should be provided by an external organisation (i.e. national or international consilium) Pharmacovigilance system A proper pharmacovigilance system should be in place Criteria Late microbiological response Patient 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 regimen Less 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 outcome Presence 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
Subjects 45 Foreign-born 44 (97.8) Eastern Europe and Caucasus region 36 (80.0) Africa 5 (11.1) Asia 3 (6.7) HIV infection 2 (4.4) HCV infection 21 (46.7) Intravenous drug use with methadone substitution 6 (13.3) Pulmonary tuberculosis localisation 44 (97.8) Bilateral lung involvement# 36 (81.8) Cavities on chest radiography# 39 (88.6) Sputum smear positive at treatment start 42 (93.3) Sputum culture-positive at treatment start 41 (91.1) Any previous tuberculosis treatment 34 (75.6) Drugs contained in the treatment regimen Ethambutol 20 (44.4) Pyrazinamide 19 (42.2) Amikacin 32 (71.1) Capreomycin 3 (6.7) Moxifloxacin (400/800 mg daily) 14 (31.1)/10 (22.2) Levofloxacin (1000 mg daily) 8 (17.8) Ethionamide 11 (24.4) p-Aminosalicylic acid 40 (88.9) Cycloserine 32 (71.1) Linezolid 43 (95.6) Clofazimine 20 (44.4) Imipenem/clavulanic acid 28 (62.2) Meropenem/clavulanic acid 2 (4.4) Age at admission years 38 (30–42) Serum albumin g·dL−1 32.5 (27.5–36.9) BMI kg·m−2 19.6 (17.8–22.0) Drugs included in the treatment regimen 7 (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 resistance Genotypic 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) Streptomycin 41/45 (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 acid 14/45 (31.1) ND Cycloserine 24/45 (54.5) ND Linezolid 0/45 ND Bedaquiline 0/22 ND 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 cohort Standard bedaquiline treatment Prolonged bedaquiline treatment p-value# Subjects 45 12 33 Any adverse event 44 (97.8) 12 (100) 32 (97.0) 1.000 Any severe adverse event 28 (62.2) 5 (41.7) 23 (69.7) 0.163 Any serious adverse event 7 (15.6) 1 (8.3) 6 (18.2) 0.655 At least one drug stopped due to adverse events 37 (82.2) 8 (66.7) 29 (87.9) 0.181 Bedaquiline stopped due to adverse events 3 (6.7) 1 (8.3) 2 (6.1) 1.000 Liver enzyme elevation 17 (37.8) 6 (50.0) 11 (33.3) 0.325 Pancreatitis 1 (2.2) 1 (8.3) 0 0.267 QTcF >500 ms 5 (11.1) 0 5 (15.2) 0.303 QTcF >60 ms increase 13 (28.9) 4 (33.3) 9 (27.3) 0.721 Maximum QTcF increase during treatment 36.2 (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 cohort Standard bedaquiline treatment Prolonged bedaquiline treatment p-value# Subjects 45 12 33 Favourable outcomes 36 (80.0) 9 (75.0) 27 (81.8) 0.682 Cured 34 (75.6) 7 (58.3) 27 (81.8) 0.131 Treatment completed 2 (4.4) 2 (16.7) 0 0.067 Unfavourable outcomes 9 (20.0) 3 (25.0) 6 (18.2) 1.000 Lost to follow-up 5 (11.1) 2 (16.7) 3 (9.1) 0.598 Died 3 (6.7) 1 (8.3) 2 (6.1) 1.000 Treatment failed 1 (2.2) 0 1 (3.0) 1.000 Follow-up at 12 months¶ No recurrence 23 (63.9) 4 (44.4) 19 (70.4) 0.235 Lost to follow-up 9 (25.0) 5 (55.6) 4 (14.8) 0.026 Died 1 (2.8) 0 1 (3.7) 1.000 Censored 3 (8.3) 0 3 (11.1) 0.558 Follow-up at 24 months¶ No recurrence 4 (17.4) 1 (25.0) 3 (15.8) 1.000 Lost to follow-up 2 (8.7) 0 2 (10.5) 1.000 Died 1 (3.7) 1 (25.0) 0 0.174 Censored 16 (69.6) 2 (50.0) 14 (73.7) 0.557 Time to sputum smear conversion 90 (36–173) 71 (22–90) 110 (47–195) 0.002 Time to sputum culture conversion 89 (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-value Multivariate HR (95% CI) p-value Age 0.765 Male 0.54 (0.24–1.22) 0.159 0.611 HCV-negative 2.64 (1.34–5.19) 0.005 2.35 (1.14–4.88) 0.021 Serum albumin 1.11 (1.05–1.18) <0.001 1.09 (1.02–1.16) 0.010 Body mass index 0.407 Absence of lung cavities 5.35 (1.70–16.87) 0.014 4.56 (1.41–14.75) 0.011 Bilateral lung involvement 0.31 (0.13–0.73) 0.013 0.270 Sputum smear positive at treatment start 0.16 (0.02–1.34) 0.173 0.524 Treatment with ethambutol 0.400 Treatment with pyrazinamide 0.52 (0.27–1.02) 0.051 0.424 Treatment with any second-line injectable 0.892 Treatment with any fluoroquinolone 1.71 (0.89–3.29) 0.105 0.334 Treatment with ethionamide 2.09 (0.97–4.53) 0.077 0.051 Surgery 0.877 Standard bedaquiline treatment duration 0.39 (0.17–0.89) 0.035 0.702 HR: hazard ratio; HCV: hepatitis C virus.
- TABLE 7
Summary of the characteristics and evolution of patients who died or experienced treatment failure
Patient Outcome TB diagnosis Initial treatment regimen Description 1 Treatment failure Extended pulmonary XDR-TB BDQ, AM, ETO, PAS, LZD, CFZ LZD, 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. 2 Death Extended pulmonary MDR-TB AM, MFX, CS, PAS, LZD, CFZ The 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. 3 Death Extended pulmonary XDR-TB BDQ, CS, PAS, LZD, IPM/CLN, AMX/CLV The 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. 4 Death Extended pulmonary XDR-TB BDQ, AM, PAS, LZD, IPM/CLN, AMX/CLV The 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. 5 Death (during follow-up) Extended pulmonary XDR-TB BDQ, CM, MFX, CFZ, LZD, IPM/CLN, AMX/CLV The 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. 6 Death (during follow-up) Extended pulmonary XDR-TB BDQ, E, Z, AM, MFX, PAS, LZD The 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.
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 materials ERJ-01799-2016_Supplementary_Tables
Supplementary Material
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
