Patients with multidrug-resistant or rifampicin-resistant tuberculosis (TB) and a normal baseline QTc interval may benefit from bedaquiline plus delamanid combination therapy, according to the findings of a study published in The Lancet Infectious Diseases.
Patients (N=84) who had drug-resistant TB with or without HIV were recruited in South Africa and Peru from 2016 to 2018 for the ongoing phase 2, open-label, randomized controlled Delamanid Bedaquiline for Resistant Tuberculosis (DELIBERATE or AIDS Clinical Trials Group A5343) study (ClinicalTrials.gov Identifier: NCT02583048). Patients were stratified by HIV status and assigned in a 1:1:1 ratio to receive bedaquiline, delamanid, or both. Corrected QT (QTc) was evaluated by electrocardiogram at baseline and over the following 24 weeks.
Study participants were a median age of 34 years, 75% were men, 52% were mixed race, 45% were Black, and 37% were HIV-1 positive. All had been treated for TB for a median of 28 days prior to enrollment in the study, and median baseline QTc was 396 ms.
The change in QTc was more pronounced later in the treatment course, during which the maximum change from baseline was 72 ms, 49 ms, and 75 ms among the bedaquiline, delamanid, and combination cohorts, respectively. These values corresponded with a mean change from baseline QTc of 12.3 ms (95% CI, 7.8-16.7) for bedaquiline, 8.6 ms (95% CI, 4.0-13.1) for delamanid, and 20.7 ms (95% CI, 16.1-25.3) for combination therapy.
The difference between combination therapy and bedaquiline alone was 8.4 ms (95% CI, 2.0-14.8) and between combination therapy and delamanid was 12.1 ms (95% CI, 5.7-18.6). The difference between combined therapy and the sum of the monotherapies was -0.1 ms (95% CI, -8.0 to 7.7).
No grade 3 or 4 QTc prolongation events were observed; 30 grade 1 events (bedaquiline, n=9; delamanid, n=11; combination therapy, n=10) and 3 grade 2 events (bedaquiline, n=1; combination therapy, n=2) occurred.
At week 8, 88% of the individuals receiving bedaquiline, 83% of the individuals receiving delamanid, and 95% of the individuals who received combination therapy had converted. At week 24, 92%, 91%, and 95% had converted, respectively.
Among participants who were HIV positive, 50% had undetectable viral load at baseline; by week 24, 85% had an undetectable viral load.
These data indicate that the combination of bedaquiline plus delamanid was not more effective than additive but may be modestly more effective than any of the 2 drugs separately, without the added risk of grade 3 or 4 QTc prolongation events.
Dooley KE, Rosenkranz SL, Conradie F, et al; and the AIDS Clinical Trials Group (ACTG) A5343 DELIBERATE Study Team. QT effects of bedaquiline, delamanid, or both in patients with rifampicin-resistant tuberculosis: a phase 2, open-label, randomised, controlled trial. Lancet Infect Dis. Published online February 12, 2021. doi:10.1016/S1473-3099(20)30770-2