All-Oral Combination Therapy May Shorten TB Treatment

A daily combination of pretomanid, 200 mg; pyrazinamide, 1500 mg; and bedaquiline, 200 mg, may be an effective oral treatment for pulmonary tuberculosis (TB) in patients with drug-susceptible TB, according to results from a new phase-2b trial.

To assess the bactericidal activity and safety profile of combinations of bedaquiline, pretomanid, pyrazinamide, and moxifloxacin in the first 8 weeks of treatment for pulmonary TB, the researchers prospectively recruited individuals aged 18 years or older with drug-susceptible or rifampicin-resistant pulmonary TB and a sputum smear grade of 1+ or higher from 10 sites in South Africa, Tanzania, and Uganda.

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Between October 24, 2014, and December 15, 2015, the researchers enrolled 180 individuals with drug-susceptible TB and 60 individuals with rifampicin-resistant TB. Each participant was randomly assigned to a 56-day treatment regimen.

Among the participants with drug-susceptible TB: 

• 61 received standard TB therapy (oral isoniazid, rifampicin, pyrazinamide, and ethambutol [HRZE])
• 59 received daily oral pretomanid, 200 mg, and daily oral pyrazinamide, 1500 mg, with daily oral bedaquiline, 400 mg, on days 1 to 14 and then daily oral bedaquiline, 200 mg, 3 times per week thereafter (B_loadPaZ) 
• 60 received daily oral pretomanid, 200 mg, and daily oral pyrazinamide, 1500 mg, with daily oral bedaquiline, 200 mg (B₂₀₀PaZ)

To measure the therapies’ efficacy, the researchers calculated the daily percentage change in time to sputum culture positivity (TTP) in liquid medium from day 0 to day 56 in the drug-susceptible TB population. By doing this, the researchers determined that B₂₀₀PaZ yielded the highest daily percentage change in TTP (5.17%), followed by B_loadPaZ (4.87%) and HRZE (4.04%).

According to the study authors, there was a significant difference in the bactericidal activity in the B₂₀₀PaZ and B_loadPaZ groups vs the HRZE group. 

When assessing for safety, the researchers found that a greater proportion of participants in the B_loadPaZ and B₂₀₀PaZ groups than in the HRZE group discontinued the study drug due to adverse events, with elevations of liver enzymes being the most common grade 3 or 4 adverse event.

“B₂₀₀PaZ is a promising regimen to treat patients with drug-susceptible [TB]. The bactericidal activity of both these regimens suggests that they have the potential to shorten treatment, and the simplified dosing schedule of B₂₀₀PaZ could improve treatment adherence in the field,” the researchers concluded. “However, these findings must be investigated further in a phase 3 trial assessing treatment outcomes.”

The individuals with rifampicin-resistant TB received 56 days of the B₂₀₀PaZ regimen plus moxifloxacin, 400 mg, daily (BPaMZ).

According to the study authors, while the treatments for drug-susceptible TB that contained bedaquiline were superior to HRZE in bactericidal activity, it was BPaMZ for the treatment of pyrazinamide-susceptible rifampicin-resistant TB that yielded the highest gain in bactericidal activity at day 56 compared with the HRZE group.

—Colleen Murphy

Reference:

Tweed CD, Dawson R, Burger DA, et al. Bedaquiline, moxifloxacin, pretomanid, and pyrazinamide during the first 8 weeks of treatment of patients with drug-susceptible or drug-resistant pulmonary tuberculosis: a multicentre, open-label, partially randomised, phase 2b trial. Lancet Respir Med. 2019;7(12):1048-1058. https://doi.org/10.1016/S2213-2600(19)30366-2.