BACKGROUND
For decades, poor treatment options and low-quality evidence plagued care for patients with rifampin-resistant tuberculosis. The advent of new drugs to treat tuberculosis and enhanced funding now permit randomized, controlled trials of shortened-duration, all-oral treatments for rifampin-resistant tuberculosis.
METHODS
We conducted a phase 3, multinational, open-label, randomized, controlled noninferiority trial to compare standard therapy for treatment of fluoroquinolone-susceptible, rifampin-resistant tuberculosis with five 9-month oral regimens that included various combinations of bedaquiline (B), delamanid (D), linezolid (L), levofloxacin (Lfx) or moxifloxacin (M), clofazimine (C), and pyrazinamide (Z). Participants were randomly assigned (with the use of Bayesian response-adaptive randomization) to receive one of five combinations or standard therapy. The primary end point was a favorable outcome at week 73, defined by two negative sputum culture results or favorable bacteriologic, clinical, and radiologic evolution. The noninferiority margin was -12 percentage points.
RESULTS
Among the 754 participants who underwent randomization, 699 were included in the modified intention-to-treat analysis, and 562 in the per-protocol analysis. In the modified intention-to-treat analysis, 80.7% of the patients in the standard-therapy group had favorable outcomes. The risk difference between standard therapy and each of the four new regimens that were found to be noninferior in the modified intention-to-treat population was as follows: BCLLfxZ, 9.8 percentage points (95% confidence interval [CI], 0.9 to 18.7); BLMZ, 8.3 percentage points (95% CI, -0.8 to 17.4); BDLLfxZ, 4.6 percentage points (95% CI, -4.9 to 14.1); and DCMZ, 2.5 percentage points (95% CI, -7.5 to 12.5). Differences were similar in the per-protocol population, with the exception of DCMZ, which was not noninferior in that population. The proportion of participants with grade 3 or higher adverse events was similar across the regimens. Grade 3 or higher hepatotoxic events occurred in 11.7% of participants overall and in 7.1% of those receiving standard therapy.
CONCLUSIONS
Consistent results across all the analyses support the noninferior efficacy of three all-oral shortened regimens for the treatment of rifampin-resistant tuberculosis. (Funded by Unitaid and others; endTB ClinicalTrials.gov number, NCT02754765.).
BACKGROUND
The 2022 WHO guidelines on multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) recommend six months of bedaquiline (Bdq) in the all-oral 9-month shorter regimen and six months or longer for Bdq and delamanid (Dlm) in the 18-20-month longer regimen. However, lack of evidence on extended treatment using Bdq or Dlm has limited their use to six months. We examine the frequency and incidence of QT prolongation based on duration of Bdq and/or Dlm use in longer regimens.
METHODS
We analyzed a prospective cohort of MDR/RR-TB patients from 16 countries who initiated treatment with Bdq and/or Dlm containing regimens from 1 April 2015-30 September 2018. Data were systematically collected using a shared protocol. The outcome of interest was the first clinically relevant prolonged QT interval (grade 3 or above) or a Serious Adverse Event (SAE) involving prolonged QT of any grade.
RESULTS
Among 2,553 patients, 59% received >6 months of Bdq and/or Dlm. Of these, 579 (20.9%) patients experienced a prolonged QT event, the majority (95.5%) being grade 1 or 2. Sixty-four(2.5%) patients experienced the outcome of interest with only 12 (0.5%) having ≥ 1 QT prolonging drugs permanently suspended. The incidence rate of the first prolonged QT event was highest in the first six months of treatment and lower in subsequent six-month periods.
CONCLUSION
We demonstrate that Bdq and/or Dlm use beyond six months is safe in longer MDR/RR-TB regimens with most clinically relevant QT prolongation events occurring in the first six months. ECG monitoring for early identification of QT prolongating events is possible in programmatic conditions.
Tuberculosis (TB) is a major public health challenge encountered across many Médecins Sans Frontières (MSF) fields. Management of drug-resistant TB is an operational priority for MSF. endTB is an MSF-sponsored randomised trial funded by Unitaid as part of the larger endTB project. The trial objective was to examine five new all-oral, shortened regimens for patients with fluoroquinolone-susceptible, rifampicin-resistant/multidrug- resistant TB (RR/MDR-TB).
METHODS
endTB was a phase 3, randomised, controlled, non-inferiority trial performed in seven countries (Georgia, India, Kazakhstan, Lesotho, Pakistan, Peru, and South Africa) in five WHO regions. Participants with RR/MDR-TB (aged ≥15 years old) were randomly assigned to six regimen groups (1:1:1:1:1:1; 9BLMZ, 9BCLLfxZ, 9BDLLfxZ, 9DCLLfxZ, 9DCMZ, or control) using Bayesian response-adapted randomisation. Experimental regimens were 9 months long; all contained 4–5 drugs, including pyrazinamide, a fluoroquinolone, either bedaquiline and/or delamanid, and linezolid and/or clofazimine. The internal, concurrent control regimen was the evolving WHO- recommended standard. Primary outcome was the proportion of favourable outcome at week 73, defined by two negative sputum culture results. The non-inferiority margin was 12%. We performed efficacy comparisons in the modified intention-to-treat population (mITT), which included all randomised participants who took at least one dose of study treatment (safety population) and who had a positive pre-randomisation TB culture, and in the per-protocol population (PP), defined as mITT excluding participants who did not receive the protocol-defined treatment. We performed safety comparisons on the safety population. This study is registered on ClinicalTrials.gov (NCT02754765).
RESULTS
Of 754 participants enrolled between 2017 and 2021, 696 and 559 were included in the mITT and PP analyses, respectively. Median age was 32.0 years (IQR 23.0–44.0), and 264 (38%) of 696 participants were female. Overall, regimens 9BLLfxCZ, 9BLMZ, and 9BDLLfxZ achieved non-inferiority in mITT and PP analyses. 9BLLfxCZ also achieved superiority. 9DCMZ regimen achieved non-inferiority in mITT, but not in PP. 9DCLLfxZ did not achieve non-inferiority. The proportion of participants experiencing grade 3 or higher adverse events or serious adverse events was similar between the regimens. Grade 3 or higher hepatotoxicity occurred in 12.6% (78/619) of participants in the experimental regimens overall and in 7.1% (9/126) of participants in the control group.
CONCLUSION
The endTB trial results increase patient-centred treatment options for RR/MDR-TB with three shortened, all-oral, non- inferior regimens to a current well-performing standard of care. A fourth regimen could be considered for patients for whom bedaquiline and/or linezolid is not available. These results could be extrapolated to children and pregnant women. The implications on the MSF TB field activities are important and could lead to improved access to care and better treatment outcome.
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.
RATIONALE
Treatment outcomes may be compromised among patients with multidrug- or rifampicin-resistant tuberculosis with additional fluoroquinolone resistance. Evidence is needed to inform optimal treatment for these patients.
OBJECTIVES
We compared the effectiveness of longer individualized regimens comprised of bedaquiline for 5 to 8 months, linezolid, and clofazimine to those reinforced with at least 1 third-tier drug and/or longer duration of bedaquiline.
METHODS
We emulated a target trial to compare the effectiveness of initiating and remaining on the core regimen to one of five regimens reinforced with (1) bedaquiline for ≥9 months, (2) bedaquiline for ≥9 months and delamanid, (3) imipenem, (4) a second-line injectable, or (5) delamanid and imipenem. We included patients in whom a fluoroquinolone was unlikely to be effective based on drug susceptibility testing and/or prior exposure. Our analysis consisted of cloning, censoring, and inverse-probability weighting to estimate the probability of successful treatment.
MEASUREMENTS AND MAIN RESULTS
Adjusted probabilities of successful treatment were high across regimens, ranging from 0.75 (95%CI:0.61, 0.89) to 0.84 (95%CI:0.76, 0.91). We found no substantial evidence that any of the reinforced regimens improved effectiveness of the core regimen, with ratios of treatment success ranging from 1.01 for regimens reinforced with bedaquiline ≥9 months (95%CI:0.79, 1.28) and bedaquiline ≥9 months plus delamanid (95%CI:0.81, 1.31) to 1.11 for regimens reinforced by a second-line injectable (95%CI:0.92, 1.39) and delamanid and imipenem (95%CI:0.90, 1.41).
CONCLUSIONS
High treatment success underscores the effectiveness of regimens comprised of bedaquiline, linezolid, and clofazimine, highlighting the need for expanded access to these drugs.
BACKGROUND
Conversion of sputum culture from positive to negative for M. tuberculosis is a key indicator of treatment response. An initial positive culture is a pre-requisite to observe conversion. Consequently, patients with a missing or negative initial culture are excluded from analyses of conversion outcomes. To identify the initial, or “baseline” culture, researchers must define a sample collection interval. An interval extending past treatment initiation can increase sample size but may introduce selection bias because patients without a positive pre-treatment culture must survive and remain in care to have a culture in the post-treatment interval.
METHODS
We used simulated data and data from the endTB observational cohort to investigate the potential for bias when extending baseline culture intervals past treatment initiation. We evaluated bias in the proportion with six-month conversion.
RESULTS
In simulation studies, the potential for bias depended on the proportion of patients missing a pre-treatment culture, proportion with conversion, proportion culture positive at treatment initiation, and proportion of patients missing a pre-treatment culture who would have been observed to be culture positive, had they had a culture. In observational data, the maximum potential for bias when reporting the proportion with conversion reached five percentage points in some sites.
CONCLUSION
Extending the allowable baseline interval past treatment initiation may introduce selection bias. If investigators choose to extend the baseline collection interval past treatment initiation, the proportion missing a pre-treatment culture and the number of deaths and losses to follow up during the post-treatment allowable interval should be clearly enumerated.
Delamanid should be effective against highly resistant strains of Mycobacteriumtuberculosis, but uptake has been slow globally. In the endTB (expand new drug markets for TB) Observational Study, which enrolled a large, heterogeneous cohorts of patients receiving delamanid as part of a multidrug regimen, 80% of participants experienced sputum culture conversion within 6 months.
Bedaquiline and delamanid offer the possibility of more effective and less toxic treatment for multidrug-resistant (MDR) tuberculosis (TB). With this treatment, however, some patients remain at high risk for an unfavorable treatment outcome. The endTB Observational Study is the largest multicountry cohort of patients with rifampin-resistant TB or MDR-TB treated in routine care with delamanid- and/or bedaquiline-containing regimens according to World Health Organization guidance.
OBJECTIVES
We report the frequency of sputum culture conversion within 6 months of treatment initiation and the risk factors for nonconversion.
METHODS
We included patients with a positive baseline culture who initiated a first endTB regimen before April 2018. Two consecutive negative cultures collected 15 days or more apart constituted culture conversion. We used generalized mixed models to derive marginal predictions for the probability of culture conversion in key subgroups.
MEASUREMENTS AND MAIN RESULTS
A total of 1,109 patients initiated a multidrug treatment containing bedaquiline (63%), delamanid (27%), or both (10%). Of these, 939 (85%) experienced culture conversion within 6 months. In adjusted analyses, patients with HIV had a lower probability of conversion (0.73; 95% confidence interval [CI], 0.62-0.84) than patients without HIV (0.84; 95% CI, 0.79-0.90; P = 0.03). Patients with both cavitary disease and highly positive sputum smear had a lower probability of conversion (0.68; 95% CI, 0.57-0.79) relative to patients without either (0.89; 95% CI, 0.84-0.95; P = 0.0004). Hepatitis C infection, diabetes mellitus or glucose intolerance, and baseline resistance were not associated with conversion.
CONCLUSIONS
Frequent sputum conversion in patients with rifampin-resistant TB or MDR-TB who were treated with bedaquiline and/or delamanid underscores the need for urgent expanded access to these drugs. There is a need to optimize treatment for patients with HIV and extensive disease.