Abstract
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.
Keywords: RR-TB, MDR-TB, pre–XDR-TB, BPaL, BPaLM
Treatment for multidrug-resistant/rifampicin-resistant tuberculosis (TB) and pre–extensively drug-resistant TB using 24-week all-oral bedaquiline, pretomanid, and linezolid–based regimens was initiated in Belarus and Uzbekistan. Treatment was successful in 94% of patients, with 10% experiencing any serious adverse event.
Graphical Abstract
Graphical Abstract.
Rifampicin-resistant tuberculosis (RR-TB) with resistance to isoniazid is defined as multidrug-resistant (MDR) TB [1]. Additional resistance to a fluoroquinolone (levofloxacin or moxifloxacin) is defined as pre–extensively drug-resistant (pre-XDR) TB [2]. Of 10.6 million people estimated to have had TB in 2022, the estimated number with MDR/RR-TB was between 370 000 and 450 000 [3]. Only approximately 43% of all people with MDR/RR-TB were enrolled in treatment in 2022 [3]. Of people enrolled in 2020, only 63% had successful treatment outcomes, significantly lower than the 88% for people with drug-susceptible TB [3]. Long treatment duration and high incidence and inadequate management of adverse events (AEs) increase the risk of poor treatment outcomes [4–7]. Furthermore, over 80% of households affected by MDR/RR-TB incur TB-related catastrophic costs, and the stigma and social isolation associated with MDR/RR-TB are important determinants of treatment completion [8, 9].
Treatment for MDR/RR-TB has evolved substantially [10–13]. In 2022, the World Health Organization (WHO) issued new guidelines conditionally recommending a 24-week all-oral regimen composed of bedaquiline (B), pretomanid (Pa), linezolid (L), and moxifloxacin (M) (BPaLM) [1]. This recommendation, made with “very low certainty of evidence,” was based on 3 studies, only 1 of which pragmatic clinical trial for a more effective, concise and less toxic regimen (TB-PRACTECAL) was a randomized controlled trial [14–16]. In this trial, in addition to BPaL alone, a second experimental arm had moxifloxacin (BPaLM) and a third had clofazimine (BPaLC). BPaLM was superior to standard of care (which was consistent with WHO 2016–2019 guidelines), with only 10% of patients in the BPaLM arm having an unfavorable outcome, including treatment discontinuation, compared to 40% in the control arm [17]. Patients in the BPaLM arm also experienced fewer AEs. Importantly, post hoc analysis showed that BPaLC was noninferior to standard of care [18].
Because of concerns about regimen performance in non-trial settings, where higher rates of treatment interruption, poor adherence, and less intensive monitoring may increase the risk of relapse and emergent resistance, there is an urgent need for operational research characterizing the real-world effectiveness of BPaL-based regimens. To date, however, evidence is limited. One study reported on 70 patients who received BPaL for RR-TB or rifampicin-intolerant TB, with 97.1% completing treatment and 2.9% experiencing relapse [19]. A second study reported 82.1% favorable treatment outcomes for patients receiving BPaL-based regimens for pre–XDR-TB and MDR-TB [20]. A third reported the programmatic implementation of BPaL for pre–XDR-TB, achieving 100% sputum culture conversion [21].
Countries have now progressed with implementing BPaL-based regimens. Belarus and Uzbekistan implemented them under operational research conditions in February and June 2022, respectively. Both countries were sites for the TB-PRACTECAL trial and early roll-out ensured uninterrupted access in the population that contributed to the trial, providing a unique opportunity to understand real-world regimen performance. In this study we aimed to characterize the treatment effectiveness and safety of BPaL-based regimens for patients with MDR/RR-TB and pre–XDR-TB in these settings.
METHODS
Study Design
This was a prospective study of 2 cohorts of patients with microbiologically confirmed RR-TB initiated on treatment with a 24-week all-oral BPaL-based regimen in Belarus and Uzbekistan from February 2022 through June 2023.
Setting
Belarus is an upper-middle-income country [22] with a high MDR/RR-TB burden [3, 23]. Médecins Sans Frontières (MSF) has worked with the national TB program since 2015 to strengthen drug-resistant (DR)–TB management. Patients from all regions with MDR/RR-TB meeting eligibility criteria were enrolled. Uzbekistan is a low-middle-income country [22] with a high MDR/RR-TB burden [3, 24]. Karakalpakstan is an autonomous republic in northwestern Uzbekistan, and MSF has worked with the Uzbekistan and Karakalpakstan Ministries of Health (MOHs) since 1998 to strengthen DR-TB management. Médecins Sans Frontières supports a centralized regional laboratory in Nukus, Karakalpakstan, allowing for standardized, high-quality data. Patients were enrolled from Karakalpakstan and Tashkent. The study was conducted entirely by national staff, who were also the study investigators and responsible for defining and documenting outcomes and deaths.
Definitions
We used WHO definitions for RR-TB, MDR-TB, pre–XDR-TB, serious AEs (SAEs), and treatment outcomes [25, 26]. To measure effectiveness, the primary outcome was the proportion of patients with a favorable end of treatment outcome, not including recurrences. The primary safety outcome was the proportion of patients with an SAE during treatment or during the 12-month post-treatment follow-up period. The standard definition of an SAE was used: any untoward medical occurrence that may present in a patient during treatment with a pharmaceutical product, but which does not necessarily have a causal relationship with this treatment, which either leads to death, a life-threatening experience, hospitalization, persistent/significant disability, a congenital abnormality, or an otherwise medically important consequence (including known side effects of the drugs used in these regimens such as bone marrow suppression or peripheral neuropathy) [25, 26].
Treatment Regimens
Patients were prescribed 1 or more of the following 24-week all-oral regimens depending on resistance pattern and availability of rapid testing for fluoroquinolone resistance:
BPaLM, if sensitive to fluoroquinolones or if sensitivity was undetermined;
BPaLC, if resistant to levofloxacin and/or moxifloxacin, chosen as it was one of the investigational regimens tested in the TB-PRACTECAL trial undertaken in the same countries [17, 18], and because investigators and clinicians felt a 4-drug regimen was more appropriate than 3-drug BPaL given the likelihood that some patients might have interruptions of linezolid (leaving them with 2 drugs if on BPaL). No patients received a 5-drug regimen, or both moxifloxacin and clofazimine concurrently. If a patient had an SAE requiring discontinuation of 1 drug, no additional drugs were added to their regimen. If a patient permanently discontinued 2 drugs, this was considered as treatment failure in line with WHO definitions [25, 26].
Study Conduct
Treatment outcomes were attributed as the outcome that occurred first during the study period for unfavorable outcomes (lost to follow-up [LTFU], died, treatment failure) or by the completion of the treatment phase for those who were cured and completed treatment (treatment success). After treatment completion, patients returned for follow-up visits at 6 and 12 months, which involved ascertaining AEs and SAEs after treatment completion, including deaths, and conducting sputum smear and culture testing for all patients to ascertain TB recurrence, irrespective of whether they had symptoms.
Inclusion and Exclusion Criteria
Patients aged over 14 years with RR-TB confirmed by conventional drug susceptibility testing (DST) (culture-based) or rapid molecular DST were eligible. Patients not eligible for treatment with a BPaL-based regimen for any of the following conditions were excluded:
Unable to take oral medication
Known resistance to bedaquiline, pretomanid, or linezolid, including when detected at baseline
Prior use anytime in the past of bedaquiline, pretomanid, or linezolid for 1 or more month
Taking medication contraindicated with the regimen
Known allergy to any drugs in the regimen
Had a corrected QT interval calculated by Fridericia's formula (QTcF) of 500 ms or more at baseline that was not corrected with medical management
Had TB meningo-encephalitis, osteoarthritis, osteomyelitis, septic arthritis, or brain abscess (as per WHO guidelines) [1]
Were participating in a clinical trial of any medicinal product
Were on RR-TB treatment for more than 4 weeks and not failing
Objectives
Our primary objective was to estimate treatment effectiveness in terms of a favorable outcome (defined as “cured” or “treatment completed”) and safety (defined as the occurrence of SAEs) of 24-week all-oral MDR/RR-TB treatment regimens in non-trial settings. Our secondary objectives were to estimate the proportion of patients who died on treatment and during follow-up, had treatment failure, were LTFU on treatment, had culture conversion, and had TB recurrence.
Dosing and Treatment Delivery
Dosing was in line with the TB-PRACTECAL trial [17, 18]. Patients received bedaquiline 400 mg once-daily (OD) for 2 weeks followed by 200 mg OD 3 times per week for 22 weeks. Pretomanid was prescribed as 200 mg OD for 24 weeks. Linezolid was prescribed as 600 mg OD for 16 weeks, then 300 mg OD for 8 weeks, or earlier when moderately tolerated (any AE requiring a clinical consultation). Moxifloxacin was prescribed as 400 mg OD and clofazimine as 100 mg OD for 24 weeks. Patients received directly observed treatment (DOT), delivered either in-person by a healthcare provider or online (video-DOT). Patients were hospitalized for treatment initiation in case of sputum smear positivity and subsequently discharged for outpatient treatment once culture conversion was achieved. Patients who required socioeconomic support were provided food parcels and/or reimbursement for transport to travel to the hospital for follow-up visits.
Procedures and Statistical Methods
We collected data on demographics, previous TB, comorbidities, smear, culture, DST, chest X-ray (CXR), treatment regimen and outcome, and AEs. When an AE occurred, the investigator responsible for the patient assessed whether the event was serious and, if it was, then an SAE form was completed and sent to the MSF pharmacovigilance unit within 48 hours. All SAEs were also reported to the relevant regional and national pharmacovigilance authority according to national guidelines. We did not collect data on grade 1 and grade 2 AEs.
Data were collected on standardized paper forms by healthcare staff, and then transferred and managed using REDCap (Research Electronic Data Capture) tools hosted at WHO as part of the ShORRT initiative [27, 28]. Only data relevant to the study were recorded and access was restricted to study investigators and treatment providers. We report descriptive analyses for baseline characteristics, culture conversion, SAEs, and treatment outcomes. We examined the differences in proportions, medians, and means between patients with MDR/RR-TB and pre–XDR-TB. Chi-square tests with Yates correction (Fisher’s exact test when the number is small) and unpaired t tests were conducted. A Kaplan-Meier estimator was used for characterizing time to culture conversion. We conducted a detailed analysis of causes of death to describe the characteristics and attribution of all deaths. All analyses were conducted using R Studio 2024.04.0 and R version 4.3.3 (Posit, Boston, USA).
Laboratory
Sputum smear and GeneXpert/Ultra (Cepheid, Sunnyvale, CA, USA) were performed for all patients at baseline. Molecular tests including MTBDRplus VER 2.0 (Hain Lifescience, Nehren, Germany) and MTBDRsl version 2.0 (Hain Lifescience, Nehren, Germany) were performed where possible in both countries, while Xpert XDR (Cepheid, Sunnyvale, CA, USA) was performed in Uzbekistan. Culture was performed on a BD BACTEC MGIT (Mycobacterial Growth Indicator Tube) SIRE kit with the 960 system (Becton Dickinson, Franklin Lakes, NJ, USA). Phenotypic DST (pDST) was performed for bedaquiline, fluoroquinolones, linezolid, and clofazimine at both sites. Additionally, pDST for pretomanid was performed in Belarus. Annual external quality assessment for both countries was provided by the WHO Supranational TB Reference Laboratory in Gauting, Germany. Sputum was collected monthly during treatment to characterize culture conversion.
Ethical Considerations
This research was approved by the Médecins Sans Frontières Ethics Review Board, the Local Ethics Committee of The Republican Scientific and Practical Centre for Pulmonology and Tuberculosis in Belarus, and the MOH Ethical Committee in Uzbekistan.
RESULTS
We included 677 patients, 440 (65%) from Belarus and 237 (35%) from Uzbekistan (Table 1). A total of 448 (66%) had MDR/RR-TB and 229 (34%) had pre–XDR-TB. Nearly all patients had pulmonary TB with CXR abnormalities and almost half had cavitation. One-third had a positive smear and one-quarter had a history of previous TB. Compared with patients with MDR/RR-TB, those with pre–XDR-TB were more likely to have hepatitis C infection (16.6% vs 8.7%; P = .003) and human immunodeficiency virus (HIV) infection (10.0% vs 2.9%; P < .001). Most of the patients with pre–XDR-TB (85.2%, 195/229) came from Belarus.
Table 1.
Baseline Characteristics of Patients Receiving BPaL-Based Regimens
| Overall (N = 677; % of total) |
MDR/RR (n = 448; % of total) |
Pre-XDR (n = 229; % of total) | P | |
|---|---|---|---|---|
| Geographic distribution | <.001** | |||
| Belarus | 440 (65.0%) | 245 (54.7%) | 195 (85.2%) | |
| Uzbekistan | 237 (35.0%) | 203 (45.3%) | 34 (14.8%) | |
| Age, median (IQR), y | 45 (34, 57) | 46 (34, 59) | 44 (34, 53) | .029 |
| Female sex | 217 (32.1%) | 147 (32.8%) | 70 (30.6%) | .55 |
| BMI, median (IQR), kg/m2 | 20.9 (18.9, 23.2) | 20.9 (18.8, 23.1) | 21.1 (19.2, 23.3) | .54 |
| Underweight (BMI <18.5 kg/m2) | 139 (20.5%) | 96 (21.4%) | 43 (18.8%) | .42 |
| Confirmed hepatitis B | 14 (2.1%) | 9 (2.0%) | 5 (2.2%) | .008a |
| Confirmed hepatitis C | 77 (11.4%) | 39 (8.7%) | 38 (16.6%) | <.001** |
| Confirmed HIV | 36 (5.3%) | 13 (2.9%) | 23 (10.0%) | <.001** |
| Confirmed diabetes mellitus | 60 (8.9%) | 48 (10.7%) | 12 (5.2%) | .025* |
| Coronary heart disease (Belarus only, n = 440) | 73 (16.6%) | 47 (19.2%) | 26 (13.3%) | .10 |
| Chronic kidney disease (Belarus only, n = 440) | 4 (0.9%) | 2 (0.8%) | 2 (1.0%) | >.99a |
| Self-reported alcohol use | 153 (22.6%) | 78 (17.4%) | 75 (32.8%) | <.001** |
| Previously treated | 174 (25.7%) | 106 (23.7%) | 68 (29.7%) | .089 |
| Pulmonary disease | 666 (98.4%) | 439 (98.0%) | 227 (99.1%) | .35a |
| Chest X-ray abnormal | 667 (99.0%) | 440 (98.9%) | 227 (99.1%) | >.99a |
| Cavitary lesion(s) | 319 (47.8%) | 216 (49.1%) | 103 (45.4%) | .36 |
| Sputum smear positive | 226 (33.4%) | 150 (33.5%) | 76 (33.2%) | .94 |
| Sputum Xpertb RR detected (n = 612) | 600 (98.0%) | 393 (97.0%) | 207 (100%) | .031 |
| Sputum culture positive | 569 (85.8%) | 347 (79.4%) | 222 (98.2%) | <.001** |
| Initially treated with BPaLM | 446 (65.9%) | 440 (98.2%) | 6 (2.6%) | <.001** |
N = 677. *P ≤ .05; **P ≤ .01.
Abbreviations: BMI, body mass index; BPaL, bedaquiline, pretomanid, and linezolid; BPaLM, bedaquiline, pretomanid, linezolid, and moxifloxacin; HIV, human immunodeficiency virus; IQR, interquartile range; MDR/RR, multidrug- or rifampicin-resistant; Pre-XDR, pre–extensively drug-resistant; RR, rifampicin-resistant.
aFisher's exact test.
bCepheid (Sunnyvale, CA, USA).
Effectiveness
A total of 85.8% of patients were culture positive at baseline (569/677), including 79.4% (347/448) and 98.2% (222/229) for MDR/RR-TB and pre–XDR-TB, respectively (Table 1). Nineteen of 569 (3.3%) of these patients terminated treatment before achieving culture conversion, either because they died, were LTFU, or had treatment failure for any reason. Culture conversion rates were 69.6% (396/569) at 30 days, 92.6% (527/569) at 60 days, and 96.5% (549/569) at 90 days (Figure 1). The median time to culture conversion was 27 days (interquartile range [IQR]: 26, 31 days). Rates were similar for patients with MDR/RR-TB and pre–XDR-TB.
Figure 1.
Culture conversion Kaplan–Meier curve for patients receiving BPaL-based regimens who had a positive baseline culture (n = 569). Abbreviations: BPaL, bedaquiline, pretomanid, and linezolid; MDR/RR, multidrug- or rifampicin-resistant; Pre-XDR, pre–extensively drug-resistant.
A total of 93.6% (634/677) of patients had a successful treatment outcome, 95.3% (427/448) for MDR/RR-TB and 90.4% (207/229) for pre–XDR-TB (Table 2). A total of 85.5% and 83.0% of patients with MDR/RR-TB and pre–XDR-TB were cured, respectively. Thirty-six of 677 patients (5.3%) had an unfavorable treatment outcome, 3.8% (17/449) for MDR/RR-TB and 8.3% (19/229) for pre–XDR-TB. We recorded 11 deaths during treatment (1.6%), 20 LTFU cases (3.0%), and 5 treatment failures (0.7%).
Table 2.
Treatment Outcomes Among Patients Receiving BPaL-Based Regimens
| Overall (n = 677; % of total) | MDR/RR (n = 448; % of total) | Pre-XDR (n = 229; % of total) | P | |
|---|---|---|---|---|
| Overall treatment success | 634 (93.6%) | 427 (95.3%) | 207 (90.4%) | .061a |
| Cured | 573 (84.6%) | 383 (85.5%) | 190 (83.0%) | |
| Treatment completed | 61 (9.0%) | 44 (9.8%) | 17 (7.4%) | |
| Death from any cause during treatment | 11 (1.6%) | 7 (1.6%) | 4 (1.7%) | |
| Lost to follow-up | 20 (3.0%) | 9 (2.0%) | 11 (4.8%) | |
| Treatment failed | 5 (0.7%) | 1 (0.2%) | 4 (1.7%) | |
| Due to lack of culture conversion after 16 wk of treatment | 2 (0.3%) | 0 (0%) | 2 (0.9%) | |
| Due to evidence of additional acquired resistance to drugs in the regimen | 1 (0.1%) | 0 (0%) | 1 (0.4%) | |
| Due to permanent change of ≥2 anti-TB drugs in the regimen because of adverse drug reactions | 2 (0.3%) | 1 (0.2%) | 1 (0.4%) | |
| Not evaluated | 5 (0.7%) | 2 (0.4%) | 3 (1.3%) | |
| Withdrew consent | 2 (0.3%) | 2 (0.4%) | 0 (0%) |
N = 677.
Abbreviations: BPaL, bedaquiline, pretomanid, and linezolid; MDR/RR, multidrug- or rifampicin-resistant; Pre-XDR, pre–extensively drug-resistant; TB, tuberculosis.
aFisher's exact test comparing distribution of outcomes between MDR/RR-TB and pre–XDR-TB.
Safety
Sixty-nine of 677 (10.2%) of patients experienced an SAE during treatment or follow-up (Table 3). Serious AEs were similarly distributed between patients with MDR/RR-TB and pre–XDR-TB (10.3% vs 10.0%; P = .9). Increased liver enzymes were the most reported SAE, with 13 patients (18.8%) having grade 3 or higher increases. Tuberculosis treatment was temporarily interrupted in 34 of SAE cases (49.3% of SAEs) and withdrawn 8 times (11.6%).
Table 3.
Safety Profile Among Patients Receiving BPaL-Based Regimens
| Overall (n = 677; % of total) | MDR/RR (n = 448; % of total) | Pre-XDR (n = 229; % of total) | P | |
|---|---|---|---|---|
| Any SAEs during treatment or 12-month post-treatment follow-up period | 69 (10.2%) | 46 (10.3%) | 23 (10.0%) | .9 |
| Type of SAE | .33a | |||
| Deathb | 24 (3.5%) | 14 (3.1%) | 10 (4.4%) | |
| Life-threatening experience | 11 (1.6%) | 6 (1.3%) | 5 (2.2%) | |
| Hospitalization or prolongation of hospitalization | 17 (2.5%) | 12 (2.7%) | 5 (2.2%) | |
| Other medically important event | 17 (2.5%) | 14 (3.1%) | 3 (1.3%) | |
| Overall (n = 69; % of total) | MDR/RR (n = 46; % of total) | Pre-XDR (n = 23, % of total) | ||
| Diagnosis (if known) or signs/symptoms | .23a | |||
| Increased liver enzymes | 13 (18.8%) | 9 (19.6%) | 4 (17.4%) | |
| Gastrointestinal disorders (nausea/vomiting/diarrhea) | 7 (10.3%) | 7 (15.2%) | 0 (0%) | |
| Allergic reaction/skin rash | 5 (7.2%) | 3 (6.5%) | 2 (8.7%) | |
| Anaemia/low absolute neutrophil count | 4 (5.8%) | 3 (6.5%) | 1 (4.6%) | |
| Acute kidney injury | 4 (5.8%) | 2 (4.3%) | 2 (8.7%) | |
| Cardiac rhythm/prolonged QTcF interval | 4 (5.9%) | 4 (8.7%) | 0 (0.0%) | |
| Other | 32 (46.4%) | 18 (39.1%) | 14 (60.9%) | |
| Clinician action taken regarding study treatment | .46a | |||
| Dose not changed | 6 (8.7%) | 3 (6.5%) | 3 (13.0%) | |
| Drug interrupted | 34 (49.3%) | 25 (54.3%) | 9 (39.1%) | |
| Drug withdrawn | 8 (11.6%) | 6 (13.0%) | 2 (8.7%) | |
| Not applicable | 21 (30.4%) | 12 (26.1%) | 9 (39.1%) | |
| SAE attribution to 1 or more anti-TB drugsc | .87a | |||
| Definite | 2 (2.9%) | 2 (4.3%) | 0 (0%) | |
| Probable | 21 (30.4%) | 15 (32.6%) | 6 (26.1%) | |
| Possible | 13 (18.8%) | 8 (17.4%) | 5 (21.7%) | |
| Unlikely | 2 (2.9%) | 1 (2.2%) | 1 (4.3%) | |
| Not related | 31 (44.9%) | 20 (43.5%) | 11 (47.8%) | |
| Final outcome of the SAE | .53a | |||
| Recovered | 39 (56.5%) | 26 (56.5%) | 13 (56.5%) | |
| Recovered with sequelae | 1 (1.4%) | 1 (2.2%) | 0 (0%) | |
| Recovering | 4 (5.8%) | 4 (8.7%) | 0 (0%) | |
| Not recovered (ie, ongoing or worsening) | 1 (1.4%) | 1 (2.2%) | 0 (0%) | |
| Fatalb | 24 (34.8%) | 14 (30.4%) | 10 (43.5%) | |
N = 677.
Abbreviations: BPaL, bedaquiline, pretomanid, and linezolid; MDR/RR, multidrug- or rifampicin-resistant; Pre-XDR, pre–extensively drug-resistant; QTcF, corrected QT interval calculated by Fridericia's formula; SAE, serious adverse event; TB, tuberculosis.
aFisher's exact test.
bDeath as a safety outcome includes all deaths from any cause on treatment and during the post-treatment safety follow-up phase.
cCausality assessment method in the study is to only rule out a reasonable causal relationship with the treatment when plausible alternative causes for the adverse events are identified or strongly suspected.
Twenty-four SAEs (3.5%) resulted in deaths during treatment or follow-up, including 11 deaths reported as treatment outcomes and 13 deaths occurring after treatment. Twenty of 24 (83.3%) of deaths were assessed to be not related to TB or TB treatment, and 25% (6/24) were in people who had advanced-stage cancer (Supplementary Appendix).
At the time of writing, of the 634 patients who had a successful treatment outcome, 470 (74.1%) had reached the point where they were eligible for a 12-month follow-up visit. Of these, 81.5% (383/470) completed the follow-up visit including sputum collection. Of patients who had been successfully treated and completed follow-up, 0.5% (2/383) had a TB recurrence. Both patients had been treated for pre–XDR-TB.
DISCUSSION
To our knowledge, this is the largest cohort study evaluating treatment outcomes in people with MDR/RR-TB and pre–XDR-TB receiving 24-week all-oral BPaL-based regimens in non-trial settings. We recorded high treatment success rates of 95.3% for patients with MDR/RR-TB using BPaLM and 90.4% for patients with pre–XDR-TB using BPaLC. These results are comparable to the TB-PRACTECAL trial, which reported treatment success rates of 96% for patients with MDR/RR-TB using BPaLM and 90% for patients with pre–XDR-TB using BPaLC [17, 18]. Overall, our results contribute important real-world evidence on the effectiveness of BPaL-based regimens, lending support to the new WHO guidance recommending their global implementation.
Our treatment success rates are also comparable to Nix-TB (89% using BPaL for 26 weeks in patients with XDR-TB or MDR-TB not responding to treatment) [14], ZeNix (84%–93% using BPaL with differing linezolid dosages and durations for 26 weeks for patients with XDR-TB, pre–XDR-TB, and MDR-TB not responding to treatment) [15], the endTB phase III trial evaluating five 9-month all-oral treatments for RR-TB [29], and a recent retrospective study in South Africa (75% treatment success in patients with RR-TB treated for 9 to 12 months with an all-oral bedaquiline-based regimen including 2 months of linezolid) [30]. Our treatment success rates are also comparable to studies in the United States [19], Thailand [20], and Georgia [21] conducted in non-trial settings.
Our 5.3% rate of unfavorable outcomes compares to 7.0% for TB-PRACTECAL, 7.4% for Nix-TB, 15.1% for endTB, and 10.7% for ZeNix. Death occurred during treatment or during the 12-month follow-up in 3.5% of our cohort compared to 0.9% for TB PRACTECAL, 0.6% for ZeNix, 2.1% for endTB, and 6.4% for Nix-TB. The higher rates for Nix-TB may relate to higher cavitation and HIV infection rates, and because patients participating in Nix-TB had predominantly pre–XDR-TB or treatment-intolerant MDR-TB. Importantly, only 4 deaths in our cohort were thought to be possibly attributable to TB or TB treatment. Nevertheless, the high rate of mortality after apparent cure highlights the need for more intensive and prolonged post-treatment follow-up. We had 3.0% LTFU during treatment compared to 4.0% in TB-PRACTECAL, 1.1% in ZeNix, 3.3% in endTB, and 0.9% in Nix-TB. The low proportion of LTFU is a strength of our study and is likely to be due to shorter treatment duration combined with the socioeconomic support provided to patients. Our 90-day culture conversion rate of 96.5% is comparable to the 12-week rates of 88.5% for the TB-PRACTECAL BPaLM regimen and 87.1% for Nix-TB. Importantly, 70% of patients had culture conversion after 30 days of treatment, highlighting the rapid potency of BPaL-based regimens.
Serious AEs were recorded in 10.2% of patients. In Nix-TB, 17.4% experienced an SAE. TB-PRACTECAL reported SAEs in 19.4% of BPaLM and 31.9% of BPaLC patients. endTB recorded SAEs in 15.2% of patients. The lower rate of SAEs in our patients may be attributed to less intensive side-effect monitoring than for clinical trial settings and variations in study populations, such as differences in the proportion of previously treated patients or the presence of comorbidities. Our study included a significant number of patients with advanced-stage cancer and other comorbidities, many of whom unfortunately died during treatment. It is noteworthy that, in rigorously designed trials, patients with such conditions are typically excluded to minimize risk and ensure more homogeneous study populations. Despite the inclusion of these patients, the treatment outcomes and rates of SAEs reported in our study are comparable to those observed in controlled trials, suggesting that the regimens maintain their efficacy and safety profile even in a more heterogeneous and unwell population.
A strength of our study is the completeness of data, which were collected in a non-trial operational setting. A limitation of this approach is that we transcribed data from records completed by frontline staff without independent verification, meaning that positive treatment outcomes may have been overreported and AEs or negative experiences may have been less likely to be reported. We were able to ascertain treatment outcomes for nearly all participants, but 5 patients were not evaluated and 2 withdrew. A further strength is that we conducted 6- and 12-month follow-up for people with treatment success, including repeat sputum collection, which enabled us to ascertain deaths after treatment and recurrence. However, we have incomplete post-treatment follow-up data as only approximately 75% of patients were eligible for this follow-up at the time of writing, limiting our ability to ascertain recurrences. When follow-up is complete, further work will characterize the clinical and laboratory characteristics of people who had recurrence.
Conclusions
The treatment of patients with MDR/RR-TB and pre–XDR-TB using all-oral, 24-week BPaL-based regimens was safe and highly effective in non-trial settings in 2 high-MDR/RR-TB–burden countries. These treatment regimens should be considered for widespread implementation to improve the health and well-being of people with MDR/RR-TB. Given our results, further research is urgently needed to evaluate the performance of BPaL-based regimens in other key populations, including children and people with severe forms of extrapulmonary TB.
Supplementary Material
Contributor Information
Animesh Sinha, Médecins Sans Frontières, London, United Kingdom.
Roland Klebe, Médecins Sans Frontières, Berlin, Germany.
Michael L Rekart, Médecins Sans Frontières, Tashkent, Uzbekistan.
Jose Luis Alvarez, Médecins Sans Frontières, London, United Kingdom.
Alena Skrahina, Republican Scientific and Practical Center for Pulmonology and Tuberculosis, Minsk, Belarus.
Natalia Yatskevich, Republican Scientific and Practical Center for Pulmonology and Tuberculosis, Minsk, Belarus.
Varvara Solodovnikova, Republican Scientific and Practical Center for Pulmonology and Tuberculosis, Minsk, Belarus.
Dzmitry Viatushka, Republican Scientific and Practical Center for Pulmonology and Tuberculosis, Minsk, Belarus.
Nargiza Parpieva, Republican Specialized Scientific and Practical Medical Center of Tuberculosis and Pulmonology, Tashkent, Uzbekistan.
Khasan Safaev, Republican Specialized Scientific and Practical Medical Center of Tuberculosis and Pulmonology, Tashkent, Uzbekistan.
Irina Liverko, Republican Specialized Scientific and Practical Medical Center of Tuberculosis and Pulmonology, Tashkent, Uzbekistan.
Zinaida Tigay, Republican Center of Tuberculosis and Pulmonology, Nukus, Uzbekistan.
Soe Moe, Republican Center of Tuberculosis and Pulmonology, Nukus, Uzbekistan; Médecins Sans Frontières, Nukus, Uzbekistan.
Aleksandr Khristusev, Republican Center of Tuberculosis and Pulmonology, Nukus, Uzbekistan; Médecins Sans Frontières, Nukus, Uzbekistan.
Sholpan Allamuratova, Republican Center of Tuberculosis and Pulmonology, Nukus, Uzbekistan; Médecins Sans Frontières, Nukus, Uzbekistan.
Sanjar Mirzabaev, Médecins Sans Frontières, Tashkent, Uzbekistan.
Muzaffar Achilov, Médecins Sans Frontières, Tashkent, Uzbekistan.
Nazgul Samieva, Médecins Sans Frontières, Tashkent, Uzbekistan.
Nathalie Lachenal, Médecins Sans Frontières, Geneva, Switzerland.
Corinne Simone Merle, Special Programme of Research and Training in Tropical Diseases (TDR), World Health Organization, Geneva, Switzerland.
Fatimata Bintou Sall, Special Programme of Research and Training in Tropical Diseases (TDR), World Health Organization, Geneva, Switzerland.
Camilo Gomez Restrepo, Médecins Sans Frontières, Tashkent, Uzbekistan.
Cecilio Tan, Médecins Sans Frontières, Minsk, Belarus.
Norman Sitali, Médecins Sans Frontières, Berlin, Germany.
Matthew J Saunders, Médecins Sans Frontières, London, United Kingdom; Department of Infection and Immunity, City St. George's University of London, School of Health and Medical Sciences, London, UK.
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
Notes
Acknowledgments. The authors acknowledge the people who participated in this study and the staff who have worked in the program over the duration that the data were collected.
Disclaimer. C. S. M. and F. B. S. are staff members of the World Health Organization (WHO); the authors alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions, policy, or views of the WHO.
Financial support This work was supported by Medecins Sans Frontieres (part of routine project support) and The Global Fund (grant number BLR-C-RSPCMT 2684).
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