Journal Article > LetterFull Text
Am J Respir Crit Care Med. 2016 October 15; Volume 194 (Issue 8); 1028-1029.; DOI:10.1164/rccm.201605-1080LE
Varaine FFV, Guglielmetti L, Huerga H, Bonnet MMB, Kiria N, et al.
Am J Respir Crit Care Med. 2016 October 15; Volume 194 (Issue 8); 1028-1029.; DOI:10.1164/rccm.201605-1080LE
Other > Pre-Print
medRxiv. 2024 January 29; DOI:10.1101/2024.01.29.24301679
Guglielmetti L, Khan U, Velasquez GE, Gouillou M, Abubakirov A, et al.
medRxiv. 2024 January 29; DOI:10.1101/2024.01.29.24301679
BACKGROUND
After a history of poor treatments for rifampin-resistant tuberculosis (RR-TB), recent advances have resulted in shorter, more effective treatments. However, they are not available to everyone and have shortcomings, requiring additional treatment options.
METHODS
endTB is an international, open-label, Phase 3 non-inferiority, randomized, controlled clinical trial to compare five 9-month all-oral regimens including bedaquiline (B), delamanid (D), linezolid (L), levofloxacin (Lfx) or moxifloxacin (M), clofazimine (C) and pyrazinamide (Z), to the standard (control) for treatment of fluoroquinolone-susceptible RR-TB. Participants were randomized to 9BLMZ, 9BCLLfxZ, 9BDLLfxZ, 9DCLLfxZ, 9DCMZ and control using Bayesian response-adaptive randomization. The primary outcome was favorable outcome at week 73 defined by two negative sputum culture results or by favorable bacteriologic, clinical and radiologic evolution. The non-inferiority margin was 12 percentage points.
RESULTS
Of 754 randomized patients, 696 and 559 were included in the modified intention to treat (mITT) and per-protocol (PP) analyses, respectively. In mITT, the control had 80.7% favorable outcomes. Regimens 9BCLLfxZ [adjusted risk difference (aRD): 9.5% (95% confidence interval (CI), 0.4 to 18.6)], 9BLMZ [aRD: 8.8% (95%CI, -0.6 to 18.2)], and 9BDLLfxZ [3.9% (95%CI, -5.8 to 13.6)] were non-inferior in mITT and in PP. The proportion of participants experiencing grade 3 or higher adverse events was similar across the regimens. Grade 3 or higher hepatotoxicity occurred in 11.7% of the experimental regimens overall and in 7.1% of the control.
CONCLUSIONS
The endTB trial increases treatment options for RR-TB with three shortened, all-oral regimens that were non-inferior to a current well-performing standard of care.
ClinicalTrials.gov: NCT02754765
After a history of poor treatments for rifampin-resistant tuberculosis (RR-TB), recent advances have resulted in shorter, more effective treatments. However, they are not available to everyone and have shortcomings, requiring additional treatment options.
METHODS
endTB is an international, open-label, Phase 3 non-inferiority, randomized, controlled clinical trial to compare five 9-month all-oral regimens including bedaquiline (B), delamanid (D), linezolid (L), levofloxacin (Lfx) or moxifloxacin (M), clofazimine (C) and pyrazinamide (Z), to the standard (control) for treatment of fluoroquinolone-susceptible RR-TB. Participants were randomized to 9BLMZ, 9BCLLfxZ, 9BDLLfxZ, 9DCLLfxZ, 9DCMZ and control using Bayesian response-adaptive randomization. The primary outcome was favorable outcome at week 73 defined by two negative sputum culture results or by favorable bacteriologic, clinical and radiologic evolution. The non-inferiority margin was 12 percentage points.
RESULTS
Of 754 randomized patients, 696 and 559 were included in the modified intention to treat (mITT) and per-protocol (PP) analyses, respectively. In mITT, the control had 80.7% favorable outcomes. Regimens 9BCLLfxZ [adjusted risk difference (aRD): 9.5% (95% confidence interval (CI), 0.4 to 18.6)], 9BLMZ [aRD: 8.8% (95%CI, -0.6 to 18.2)], and 9BDLLfxZ [3.9% (95%CI, -5.8 to 13.6)] were non-inferior in mITT and in PP. The proportion of participants experiencing grade 3 or higher adverse events was similar across the regimens. Grade 3 or higher hepatotoxicity occurred in 11.7% of the experimental regimens overall and in 7.1% of the control.
CONCLUSIONS
The endTB trial increases treatment options for RR-TB with three shortened, all-oral regimens that were non-inferior to a current well-performing standard of care.
ClinicalTrials.gov: NCT02754765
Journal Article > ResearchFull Text
Int J Tuberc Lung Dis. 2018 July 1; Volume 22 (Issue 7); 766-772.; DOI:10.5588/ijtld.17.0840
Hewison CCH, Bastard M, Khachatryan N, Kotrikadze T, Hayrapetyan A, et al.
Int J Tuberc Lung Dis. 2018 July 1; Volume 22 (Issue 7); 766-772.; DOI:10.5588/ijtld.17.0840
BACKGROUND AND SETTING
Bedaquiline (BDQ) was initially only available through compassionate use programmes.
OBJECTIVE
To assess the effectiveness and safety of multidrug-resistant tuberculosis (MDR-TB) treatment containing BDQ.
METHOD
Retrospective analysis of data from patients receiving BDQ through compassionate use in Armenia and Georgia from April 2013 to April 2015. Logistic regression was used to assess the risk factors associated with unsuccessful treatment outcomes.
RESULTS
Of 82 patients included, 84.2% (69/82) had fluoroquinolone-resistant MDR-TB and 43.4% (23/53) were seropositive for the hepatitis C virus (HCV). The culture conversion rate was 84.4% (54/64), and 18.5% (10/54) reverted back to positive. In total, 79.3% (65/82) of the patients reported at least one adverse event. Serious adverse events were reported in 14 patients, with 10/14 patients experiencing fatal outcomes—6/10 related to advanced TB and 2/10 assessed as possibly related to BDQ. Treatment outcomes were as follows: 58.5% treatment success, 12.2% deaths, 7.3% failures and 21.9% lost to follow-up. HCV coinfection was associated with unsuccessful outcomes (adjusted OR 4.45, 95%CI 1.23–16.13).
CONCLUSION
BDQ through compassionate use showed relatively good success rates and safety profiles in a cohort with difficult-to-treat MDR-TB. High rates of reversion may indicate that >24 weeks of BDQ is necessary in some cases. HCV coinfection should be diagnosed and treatment considered in MDR-TB patients.
Bedaquiline (BDQ) was initially only available through compassionate use programmes.
OBJECTIVE
To assess the effectiveness and safety of multidrug-resistant tuberculosis (MDR-TB) treatment containing BDQ.
METHOD
Retrospective analysis of data from patients receiving BDQ through compassionate use in Armenia and Georgia from April 2013 to April 2015. Logistic regression was used to assess the risk factors associated with unsuccessful treatment outcomes.
RESULTS
Of 82 patients included, 84.2% (69/82) had fluoroquinolone-resistant MDR-TB and 43.4% (23/53) were seropositive for the hepatitis C virus (HCV). The culture conversion rate was 84.4% (54/64), and 18.5% (10/54) reverted back to positive. In total, 79.3% (65/82) of the patients reported at least one adverse event. Serious adverse events were reported in 14 patients, with 10/14 patients experiencing fatal outcomes—6/10 related to advanced TB and 2/10 assessed as possibly related to BDQ. Treatment outcomes were as follows: 58.5% treatment success, 12.2% deaths, 7.3% failures and 21.9% lost to follow-up. HCV coinfection was associated with unsuccessful outcomes (adjusted OR 4.45, 95%CI 1.23–16.13).
CONCLUSION
BDQ through compassionate use showed relatively good success rates and safety profiles in a cohort with difficult-to-treat MDR-TB. High rates of reversion may indicate that >24 weeks of BDQ is necessary in some cases. HCV coinfection should be diagnosed and treatment considered in MDR-TB patients.
Journal Article > ResearchFull Text
Int J Tuberc Lung Dis. 2017 February 1; Volume 21 (Issue 2); 167-174.; DOI:10.5588/ijtld.16.0493
Guglielmetti L, Hewison CCH, Avaliani Z, Hughes AJ, Kiria N, et al.
Int J Tuberc Lung Dis. 2017 February 1; Volume 21 (Issue 2); 167-174.; DOI:10.5588/ijtld.16.0493
BACKGROUND
For the first time in almost 50 years, there are new drugs available for the treatment of tuberculosis (TB), including bedaquiline (BDQ) and delamanid (DLM). The rate of introduction, however, has not kept pace with patient needs. It is estimated that as many as 23% of multidrug-resistant TB (MDR-TB) patients have an indication for receiving BDQ. As this is the first time the MDR-TB community is introducing new medications, it is important to understand how implementation can be developed in a variety of settings.
METHODS
A qualitative assessment of country TB programs in which more than 5% of MDR-TB patients were started on BDQ under program conditions.
RESULTS
National TB programs in Belarus, France, Georgia, South Africa, and Swaziland all started sizeable cohorts of patients on BDQ in 2015. Common factors observed in these programs included experience with compassionate use/expanded access, support from implementing partners, and adequate national or donor-supported budgets. Barriers to introduction included restriction of BDQ to the in-patient setting, lack of access to companion drugs, and the development of systems for pharmacovigilance.
CONCLUSION
The five countries in this paper are examples of the introduction of new therapeutic options for the treatment of TB.
For the first time in almost 50 years, there are new drugs available for the treatment of tuberculosis (TB), including bedaquiline (BDQ) and delamanid (DLM). The rate of introduction, however, has not kept pace with patient needs. It is estimated that as many as 23% of multidrug-resistant TB (MDR-TB) patients have an indication for receiving BDQ. As this is the first time the MDR-TB community is introducing new medications, it is important to understand how implementation can be developed in a variety of settings.
METHODS
A qualitative assessment of country TB programs in which more than 5% of MDR-TB patients were started on BDQ under program conditions.
RESULTS
National TB programs in Belarus, France, Georgia, South Africa, and Swaziland all started sizeable cohorts of patients on BDQ in 2015. Common factors observed in these programs included experience with compassionate use/expanded access, support from implementing partners, and adequate national or donor-supported budgets. Barriers to introduction included restriction of BDQ to the in-patient setting, lack of access to companion drugs, and the development of systems for pharmacovigilance.
CONCLUSION
The five countries in this paper are examples of the introduction of new therapeutic options for the treatment of TB.