Journal Article > ResearchFull Text
Clin Infect Dis. 2022 October 15; Volume 75 (Issue 8); 1307-1314.; DOI:10.1093/cid/ciac176
Huerga H, Khan UT, Bastard M, Mitnick CD, Lachenal N, et al.
Clin Infect Dis. 2022 October 15; Volume 75 (Issue 8); 1307-1314.; DOI:10.1093/cid/ciac176
BACKGROUND
Concomitant use of bedaquiline (Bdq) and delamanid (Dlm) for multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) has raised concerns about a potentially poor risk-benefit ratio. Yet, this combination is an important alternative for patients infected with strains of TB with complex drug resistance profiles or who cannot tolerate other therapies. We assessed safety and treatment outcomes of MDR/RR-TB patients receiving concomitant Bdq and Dlm, along with other second-line anti-TB drugs.
METHODS
We conducted a multi-centric, prospective observational cohort study across 14 countries among patients receiving concomitant Bdq-Dlm treatment. Patients were recruited between April 2015 and September 2018 and were followed until the end of treatment. All serious adverse events and adverse events of special interest (AESI), leading to a treatment change, or judged significant by a clinician, were systematically monitored and documented.
RESULTS
Overall, 472 patients received Bdq and Dlm concomitantly. A large majority also received linezolid (89.6%) and clofazimine (84.5%). Nearly all (90.3%) had extensive disease; most (74.2%) had resistance to fluoroquinolones. The most common AESI were peripheral neuropathy (134, 28.4%) and electrolyte depletion (94, 19.9%). Acute kidney injury and myelosuppression were seen in 40 (8.5%) and 24 (5.1%) of patients, respectively. QT prolongation occurred in 7 (1.5%). Overall, 78.0% (358/458) had successful treatment outcomes, 8.9% died and 7.2% experienced treatment failure.
CONCLUSIONS
Concomitant use of Bdq and Dlm, along with linezolid and clofazimine, is safe and effective for MDR/RR-TB patients with extensive disease. Using these drugs concomitantly is a good therapeutic option for patients with resistance to many anti-TB drugs.
Concomitant use of bedaquiline (Bdq) and delamanid (Dlm) for multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) has raised concerns about a potentially poor risk-benefit ratio. Yet, this combination is an important alternative for patients infected with strains of TB with complex drug resistance profiles or who cannot tolerate other therapies. We assessed safety and treatment outcomes of MDR/RR-TB patients receiving concomitant Bdq and Dlm, along with other second-line anti-TB drugs.
METHODS
We conducted a multi-centric, prospective observational cohort study across 14 countries among patients receiving concomitant Bdq-Dlm treatment. Patients were recruited between April 2015 and September 2018 and were followed until the end of treatment. All serious adverse events and adverse events of special interest (AESI), leading to a treatment change, or judged significant by a clinician, were systematically monitored and documented.
RESULTS
Overall, 472 patients received Bdq and Dlm concomitantly. A large majority also received linezolid (89.6%) and clofazimine (84.5%). Nearly all (90.3%) had extensive disease; most (74.2%) had resistance to fluoroquinolones. The most common AESI were peripheral neuropathy (134, 28.4%) and electrolyte depletion (94, 19.9%). Acute kidney injury and myelosuppression were seen in 40 (8.5%) and 24 (5.1%) of patients, respectively. QT prolongation occurred in 7 (1.5%). Overall, 78.0% (358/458) had successful treatment outcomes, 8.9% died and 7.2% experienced treatment failure.
CONCLUSIONS
Concomitant use of Bdq and Dlm, along with linezolid and clofazimine, is safe and effective for MDR/RR-TB patients with extensive disease. Using these drugs concomitantly is a good therapeutic option for patients with resistance to many anti-TB drugs.
Journal Article > ResearchFull Text
Effectiveness of bedaquiline use beyond six months in patients with multidrug-resistant tuberculosis
Am J Respir Crit Care Med. 2023 June 1; Volume 207 (Issue 11); 1525-1532.; DOI:10.1164/rccm.202211-2125OC
Trevisi L, Hernán MA, Mitnick CD, Khan UT, Seung KJ, et al.
Am J Respir Crit Care Med. 2023 June 1; Volume 207 (Issue 11); 1525-1532.; DOI:10.1164/rccm.202211-2125OC
RATIONALE
Current recommendations for the treatment of rifampin- and multidrug-resistant tuberculosis include bedaquiline used for six months or longer. Evidence is needed to inform the optimal duration of bedaquiline.
OBJECTIVES
We emulated a target trial to estimate the effect of three bedaquiline duration treatment strategies (6 months, 7-11 months, ≥ 12 months) on the probability of successful treatment among patients receiving a longer individualized regimen for multidrug-resistant tuberculosis.
METHODS
To estimate the probability of successful treatment, we implemented a three-step approach comprising cloning, censoring, and inverse-probability weighting.
MAIN RESULTS
The 1,468 eligible individuals received a median of four (IQR: 4-5) likely effective drugs. In 87.1% and 77.7%, this included linezolid and clofazimine, respectively. The adjusted probability of successful treatment (95% CI) was 0.85 (0.81, 0.88) for 6 months of BDQ, 0.77 (0.73, 0.81) for 7-11 months, and 0.86 (0.83, 0.88) for > 12 months. Compared with 6 months of bedaquiline, the ratio of treatment success (95% CI) was 0.91 (0.85, 0.96) for 7-11 months and 1.01 (0.96, 1.06) for > 12 months. Analyses that did not account for immortal time bias found a higher probability of successful treatment with > 12 months: ratio 1.09 (1.05, 1.14).
CONCLUSIONS
Bedaquiline use beyond six months did not increase the probability of successful treatment among patients receiving longer regimens that commonly included new and repurposed drugs. When not properly accounted for, immortal person-time can bias estimate of effects of treatment duration. Future analyses should explore the effect of duration of bedaquiline and other drugs in subgroups with advanced disease and/or receiving less potent regimens.
Current recommendations for the treatment of rifampin- and multidrug-resistant tuberculosis include bedaquiline used for six months or longer. Evidence is needed to inform the optimal duration of bedaquiline.
OBJECTIVES
We emulated a target trial to estimate the effect of three bedaquiline duration treatment strategies (6 months, 7-11 months, ≥ 12 months) on the probability of successful treatment among patients receiving a longer individualized regimen for multidrug-resistant tuberculosis.
METHODS
To estimate the probability of successful treatment, we implemented a three-step approach comprising cloning, censoring, and inverse-probability weighting.
MAIN RESULTS
The 1,468 eligible individuals received a median of four (IQR: 4-5) likely effective drugs. In 87.1% and 77.7%, this included linezolid and clofazimine, respectively. The adjusted probability of successful treatment (95% CI) was 0.85 (0.81, 0.88) for 6 months of BDQ, 0.77 (0.73, 0.81) for 7-11 months, and 0.86 (0.83, 0.88) for > 12 months. Compared with 6 months of bedaquiline, the ratio of treatment success (95% CI) was 0.91 (0.85, 0.96) for 7-11 months and 1.01 (0.96, 1.06) for > 12 months. Analyses that did not account for immortal time bias found a higher probability of successful treatment with > 12 months: ratio 1.09 (1.05, 1.14).
CONCLUSIONS
Bedaquiline use beyond six months did not increase the probability of successful treatment among patients receiving longer regimens that commonly included new and repurposed drugs. When not properly accounted for, immortal person-time can bias estimate of effects of treatment duration. Future analyses should explore the effect of duration of bedaquiline and other drugs in subgroups with advanced disease and/or receiving less potent regimens.