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.
Journal Article > Research
PLOS Glob Public Health. 2023 April 28; Volume 3 (Issue 4); e0000818.; DOI:10.1371/journal.pgph.0000818
Rodriguez CA, Lodi S, Horsburgh CR, Mitnick CD, Bastard M, et al.
PLOS Glob Public Health. 2023 April 28; Volume 3 (Issue 4); e0000818.; DOI:10.1371/journal.pgph.0000818
Clarity about the role of delamanid in longer regimens for multidrug-resistant TB is needed after discordant Phase IIb and Phase III randomized controlled trial results. The Phase IIb trial found that the addition of delamanid to a background regimen hastened culture conversion; the results of the Phase III trial were equivocal. We evaluated the effect of adding delamanid for 24 weeks to three-drug MDR/RR-TB regimens on two- and six-month culture conversion in the endTB observational study. We used pooled logistic regression to estimate the observational analogue of the intention-to-treat effect (aITT) adjusting for baseline confounders and to estimate the observational analogue of the per-protocol effect (aPP) using inverse probability of censoring weighting to control for time-varying confounding. At treatment initiation, 362 patients received three likely effective drugs (delamanid-free) or three likely effective drugs plus delamanid (delamanid-containing). Over 80% of patients received two to three Group A drugs (bedaquiline, linezolid, moxifloxacin/levofloxacin) in their regimen. We found no evidence the addition of delamanid to a three-drug regimen increased two-month (aITT relative risk: 0.90 (95% CI: 0.73–1.11), aPP relative risk: 0.89 (95% CI: 0.66–1.21)) or six-month culture conversion (aITT relative risk: 0.94 (95% CI: 0.84, 1.02), aPP relative risk: 0.93 (95% CI: 0.83, 1.04)). In regimens containing combinations of three likely effective, highly active anti-TB drugs the addition of delamanid had no discernible effect on culture conversion at two or six months. As the standard of care for MDR/RR-TB treatment becomes more potent, it may become increasingly difficult to detect the benefit of adding a single agent to standard of care MDR/RR-TB regimens. Novel approaches like those implemented may help account for background regimens and establish effectiveness of new chemical entities.
Journal Article > ResearchAbstract Only
Eur Respir J. 2021 June 17; Online ahead of print; 2004345.; DOI:10.1183/13993003.04345-2020
Khan PY, Franke MF, Hewison CCH, Seung KJ, Huerga H, et al.
Eur Respir J. 2021 June 17; Online ahead of print; 2004345.; DOI:10.1183/13993003.04345-2020
BACKGROUND
Recent World Health Organisation guidance on drug-resistant tuberculosis treatment de-prioritised injectable agents, in use for decades, and endorsed all-oral longer regimens. However, questions remain about the role of the injectable agent, particularly in the context of regimens using new and repurposed drugs. We compared the effectiveness of an injectable-containing regimen to that of an all-oral regimen among patients with drug-resistant tuberculosis who received bedaquiline- and/or delamanid as part of their multidrug regimen.
METHODS
Patients with a positive baseline culture were included. Six-month culture conversion was defined as two consecutive negative cultures collected >15 days apart. We derived predicted probabilities of culture conversion and relative risk using marginal standardisation methods.
RESULTS
Culture conversion was observed in 83.8% (526/628) of patients receiving an all-oral regimen and 85.5% (425/497) of those receiving an injectable-containing regimen. The adjusted relative risk comparing injectable-containing regimens to all-oral regimens was 0.96 (95%CI: 0.88–1.04). We found very weak evidence of effect modification by HIV status: among patients living with HIV, there was a small increase in the frequency of conversion among those receiving an injectable-containing regimen, relative to an all-oral regimen, which was not apparent in HIV-negative patients.
CONCLUSIONS
Among individuals receiving bedaquiline and/or delamanid as part of a multidrug regimen for drug-resistant tuberculosis, there was no significant difference between those who received an injectable and those who did not regarding culture conversion within 6 months. The potential contribution of injectable agents in the treatment of drug-resistant tuberculosis among those who were HIV positive requires further study.
Recent World Health Organisation guidance on drug-resistant tuberculosis treatment de-prioritised injectable agents, in use for decades, and endorsed all-oral longer regimens. However, questions remain about the role of the injectable agent, particularly in the context of regimens using new and repurposed drugs. We compared the effectiveness of an injectable-containing regimen to that of an all-oral regimen among patients with drug-resistant tuberculosis who received bedaquiline- and/or delamanid as part of their multidrug regimen.
METHODS
Patients with a positive baseline culture were included. Six-month culture conversion was defined as two consecutive negative cultures collected >15 days apart. We derived predicted probabilities of culture conversion and relative risk using marginal standardisation methods.
RESULTS
Culture conversion was observed in 83.8% (526/628) of patients receiving an all-oral regimen and 85.5% (425/497) of those receiving an injectable-containing regimen. The adjusted relative risk comparing injectable-containing regimens to all-oral regimens was 0.96 (95%CI: 0.88–1.04). We found very weak evidence of effect modification by HIV status: among patients living with HIV, there was a small increase in the frequency of conversion among those receiving an injectable-containing regimen, relative to an all-oral regimen, which was not apparent in HIV-negative patients.
CONCLUSIONS
Among individuals receiving bedaquiline and/or delamanid as part of a multidrug regimen for drug-resistant tuberculosis, there was no significant difference between those who received an injectable and those who did not regarding culture conversion within 6 months. The potential contribution of injectable agents in the treatment of drug-resistant tuberculosis among those who were HIV positive requires further study.