BPaLM regimen continues to show benefit against rifampicin-resistant tuberculosis

In the treatment of patients with rifampicin-resistant tuberculosis, a 6-month oral regimen consisting of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) is safe and efficacious and compares favourably with standard of care, as shown in the final data from the phase IIB-III TB-PRACTECAL study.

Results of the interim analysis, published in 2022, showed a difference in the primary endpoint of unfavourable outcome (a composite of treatment failure, death, treatment discontinuation, disease recurrence, or loss to follow-up) at week 72 in favour of BPaLM vs standard of care (risk difference, −37.2 percentage points, 96.6 percent confidence interval [CI], −52.8 to −21.6). The analysis involved modified intention-to-treat (mITT) population comprising 66 patients in the standard of care group and 62 in the BPaLM group. [N Engl J Med 2022;387:2331-2343]

The final data was consistent with the findings of the interim analysis, with the primary endpoint occurring less frequently with BPaLM than with standard of care (12 percent vs 41 percent; risk difference −29.2 percentage points, 96.6 percent CI, −39.8 to −18.6; p<0.0001 for noninferiority and superiority). The mITT population included 137 patients in the standard care group and 138 in the BPaLM group. [Lancet Respir Med 2023;doi:10.1016/S2213-2600(23)00389-2]

Furthermore, BPaLM was associated with a lower risk of having grade 3 or higher adverse events (AEs) or serious AEs (23 percent vs 48 percent; risk difference, −25.2 percentage points, 96.6 percent CI, −36.4 to −13.9).

By week 72, five patients in the standard care group had died. One had COVID-19 pneumonia that was unrelated to treatment; the other four had acute pancreatitis, suicide, sudden death, or sudden cardiac death that were deemed to be treatment-related.

“This final analysis of the TB-PRACTECAL trial substantiates, with improved precision, the noninferiority of the BPaLM regimen when compared with the standard of care,” the investigators said.

It is worth noting that the effect estimate for the primary outcome comparing BPaLM vs standard care at 72 weeks was smaller in the final analysis (risk difference, −29.2 percentage points) than in the interim analysis (−37.2 percentage points). According to the investigators, the difference can be mostly attributed to the better performance of the standard care group in the final analysis, possibly due to improvements in standard care throughout the trial. [N Engl J Med 2022;387:2331-2343]

The improvements were in line with the 2019 update to the WHO consolidated guidelines on drug-resistant tuberculosis treatment, which prioritized the addition of bedaquiline and linezolid to most regimens, discontinued the use of second-line injectable agents, and allowed shorter regimens of 9–12 months duration.

Post hoc analyses

A post hoc evaluation of outcomes was also conducted for bedaquiline, pretomanid, and linezolid (BPaL) and BPaL plus clofazimine (BPaLC). Both regimens proved noninferior to standard care in terms of the primary endpoint in the mITT population, with unadjusted risk differences of −17.4 percentage points (95 percent CI, −28.7 to −6.1) for BPaLC and −27.4 percentage points (95 percent CI, −37.8 to −17.0) for BPaL.

Noninferiority was also shown in the per-protocol population for BPaL (−3.2 percentage points, 95 percent CI, −10.0 to 3.6) but not for BPaLC (8.3 percentage points, 95 percent CI, −0.1 to 17.2).

Taken together, the findings suggest that BPaLM, BPaLC, and BPaL have the potential to improve the outcomes of people with rifampicin-resistant tuberculosis, according to the investigators, who called for the accelerated implementation of these regimens.

Generalizable data

TB-PRACTECAL included 552 patients who were randomly assigned to receive standard care (n=152), BPaLM (n=151), BPaLC (n=126), or BPaL (n=123). Of the 507 participants included in the mITT population, the median age was 35 years, 41 percent were women, 28 percent were living with HIV (median CD4 count 319 cells per μL), 65 percent had smear-positive tuberculosis, 61 percent had tuberculosis cavities, and 89 percent had culture-positive tuberculosis.

“The study provides robust, generalizable data showing efficacy among similar numbers of male and female participants from three countries (Belarus, South Africa, and Uzbekistan), and is inclusive of people with HIV coinfection and severe rifampicin-resistant disease with and without fluoroquinolone resistance; as such, the participants are broadly representative of adult and adolescent patients with rifampicin-resistant tuberculosis worldwide,” the investigators said.

They believe that the TB-PRACTECAL data will be key to BPaLM becoming the preferred regimen for adolescents and adults with pulmonary rifampicin-resistant tuberculosis.