Severe QT prolongation rare with bedaquiline-based treatment for drug-resistant TB

A regimen containing bedaquiline appears to be safe in the treatment of patients with rifampin-resistant tuberculosis (RR-TB), with severe prolongation of the QT interval occurring infrequently and requiring no permanent discontinuation of therapy, as reported in a recent study.

“Treatment outcomes were generally favourable… Few participants experienced a QT interval [corrected according to Fridericia's formula (QTcF)] >500 ms or an absolute increase of >60 ms from baseline,” according to the investigators.

“This is an important finding, given the World Health Organization’s recommendation that most patients with RR-TB be treated with both bedaquiline and clofazimine,” they added.

The study population comprised 195 RR-TB patients (median age 33 years, 57 percent female) across three provinces in South Africa who received regimens containing bedaquiline. Eighty (41 percent) of them had extensively drug-resistant (XDR) TB. Most patients had cavitary disease (77 percent) and previously had TB (66 percent).

A total of 190 (97 percent) patients received concurrent clofazimine, and 179 (92 percent) took linezolid concomitantly. Among those with HIV infection (n=123), 26 were given an antiretroviral therapy (ART) regimen containing lopinavir–ritonavir during the study.

About three-fourths of the population were cured or successfully completed TB treatment, with outcomes showing no difference by HIV status. QTcF increased throughout bedaquiline therapy, with a mean of 23.7 ms from baseline to month 6. The largest increase occurred in the first month of treatment, and the mean maximum QTcF for all patients was 434.4 ms. [Clin Infect Dis 2021;doi:10.1093/cid/ciab335]

Four (2.2 percent) patients developed QTcF >500 ms, all of whom were taking concurrent clofazimine, while two received lopinavir–ritonavir. Meanwhile, 19 patients (10.4 percent) experienced QTcF >60 ms at any time; all of them received concurrent clofazimine, four had lopinavir-ritonavir, and two did not undergo a moxifloxacin washout prior to bedaquiline initiation.

Multivariable regression analysis confirmed that older age (>30 years) was independently associated with QT prolongation (QTcF >450 ms), with the greatest effect seen among patients aged >50 years (vs age 21–30: adjusted odds ratio, 8.3, 95 percent confidence interval, 2.1–32.8).

QT-prolongation was neither more common nor severe in participants receiving concurrent lopinavir–ritonavir. This finding, according to the investigators, may be attributed to the drug’s minimal effect on plasma concentrations of bedaquiline’s M2 metabolite, which is responsible for the QT-prolongation seen with the TB drug. [Int J Antimicrob Agents 2017;49:212-217; Antimicrob Agents Chemother 2019;63:e00445-19].

“Our study adds to the literature establishing the cardiac safety of bedaquiline when given with other QT-prolonging medications, including a randomized controlled trial … of concomitant bedaquiline and delamanid,” they said. [Lancet Infect Dis 2021;doi:10.1016/S1473-3099(20)30770-2; Clin Infect Dis 2020;71:2336-2344]

Also, demonstrating the safety of lopinavir–ritonavir with bedaquiline has important implications for clinical practice, given that an important population of HIV-infected patients worldwide will require protease inhibitor-based ART, they added.

Nevertheless, the investigators stressed that QT monitoring be performed in the later months of therapy to ensure that the QTcF does not reach dangerous levels. “Older patients, particularly [those] >50 years, may warrant close cardiac monitoring.”