By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC
Professor of Internal Medicine, Northeast Ohio Medical University
SYNOPSIS: A multicenter, randomized, controlled, noninferiority clinical trial found a 24-week, all-oral regimen (bedaquiline, pretomanid, linezolid, and moxifloxacin) to be safe and effective for patients aged 15 years and older with rifampin-resistant tuberculosis.
SOURCE: Nyang’wa BT, Berry C, Kazounis E, et al. A 24-week, all-oral regimen for rifampin-resistant tuberculosis. N Engl J Med 2022;387:2331-2343.
Despite decades of research and the availability of effective antibiotic therapy, tuberculosis (TB) remains a leading cause of mortality worldwide. Drug resistance contributes to many fatal outcomes. Patients with rifampin-resistant TB face significant obstacles compared to those with susceptible strains. These include a longer duration of treatment (i.e., nine to 20 months), increased adverse events, greater cost, and higher pill burden. Thus, safer, shorter, and less costly regimens are urgently needed. Nyang’wa and colleagues aimed to evaluate the safety and effectiveness of an all-oral 24-week treatment regimen for rifampin-resistant TB.
The study was an open-label, Phase II-III, randomized, controlled, noninferiority trial that enrolled patients from seven sites in Belarus, South Africa, and Uzbekistan (TB-PRACTECAL, NCT02589782 at www.clinicaltrials.gov). Patients were included who were 15 years of age or older and had Mycobacterium tuberculosis infection confirmed by a positive sputum smear that was resistant to rifampin. Exclusion criteria included pregnancy, an alanine aminotransferase or an aspartate aminotransferase level higher than three times normal, a corrected QT interval (QTcF) greater than 450 msec, structural heart disease, or resistance to bedaquiline, pretomanid, or linezolid. Patients were randomly assigned to one of four treatment groups: locally accepted standard-care regimen; the BPaL regimen consisting of bedaquiline 400 mg daily for two weeks, then 200 mg three times a week for 22 weeks, pretomanid 200 mg daily for 24 weeks, and linezolid 600 mg daily for 16 weeks, then 300 mg daily for eight weeks; the BPaLM regimen consisting of the BPaL regimen plus moxifloxacin 400 mg daily for 24 weeks; and the BPaLC regimen consisting of BPaL plus clofazimine 100 mg daily for 24 weeks.
Patients had study visits weekly for the first two weeks, then monthly until week 24, then every two months up to week 108. Each visit included laboratory testing, three electrocardiographic (ECG) assessments, and a physical exam. Visual acuity, color blindness testing, and audiometric testing also were conducted at standard intervals. At inclusion and set intervals, two sputum samples were obtained for smear and culture. Drug susceptibility testing was performed on M. tuberculosis samples from baseline and in any samples that were culture-positive at week 16 or later. Patients were considered to be culture converted when they had two negative cultures at least two weeks apart.
The primary efficacy outcomes were culture conversion at eight weeks after randomization and an unfavorable status, defined as a composite of death, treatment failure or discontinuation, loss to follow-up, or recurrence of TB at 72 weeks after randomization. The primary safety outcomes were the incidence of death or discontinuation of treatment for any reason by week 8, and at least one serious adverse event or an adverse event of grade 3 or higher at 72 and 108 weeks after randomization and at the end of treatment, and the incidence of QTcF interval prolongation at week 24.
There were 552 patients randomized to one of the four groups. The percentages of patients with culture conversion at eight weeks were 77% in the BPaLM group, 67% in the BPaLC group, and 46% in the BPaL group. The rates of treatment discontinuation or death were 8%, 6%, and 10%, respectively. The study was terminated early for benefit after 75% of the planned sample. The investigators then selected the BPaLM group for further analysis. By 72 weeks, 52% of patients in the standard care group had a favorable outcome compared to 89% in the BPaLM group based on the modified intention-to-treat population. There was no evidence of treatment being affected by age, sex, human immunodeficiency virus status, presence of cavities on chest radiograph, sputum smear status, or fluoroquinolone resistance in subgroup analysis. At 48 weeks, there were no instances of TB recurrence in the BPaLM group.
Regarding safety outcomes, by 72 weeks of follow-up, 59% of patients in the standard care group had at least one serious adverse event compared to 19% in the BPaLM group. The most frequently identified adverse event was hepatic toxicity. Next was QTcF prolongation and third was peripheral neuropathy, which occurred in 19% of patients in the standard care group and 9% in the BPaLM group. There were no cases of optic neuropathy. Ten out of 549 patients in the study died (2%), of whom seven were in the standard care group. Four of the deaths, which were all in the standard care group, were classified by the investigators as treatment related. None of the deaths were directly due to TB.
COMMENTARY
This is an important study because it provides clear guidance to clinicians treating patients with rifampin-resistant TB. Indeed, it likely will be regarded as a seminal investigation and incorporated into future treatment guidelines for the management of TB. The safety signals are encouraging, especially when compared to standard therapy. They also need to be conceptualized in the context of the high risk for mortality associated with untreated rifampin-resistant TB.
It is reassuring that none of the patients who received BPaLM died due to treatment. Another concern is that drug resistance testing will be necessary to maintain the efficacy of BPaLM, but unfortunately this is expensive and currently not widely available.
Despite the robust design of the trial, it has a few limitations worth mentioning. First, patients were followed very closely, with frequent laboratory and ECG testing. This is likely not possible to achieve in most settings outside of a clinical trial. Second, BPaLM is expensive and most cases of rifampin-resistant TB occur in resource-limited settings. Third, minimum inhibitory concentrations of the antibiotics against the M. tuberculosis strains were not performed. Finally, the standard of care regimens changed during the study period according to updated World Health Organization guidelines, which may have affected the trial results in uncertain ways.
With BPaLM, clinicians have an oral regimen that is superior and safer than standard therapy for rifampin-resistant TB. Care must be taken to monitor closely for side effects and toxicities. Although BPaLM is a welcome advancement, continued work on shorter, safer, and more effective therapies must continue to be a priority for drug developers, governmental organizations, and the research community.
