Bedaquiline-containing regimens show sustained benefit in rifampicin-resistant TB

In the treatment of patients with rifampicin-resistant tuberculosis (TB), two bedaquiline-containing regimens, namely a 9-month all-oral regimen and a shorter 6-month regimen with 8 weeks of aminoglycoside, maintains superior efficacy to a 9-month injectable regimen through 132 weeks, according to long-term data from the STREAM 2 trial.

In the modified intention-to-treat population (n=517), comparison of the 9-month all-oral bedaquiline-containing regimen (oral group) and the 9-month injectable control regimen (control group) showed that significantly fewer patients in the oral group had an unfavourable outcome at week 132 (19.6 percent vs 29.3 percent; –9.7 percentage points difference, 95 percent confidence interval [CI], –18.7 to –1.8; p=0.024 for superiority). [Lancet Respir Med 2024;doi:10.1016/S2213-2600(24)00186-3]

Meanwhile, comparison of the 6-month bedaquiline-containing regimen (6-month group) and the concurrent oral and control regimens indicated that the 6-month regimen was superior to both comparators. An unfavourable outcome occurred in 9.8 percent, 23.8 percent, and 32.5 percent of patients in the respective groups (6-month vs oral: –14.0 percentage points difference; p=0.013 for superiority; 6-month vs control: –22.8 percentage points difference; p<0.0001 for superiority).

“Very few additional unfavourable events occurred between week 76 and week 132… We found no indication of a difference between the regimens in the proportion of participants who had a serious adverse event or a severe adverse event, consistent with results previously reported,” the investigators reported. [Lancet 2022;400:1858-1868]

At week 132, treatment-emergent hearing loss occurred in significantly fewer patients in the oral group than in the control group (3 percent vs 8 percent; p=0.041). However, no significant difference in severe hearing loss was observed between the oral and the 6-month groups (4 percent in both; p=0.72).

Death rates were low, with an incidence rate of 1.01 per 100 person-years in the combined oral and 6-month groups as opposed to 1.52 per 100 person-years in the control group (p=0.49).

The mortality data provide evidence against concerns regarding the significant increase in all-cause mortality observed in the bedaquiline-containing group vs the placebo group in the C208 phase 2 trial of bedaquiline, the investigators said. [N Engl J Med 2014;371:723-732] 

“There is no evidence in the data presented here that bedaquiline is responsible for an increase in mortality; the slight increase in reported mortality in the oral regimen compared with the control regimen is nonsignificant and is probably due to chance. This conclusion is supported by the low mortality seen in the 6-month regimen; there was no suggestion of any excess mortality when mortality in both bedaquiline-containing regimens were combined and compared with the control regimen,” they noted.

Shortened intensive treatment phase

For rifampicin-resistant tuberculosis, clinicians have the option of prescribing either a 9-or 6-month treatment regimen, with most treatment programs having moved away from injectable-based regimens. However, the investigators pointed out that the results for the 6-month regimen in STREAM 2 raise the possibility that a shortened intensive phase that includes an aminoglycoside (eg, amikacin, the drug recommended by the World Health Organization [WHO] in this class) may be a promising option.

“It is possible that a shortened intensive phase that includes an aminoglycoside would provide protection during the early stages of treatment before bedaquiline has reached therapeutic concentrations, thereby mitigating the risk of acquired bedaquiline resistance,” they explained.

“It will be very important to monitor outcomes in program conditions and to continue to develop regimens that are highly effective with reduced instances of adverse drug-related events and protect against the development of acquired resistance. In addition … future trials of rifampicin-resistant tuberculosis treatments should assess outcomes important to patients, such as speed of symptom resolution, quality of life, and mental health outcomes, in addition to health economic implications of new regimens,” the investigators said. [Glob Public Health 2023;18:2234450]

Of the patients included in the mITT population, 187 were in the control group (56 percent aged 25–44 years, 61 percent male, 47 percent Asian), 196 in oral group (61 percent aged 25–44 years, 63 percent male, 47 percent Asian), and 134 in 6-month group (59 percent aged 25–44 years, 60 percent male, 53 percent Asian).