BACKGROUND
Only 63% of patients initiating multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment in 2020 were treated successfully. 24-Week all-oral bedaquiline, pretomanid, and linezolid (BPaL)–based regimens have demonstrated higher rates of treatment success and have been recommended by the World Health Organization. Operational research is urgently required to evaluate these regimens in non-trial settings.
METHODS
This was a prospective cohort study of patients with microbiologically confirmed MDR/RR-TB and pre–extensively drug-resistant TB (pre-XDR-TB) initiated on BPaL-based regimens in Belarus and Uzbekistan (February 2022–June 2023). All clinical care and research procedures were delivered by treating physicians. After treatment completion, patients were followed up at 6 and 12 months, including collecting sputum to ascertain recurrence. The primary objective was to estimate the effectiveness (cured or treatment completed) and safety (the occurrence of serious adverse events) of BPaL-based regimens.
RESULTS
A total of 677 patients initiated treatment with BPaL-based regimens during the study. We documented successful treatment outcomes in 95.3% (427/448) of patients with MDR/RR-TB treated with BPaL plus moxifloxacin and 90.4% (207/229) of patients with pre–XDR-TB treated with BPaL plus clofazimine. 10.2% (69/677) experienced serious adverse events including 24 deaths (3.5%), 11 of which occurred during treatment. 83.3% (20/24) of deaths were not related to TB or TB treatment. Of patients who were successfully treated and completed 12-month follow-up, 0.5% (2/383) had recurrence.
CONCLUSIONS
BPaL-based regimens for MDR/RR-TB and pre–XDR-TB are safe and highly effective in non-trial settings. These regimens should be considered for widespread implementation globally, and further research is needed to evaluate their performance in other key populations.
The total duration of treatment for rifampicin-resistant tuberculosis (RR-TB) in Belarus prior to December 2022 was 18-20 months. The efficacy of treatment with such regimens is low, with the WHO’s Global TB Report suggesting that efficacy was around 73% in Belarus in 2018. The development of effective short regimens for RR-TB treatment is urgent. In Belarus, six-month long treatment with all-oral regimens is used in patients with RR-TB, under operational research conditions, following WHO recommendations.
METHODS
A preliminary assessment of the effectiveness of six-month all-oral regimens containing bedaquiline, pretomanid, linezolid, and moxifloxacin or clofazimine (BPaLM/BPaLC), was performed in a cohort of RR-TB patients. Treatment outcomes, time to culture conversion, and time to adverse event (AE) occurrence, AE types, frequency, and outcomes are described.
ETHICS
This study was approved by the MSF Ethics Review Board (ERB) and by the Belarus Ministry of Health ERB.
RESULTS
Of 177 patients who were enrolled from February 2022 to July 2022, one patient was excluded due to linezolid resistance; this patient continued treatment under an individualised regimen. Of the rest of the cohort (133 (76%) male, 43 female (24%); median age, 44 years (interquartile range, IQR, 25-29 years), 93.2% (164/176) had a favourable treatment outcome, 11 patients were lost to follow-up, and one died. 52 (30%) patients had a sputum smear positive result at treatment start, 59 (34%) a cavitary lesion on chest X-ray, and 42 (24%) patients had been previously treated. 12 patients (7%) were HIV-positive; 23 (13%) had had hepatitis C infection; 45 (26%) abused alcohol, and 6 (3%) of patients had diabetes mellitus. Median time to culture conversion was 27 days (IQR, 25-29). In 96.0% of patients, culture conversion was achieved within 2 months of treatment. 9% of patients had serious AE’s (SAE). Out of total 19 SAE’s, 12 resolved, two resolved with sequelae, three were resolving at the time of assessment, one did not resolve, and one was fatal. Median time from treatment start to the first SAE was 92.5 days (IQR, 12.5-143). The most frequent SAE’s were elevated liver function (6 (32%) cases), acute kidney injury (4 (21%) cases), and amylase increased/pancreatitis (3 (16%) cases). Two cases also revealed cancer or progression of cancer; one showed QTcF prolongation; one, anemia, one, thrombotic cerebral infarction, and one, Clostridium difficile infection. Two cases of cancer and thrombotic cerebral infarction (a patient with a long-standing history of multiple strokes) were assessed as unrelated to study drugs. The one death from cancer was assessed as not related to treatment. Permanent withdrawal of one study drug (linezolid or clofazimine) was done only in three instances (15.8%).
CONCLUSION
The effectiveness of six-month all-oral regimens in this cohort was very high (93.2%). BPaLM/BPaLC regimens were observed to be characterised by a good safety profile. Further data are necessary to evaluate longer-term treatment outcomes.
CONFLICTS OF INTEREST
None declared
Current treatment regimens for multidrug-resistant tuberculosis (MDR-TB) are long, poorly tolerated and have poor outcomes. Furthermore, the costs of treating MDR-TB are much greater than those for treating drug-susceptible TB, both for health service and patient-incurred costs. Urgent action is needed to identify short, effective, tolerable and cheaper treatments for people with both quinolone-susceptible and quinolone-resistant MDR-TB. We present the protocol for an economic evaluation (PRACTECAL-EE substudy) alongside an ongoing clinical trial (TB-PRACTECAL) aiming to assess the costs to patients and providers of new regimens, as well as their cost-effectiveness and impact on participant poverty levels. This substudy is based on data from the three countries participating in the main trial.
METHODS AND ANALYSIS
Primary cost data will be collected from the provider and patient perspectives, following economic best practice. We will estimate the probability that new MDR-TB regimens containing bedaquiline, pretomanid and linezolid are cost-effective from a societal perspective as compared with the standard of care for MDR-TB patients in Uzbekistan, South Africa and Belarus. Analysis uses a Markov model populated with primary cost and outcome data collected at each study site. We will also estimate the impact of new regimens on prevalence of catastrophic patient costs due to TB.
ETHICS AND DISSEMINATION
Ethical approval has been obtained from the London School of Hygiene & Tropical Medicine and Médecins Sans Frontières. Local ethical approval will be sought in each study site. The results of the economic evaluation will be shared with the country health authorities and published in a peer-reviewed journal.