An All-Oral 6-Month Regimen for Multidrug-Resistant Tuberculosis: A Multicenter, Randomized Controlled Clinical Trial (the NExT Study).

Rationale: Improving treatment outcomes while reducing drug toxicity and shortening the treatment duration to ∼6 months remains an aspirational goal for the treatment of multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB). Objectives: To conduct a multicenter randomized controlled trial in adults with MDR/RR-TB (i.e., without resistance to fluoroquinolones or aminoglycosides). Methods: Participants were randomly assigned (1:1 ratio) to a ∼6-month all-oral regimen that included levofloxacin, bedaquiline, and linezolid, or the standard-of-care (SOC) ⩾9-month World Health Organization (WHO)-approved injectable-based regimen. The primary endpoint was a favorable WHO-defined treatment outcome (which mandates that prespecified drug substitution is counted as an unfavorable outcome) 24 months after treatment initiation. The trial was stopped prematurely when bedaquiline-based therapy became the standard of care in South Africa. Measurements and Main Results: In total, 93 of 111 randomized participants (44 in the comparator arm and 49 in the interventional arm) were included in the modified intention-to-treat analysis; 51 (55%) were HIV coinfected (median CD4 count, 158 cells/ml). Participants in the intervention arm were 2.2 times more likely to experience a favorable 24-month outcome than participants in the SOC arm (51% [25 of 49] vs. 22.7% [10 of 44]; risk ratio, 2.2 [1.2-4.1]; P = 0.006). Toxicity-related drug substitution occurred more frequently in the SOC arm (65.9% [29 of 44] vs. 34.7% [17 of 49]; P = 0.001)], 82.8% (24 of 29) owing to kanamycin (mainly hearing loss; replaced by bedaquiline) in the SOC arm, and 64.7% (11 of 17) owing to linezolid (mainly anemia) in the interventional arm. Adverse event-related treatment discontinuation in the safety population was more common in the SOC arm (56.4% [31 of 55] vs. 32.1% [17 of 56]; P = 0.007). However, grade 3 adverse events were more common in the interventional arm (55.4% [31 of 56] vs. 32.7 [18 of 55]; P = 0.022). Culture conversion was significantly better in the intervention arm (hazard ratio, 2.6 [1.4-4.9]; P = 0.003) after censoring those with bedaquiline replacement in the SOC arm (and this pattern remained consistent after censoring for drug replacement in both arms; P = 0.01). Conclusions: Compared with traditional injectable-containing regimens, an all-oral 6-month levofloxacin, bedaquiline, and linezolid-containing MDR/RR-TB regimen was associated with a significantly improved 24-month WHO-defined treatment outcome (predominantly owing to toxicity-related drug substitution). However, drug toxicity occurred frequently in both arms. These findings inform strategies to develop future regimens for MDR/RR-TB.Clinical trial registered with www.clinicaltrials.gov (NCT02454205).

QT Interval Prolongation in People Treated With Bedaquiline for Drug-Resistant Tuberculosis Under Programmatic Conditions: A Retrospective Cohort Study.

BACKGROUND: Bedaquiline has a black-box warning of the risk of arrhythmias and sudden death. This study aimed to determine the incidence of QTc prolongation and cardiac events in patients receiving bedaquiline for drug-resistant tuberculosis (DR-TB) under programmatic conditions. METHODS: Retrospective cohort study of patients receiving bedaquiline at a DR-TB hospital in KwaZulu Natal, South Africa from September 2017 to February 2019. The primary outcome, a prolonged QT interval corrected using the Fridericia formula (QTcF), was defined as QTcF >500 ms, QTcF change >60 ms from baseline, or both. RESULTS: Among 420 patients (66.2% male, median age 36 years), the median QTcF was 406.4 (interquartile range [IQR], 389.1-421.3) ms at baseline, increasing to 430.5 (IQR, 414.4-445.1) ms by 3 months and 434.0 (IQR, 419.0-447.9) ms at 6 months. Eighteen of 420 patients (4.3%) had a QTcF >500 ms and 110 of 420 patients (26.2%) had a QTcF change >60 ms. There were no recorded arrhythmias or cardiac deaths. Odds of prolonged QTcF were increased with concomitant azoles (adjusted odds ratio [aOR], 5.61 [95% confidence interval (CI), 2.26-13.91]; P < .001) and an inverse association with HIV-positive status (aOR, 0.34 [95% CI, .15-.75]; P = .008) and hypertension (aOR, 0.13 [95% CI, .02-.86]; P = .02). After prolongation, the QTcF declined to <500 ms, whether drugs were interrupted or not. CONCLUSIONS: We observed a modest prolongation of QTcF, maximal at week 15; there were no recorded arrhythmias or related deaths.