Shorter treatment regimen feasible for rifampin-resistant TB?

Individuals with rifampin-resistant tuberculosis (RR-TB) may have the option to undergo shorter treatment periods, as findings from the phase II/III TB-PRACTECAL* trial show the noninferiority and superiority of a 24-week, all-oral regimen to standard of care (SoC). It also had a better safety profile than SoC.

“The recommended treatment duration for RR-TB in programmatic care settings is 9 to 20 months,” said the researchers. Apart from the lengthy treatment, it involves up to 20 tablets daily.

Cost, adverse events (AEs), and social disruption are major challenges in treating RR-TB. [apps.who.int/iris/rest/bitstreams/1280998/retrieve, accessed February 10, 2023; Eur Respir J 2014;43:1763-1775; Lancet Respir Med 2020;8:383-394] “[Hence,] all-oral treatment regimens that are more effective, shorter, with a more acceptable side effect profile are needed,” they said.

During stage 1 of the study, 552 patients from Belarus, South Africa, and Uzbekistan were randomized 1:1:1:1 to either BPaL**, BPaLC (BPaL + clofazimine***), or BPaLM (BPaL + moxifloxacin^#), or to locally accepted SoC regimens^##. A total of 303 patients entered stage 2, wherein they were randomized 1:1 to either BPaLM or SoC. [N Engl J Med 2022;387:2331-2343]

In the modified intention-to-treat population (mITT; n=128 evaluable patients) analysis during stage 2, BPaLM was both noninferior and superior to SoC in terms of the primary composite outcome of death, treatment failure, treatment discontinuation, loss to follow up, or TB recurrence. Only 11 percent of BPaLM recipients had a primary outcome event, whereas with SoC, the corresponding rate was nearly 50 percent.

At 72 weeks of follow up, 19 percent of BPaLM recipients had a total of 16 events (at least one serious or grade ≥3 AE). In the SoC arm, 59 percent had 69 events. The most frequently observed serious or grade ≥3 AEs were hepatic disorders, affecting 11 percent of SoC recipients. Only 4 percent were affected in the BPaLM arm. The second most frequent serious or grade ≥3 AE was QTcF prolongation, which affected one and 10 patients in the respective BPaLM and SoC arms.

Other regimens with potential: BPaL, BPaLC

BPaLC and BPaL were also highly efficacious. In the additional efficacy analyses of the mITT cohort, at 72 weeks, the percentages of patients who had an unfavourable composite outcome event with BPaL and BPaLC were 23 percent and 19 percent, respectively. These rates were still lower than that seen with SoC.

“In the additional safety analyses, BPaL and BPaLC were also safer than SoC,” the researchers added. With BPaL, 22 percent had at least one serious or grade ≥3 AE, 3 percent had hepatic disorders, while none had QTcF prolongation. The corresponding rates with BPaLC were 32 percent, 4 percent, and 4 percent.

Improve TB treatment landscape?

“The difference between the SoC and investigational arms was less pronounced in the per-protocol analysis in which early discontinuations were excluded. These findings suggest that the SoC treatment was similarly efficacious when patients could receive it without adverse effects,” the researchers noted.

The findings underline the potential of three investigational bedaquiline-containing regimens as treatment alternative for RR-TB, with BPaLM yielding better outcomes than the other two. This might help improve the treatment landscape of RR-TB which, despite the reported successful outcomes following treatment in more than half of patients worldwide, has not seen much improvement over the past 5 years. [apps.who.int/iris/rest/bitstreams/1379788/retrieve, accessed February 10, 2023]