A study of tuberculosis (TB) patients in South Africa found that more than half receiving treatment with a bedaquiline-containing regimen had isolates with bedaquiline resistance, researchers reported last week in The Lancet Microbe.
For the retrospective longitudinal study, a team led by researchers with Stellenbosch University collected and analyzes sputum samples from adults with culture-positive pulmonary TB who received at least 4 months of a bedaquiline-containing regimen from January 20, 2016, to November 20, 2017. Bedaquiline has recently become part of all standard drug-resistant TB regimens globally, but it was introduced for compassionate use in South Africa in 2012. To monitor treatment response and resistance emergence, the researchers conducted phenotypic drug-susceptibility testing for bedaquiline on baseline samples and samples from each month, and performed whole-genome sequencing (WGS).
Bedaquiline resistance gain
Of the 38 patients with isolates assessable for phenotypic drug susceptibility testing, 3 (8%) had bedaquiline resistance at baseline (primary resistance), 18 (47%) gained resistance (due to acquisition or reinfection), and 17 (45%) were susceptible at both baseline and follow-up. WGS revealed that several Rv0678 and pepQ single-nucleotide polymorphisms and indels were associated with resistance, while isolates with Rv0676c, Rv0677c, and Rv1979c variants were seen with both resistant and susceptible isolates. Patients with baseline fluoroquinolone resistance, clofazimine exposure, and four or fewer effective drugs were more likely to have bedaquiline-resistance gain.
Our study highlights risks associated with implementing life-saving new drugs and shows evidence of bedaquiline-resistance transmission.
The authors say the study is one of the first to report individual-level bedaquiline resistance gain over time among patients treated in a programmatic setting with a bedaquiline-containing regimen, and underscores the importance of adequate drug-susceptibility testing capacity.
"Our study highlights risks associated with implementing life-saving new drugs and shows evidence of bedaquiline-resistance transmission," they wrote. "Routine drug susceptibility testing should urgently accompany scale-up of new drugs; however, rapid drug susceptibility testing for bedaquiline remains challenging given the diversity of variants observed."