UCSF

Abstract: Background: Shortened all-oral regimens for multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB) combine multiple QTc prolonging agents, including bedaquiline and delamanid, which act partly through hERG potassium channel binding. Promethazine, a first-generation antihistamine used for nausea during TB therapy, shares this mechanism. Whether adjunctive promethazine further raises the risk of clinically relevant QTc prolongation in this setting is unclear. Methods: We conducted secondary analyses from a prospective observational cohort study of patients ≥15 years in Lesotho who received a 9- to 12-month all-oral regimen (bedaquiline, linezolid, levofloxacin, clofazimine, delamanid) for pulmonary MDR/RR-TB. We modelled time-varying promethazine exposure using the Andersen-Gill formulation of Cox regression, with time-to-first grade ≥3 (>500 ms) QTc event as the outcome of interest. We conducted comparator analyses with time-varying exposure to metoclopramide, ondansetron, and episodes of nausea, dizziness, and vomiting. Results: Among 247 participants (median age 41, 63.2% living with HIV), 62 (25.1%) received promethazine. Grade ≥3 QTc prolongation occurred in 10 (4.0%). Incident clinically significant QTc prolongation was higher during promethazine-exposed than unexposed periods (7.4 versus 1.3 per 10 000 person-days; HR 7.0, 95% CI: 1.4–35.3). No comparable elevation was seen in analyses of exposure to metoclopramide (HR 1.0, 95% CI: 0.3–3.6), ondansetron, or episodes of nausea, dizziness, or vomiting (HR 1.5, 95% CI: 0.3–6.9). Conclusions: Promethazine use was associated with increased risk of clinically relevant QTc prolongation within a QTc-burdened all-oral MDR/RR-TB regimen. These findings provide preliminary evidence that clinicians may consider when selecting anti-emetics as part of MDR/RR-TB therapy with a shortened all-oral regimen and highlight the importance of evaluating adjunctive medications in DR-TB care.