How short can we go?

Researchers have conducted a phase 2-3 open-label noninferiority trial to determine if a shorter treatment duration is possible for drug-susceptible pulmonary tuberculosis (TB). The trial compared the standard 6-month regimen of rifampin, isoniazid, pyrazinamide, and ethambutol (RIPE) to four different regimens that included rifampin-linezolid, rifampin-clofazimine, rifapentine-linezolid, or bedaquiline-linezolid. All regimens were given along with isoniazid, pyrazinamide, and ethambutol, with the experimental regimens being administered in an initial 8-week course that was extended by 4 more weeks in patients with ongoing symptoms and a positive sputum smear. Patients who still had symptoms or relapsed were switched to standard treatment. Two regimens were discontinued on a pragmatic basis, and the remaining regimens were compared to the control group.

The trial enrolled 674 participants and the primary composite endpoint, which included death, ongoing therapy, or active infection at 96 weeks, was used to evaluate the efficacy of the regimens. The control arm had a 3.9% incidence rate of the primary composite endpoint, while the rifampin-linezolid and bedaquiline-linezolid arms had incidence rates of 11.4% and 5.8%, respectively. The bedaquiline-linezolid regimen met the predefined noninferiority criteria, meaning that it was not significantly worse than the standard RIPE regimen. The mean total duration of therapy was 180 days for the control arm, 106 days for the rifampin-linezolid arm, and 85 days for the bedaquiline-linezolid arm. The incidence of adverse events was similar among the three groups, but acquired resistance to bedaquiline was observed in two patients in the bedaquiline-linezolid arm.

The trial's small sample size and relatively short follow-up period for TB mean that the results must be viewed with caution. However, the results offer hope that shorter TB treatment options will eventually become available, likely in a redesigned treatment strategy. The trial's findings also suggest that the concerns about the toxicity of bedaquiline and linezolid may be unwarranted, but the potential for drug resistance to bedaquiline is a cause for concern. Bedaquiline has a terminal half-life with subtherapeutic levels that can last several months, which may contribute to the development of resistance.

In conclusion, the trial's results suggest that shorter TB treatment options may be possible, but further research is necessary to confirm these findings. The development of drug resistance is a significant concern, and new treatment strategies must address this issue. Overall, the trial's findings are promising and offer hope for improved TB treatment options in the future.