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68 result(s)
Journal Article > ResearchFull Text

The effectiveness and safety of bedaquiline, pretomanid, and linezolid (BPaL)-based regimens for rifampicin-resistant tuberculosis in non-trial settings - A prospective cohort study in Belarus and Uzbekistan

Clin Infect Dis. 18 February 2025; Online ahead of print; DOI:10.1093/cid/ciaf035
Sinha A, Klebe R, Rekart ML, Alvarez JL, Skrahina A,  et al.
Clin Infect Dis. 18 February 2025; Online ahead of print; DOI:10.1093/cid/ciaf035

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.

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Journal Article > ResearchFull Text

24-week, all-oral regimens for pulmonary rifampicin-resistant tuberculosis in TB-PRACTECAL trial sites: an economic evaluation

Lancet Global Health. 1 February 2025; Volume 13 (Issue 2); e355-e363.; DOI:10.1016/S2214-109X(24)00467-4
Sweeney S, Laurence YV, Berry C, Singh MP, Dodd M,  et al.
Lancet Global Health. 1 February 2025; Volume 13 (Issue 2); e355-e363.; DOI:10.1016/S2214-109X(24)00467-4

BACKGROUND

New 6-month rifampicin-resistant tuberculosis treatment regimens containing bedaquiline, pretomanid, and linezolid (BPaL) with or without moxifloxacin or clofazimine, could improve treatment efficacy, safety, and tolerability, and free up resources within the health system. Following a change to WHO rifampicin-resistant tuberculosis treatment guidelines, countries are facing difficult decisions about when and how to incorporate new drug regimens into national guidelines. We aimed to assess the probability of BPaL-based regimens being cost-saving using data collected in the TB-PRACTECAL trial.


METHODS

This economic evaluation using a cost-utility analysis was embedded in five TB-PRACTECAL trial sites in Belarus, Uzbekistan, and South Africa. Between Nov 19, 2020, and Sept 27, 2022, we collected detailed primary unit cost data in six hospitals and four ambulatory health facilities and collected data on patient-incurred costs from 73 trial participants. The primary efficacy endpoint of the main trial, a composite of unfavourable outcomes (death, disease recurrence, treatment failure, early discontinuation of therapy, withdrawal, or loss to follow-up) and clinically important safety outcomes by 72 weeks of follow-up were incorporated into the analysis. Societal perspective cost data and effect outcome data were input into a Markov model to estimate the cost per disability-adjusted life-year (DALY) averted by BPaL-based regimens compared with the standard of care over a 20-year time horizon. We conducted a range of univariate and probabilistic sensitivity analyses to test our findings.


FINDINGS

BPaL-based regimens averted a mean of 1·28 DALYs and saved a mean of US$14 868 (SD 291) per person from the provider perspective compared with standard-of-care regimens over 20 years. Patient-incurred costs were reduced by a mean of $172 (SD 0·84) in BPaL-based regimen groups compared with standard of care. The main cost drivers for both providers and patients were inpatient bed-days; the duration of the inpatient period varied across countries. Varying a range of model parameters affected the degree of cost savings but did not change the finding that BPaL-based regimens are cost-saving compared with standard of care.


INTERPRETATION

This trial-based evidence adds to consistent indications from modelling studies that BPaL-based regimens are cost-saving for both the patient and health system. Urgent implementation of BPaL-based regimens in countries with a high burden of tuberculosis could improve treatment of rifampicin-resistant tuberculosis, reduce pill burden, and free up desperately needed resources within the health system.

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Journal Article > ResearchFull Text

Second-line drug-resistant TB and associated risk factors in Karakalpakstan, Uzbekistan

IJTLD OPEN. 1 September 2024; Volume 1 (Issue 9); 391-397.; DOI:10.5588/ijtldopen.24.0351
Moe S, Azamat I, Allamuratova S, Oluya M, Khristusev A,  et al.
IJTLD OPEN. 1 September 2024; Volume 1 (Issue 9); 391-397.; DOI:10.5588/ijtldopen.24.0351

BACKGROUND

Drug-resistant TB (DR-TB) remains a major public health threat. In 2022, Uzbekistan reported 2,117 cases of DR-TB, with 69% tested for fluoroquinolone resistance. Limited information is available on the prevalence of resistance to bedaquiline, linezolid, and fluoroquinolone, which are key components of the all-oral treatment regimen for rifampicin-resistant TB in Uzbekistan.


METHODS

A retrospective study was conducted using extensive programmatic data from 2019 to 2023 in Uzbekistan. We assessed second-line drug-resistant TB (SLDR-TB) rates using phenotypic drug susceptibility testing (pDST). Demographic and clinical characteristics associated with SLDR-TB were analysed using multivariable logistic regression models based on the Allen-Cady approach.


RESULTS 

In total, 2,405 patients with TB who had undergone pDST were included (median age 40 years, 47% female). The overall SLDR-TB resistance rate was 24% (95% CI 22-26). Prevalence of resistance to bedaquiline, linezolid, moxifloxacin, levofloxacin, and amikacin were respectively 3.1%, 0.8%, 15%, 13%, and 12%. Risk factors for SLDR-TB were resistance to rifampicin and/or isoniazid, exposure to clofazimine, retreatment status, contact with drug-susceptible TB case or DR-TB case, and diabetes.


CONCLUSIONS

The high prevalence of SLDR-TB is of major concern, emphasising the need for baseline pDST in RR-TB treatment. Identified risk factors can aid early detection of at-risk individuals and inform clinical practice.

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Journal Article > ResearchFull Text

A 10-year review of isoniazid-resistant TB management in Uzbekistan 2009-2020

IJTLD OPEN. 1 July 2024; Volume 1 (Issue 7); 285-291.; DOI:10.5588/ijtldopen.23.0533
Rekart M, Thit P, Oluya M, Moe S, Hasan T,  et al.
IJTLD OPEN. 1 July 2024; Volume 1 (Issue 7); 285-291.; DOI:10.5588/ijtldopen.23.0533

Background

Isoniazid (INH, H) resistance is the most common drug-resistant TB pattern, with treatment success rates lower than those in drug-susceptible TB. The WHO recommends a 6-month regimen of rifampicin (RIF, R), ethambutol (EMB, E), pyrazinamide (PZA, Z), and levofloxacin (Lfx) (6REZLfx) for INH-resistant, RIF-susceptible TB (HRRS-TB). Uzbekistan has a high burden of TB (62/100,000 population) and multidrug-resistant TB (12/100,000 population).


Methods

We conducted a retrospective, descriptive study of microbiologically confirmed HRRS-TB using routinely collected programmatic data from 2009 to 2020.


Results

We included 854 HRRS-TB cases. Treatment success was 80.2% overall. For REZLfx, the treatment success rate was 92.0% over a short treatment duration, with no amplifications to RIF or second-line anti-TB drug resistance. We documented 46 regimens with REZLfx plus linezolid (success 87.0%) and 539 regimens using kanamycin or capreomycin (success 76.6%). We identified 37 treatment failures (4.3%), 30 deaths (3.5%), 25 resistance amplifications (2.9%), including eight to RIF (0.9%), and 99 lost to follow-up (LTFU) cases (11.6%). Unsuccessful outcomes were more common with older age, diabetes, chest X-ray cavities, smear positivity, smear-positive persistence, and male sex. LTFU was more common with injection-containing regimens.


Conclusions

REZLfx is a safe and effective first-line treatment for INH-resistant, RIF-susceptible TB. Treatment success was lower and LTFU was higher for injection-containing regimens.

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Journal Article > ResearchFull Text

How much should we still worry about QTc prolongation in rifampicin-resistant tuberculosis? ECG findings from TB-PRACTECAL clinical trial

Antimicrob Agents Chemother. 6 June 2024; Volume 68 (Issue 7); e0053624.; DOI:10.1128/aac.00536-24
Motta I, Cusinato M, Ludman AJ, Lachenal N, Dodd M,  et al.
Antimicrob Agents Chemother. 6 June 2024; Volume 68 (Issue 7); e0053624.; DOI:10.1128/aac.00536-24
Regimens for the treatment of rifampicin-resistant tuberculosis currently rely on the use of QT-prolonging agents. Using data from the randomized controlled trial, TB-PRACTECAL, we investigated differences in QTcF among participants in the three interventional arms: BPaL (bedaquiline, pretomanid, and linezolid), BPaLC (BPaL with clofazimine), and BPaLM (BPaL with moxifloxacin). Additionally, we assessed whether age, body mass index, and country were causally associated with QTcF prolongation. The trial included participants from South Africa, Uzbekistan, and Belarus. A post hoc analysis of electrocardiogram data was undertaken. Random effects regression was used to model QTcF longitudinally over 24 weeks and causal frameworks guided the analysis of non-randomized independent variables. 328 participants were included in BPaL-based arms. The longitudinal analysis of investigational arms showed an initial QTcF steep increase in the first week. QTcF trajectories between weeks 2 and 24 differed slightly by regimen, with highest mean peak for BPaLC (QTcF 446.5 ms). Overall, there were 397 QTcF >450 ms (of 3,744) and only one QTcF >500 ms. The odds of QTcF >450 ms among participants in any investigational arm, was 8.33 times higher in Uzbekistan compared to Belarus (95% confidence interval: 3.25–21.33). No effect on QTcF prolongation was found for baseline age or body mass index (BMI). Clinically significant QTc prolongation was rare in this cohort of closely monitored participants. Across BPaL-based regimens, BPaLC showed a slightly longer and sustained effect on QTcF prolongation, but the differences (both in magnitude of change and trajectory over time) were clinically unimportant. The disparity in the risk of QTc prolongation across countries would be an important factor to further investigate when evaluating monitoring strategies.More
Journal Article > ReviewFull Text

The safety and tolerability of linezolid in novel short-course regimens containing bedaquiline, pretomanid, and linezolid to treat rifampicin-resistant tuberculosis: An individual patient data meta-analysis

Clin Infect Dis. 20 March 2024; Volume 78 (Issue 3); 730-741.; DOI:10.1093/cid/ciad653
Hasan T, Medcalf E, Nyang'wa BT, Egizi E, Berry C,  et al.
Clin Infect Dis. 20 March 2024; Volume 78 (Issue 3); 730-741.; DOI:10.1093/cid/ciad653
BACKGROUND
Effectiveness, safety, tolerability, and adherence are critical considerations in shifting to shorter tuberculosis (TB) regimens. Novel 6-month oral regimens that include bedaquiline (B), pretomanid (Pa), and linezolid (L), with or without a fourth drug, have been shown to be as or more effective than the established longer regimens for the treatment of multidrug-resistant/rifampicin-resistant TB (MDR/RR-TB). We aimed to evaluate the safety and tolerability of linezolid in BPaL-containing regimens for the treatment of MDR/RR-TB among recently completed clinical trials.

METHODS
A review and meta-analysis was undertaken including published and unpublished data from clinical trials, conducted between 2010 and 2021, that evaluated regimens containing BPaL for the treatment of MDR/RR-TB. Individual patient data were obtained. For each BPaL-containing regimen, we evaluated the frequency and severity of treatment-related adverse events. The risk difference of adverse events for each regimen was calculated, in comparison to patients assigned to receiving the lowest cumulative exposure of linezolid.

RESULTS
Data from 3 clinical trials investigating 8 unique BPaL-containing regimens were included, comprising a total of 591 participants. Adverse events were more frequent in groups randomized to a higher cumulative linezolid dose. Among patients who were randomized to a daily dose of 1200 mg linezolid, 68 of 195 (35%) experienced a grade 3–4 adverse event versus 89 of 396 (22%) patients receiving BPaL-containing regimens containing 600 mg linezolid.

CONCLUSIONS
Regimens containing BPaL were relatively well tolerated when they included a daily linezolid dose of 600 mg. These novel regimens promise to improve the tolerability of treatment for MDR/RR-TB.
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Journal Article > ResearchFull Text

Short oral regimens for pulmonary rifampicin-resistant tuberculosis (TB-PRACTECAL): an open-label, randomised, controlled, phase 2B-3, multi-arm, multicentre, non-inferiority trial

Lancet Respir Med. 1 February 2024; Volume 12 (Issue 2); 117-128.; DOI:10.1016/S2213-2600(23)00389-2
Nyang'wa BT, Berry C, Kazounis E, Motta I, Parpieva N,  et al.
Lancet Respir Med. 1 February 2024; Volume 12 (Issue 2); 117-128.; DOI:10.1016/S2213-2600(23)00389-2
BACKGROUND
Around 500,000 people worldwide develop rifampicin-resistant tuberculosis each year. The proportion of successful treatment outcomes remains low and new treatments are needed. Following an interim analysis, we report the final safety and efficacy outcomes of the TB-PRACTECAL trial, evaluating the safety and efficacy of oral regimens for the treatment of rifampicin-resistant tuberculosis.

METHODS
This open-label, randomised, controlled, multi-arm, multicentre, non-inferiority trial was conducted at seven hospital and community sites in Uzbekistan, Belarus, and South Africa, and enrolled participants aged 15 years and older with pulmonary rifampicin-resistant tuberculosis. Participants were randomly assigned, in a 1:1:1:1 ratio using variable block randomisation and stratified by trial site, to receive 36-80 week standard care; 24-week oral bedaquiline, pretomanid, and linezolid (BPaL); BPaL plus clofazimine (BPaLC); or BPaL plus moxifloxacin (BPaLM) in stage one of the trial, and in a 1:1 ratio to receive standard care or BPaLM in stage two of the trial, the results of which are described here. Laboratory staff and trial sponsors were masked to group assignment and outcomes were assessed by unmasked investigators. The primary outcome was the percentage of participants with a composite unfavourable outcome (treatment failure, death, treatment discontinuation, disease recurrence, or loss to follow-up) at 72 weeks after randomisation in the modified intention-to-treat population (all participants with rifampicin-resistant disease who received at least one dose of study medication) and the per-protocol population (a subset of the modified intention-to-treat population excluding participants who did not complete a protocol-adherent course of treatment (other than because of treatment failure or death) and those who discontinued treatment early because they violated at least one of the inclusion or exclusion criteria). Safety was measured in the safety population. The non-inferiority margin was 12%. This trial is registered with ClinicalTrials.gov, NCT02589782, and is complete.

FINDINGS
Between Jan 16, 2017, and March 18, 2021, 680 patients were screened for eligibility, of whom 552 were enrolled and randomly assigned (152 to the standard care group, 151 to the BPaLM group, 126 to the BPaLC group, and 123 to the BPaL group). The standard care and BPaLM groups proceeded to stage two and are reported here, post-hoc analyses of the BPaLC and BPaL groups are also reported. 151 participants in the BPaLM group and 151 in the standard care group were included in the safety population, with 138 in the BPaLM group and 137 in the standard care group in the modified intention-to-treat population. In the modified intention-to-treat population, unfavourable outcomes were reported in 16 (12%) of 137 participants for whom outcome was assessable in the BPaLM group and 56 (41%) of 137 participants in the standard care group (risk difference -29·2 percentage points [96·6% CI -39·8 to -18·6]; non-inferiority and superiority p<0·0001). 34 (23%) of 151 participants receiving BPaLM had adverse events of grade 3 or higher or serious adverse events, compared with 72 (48%) of 151 participants receiving standard care (risk difference -25·2 percentage points [96·6% CI -36·4 to -13·9]). Five deaths were reported in the standard care group by week 72, of which one (COVID-19 pneumonia) was unrelated to treatment and four (acute pancreatitis, suicide, sudden death, and sudden cardiac death) were judged to be treatment-related.

INTERPRETATION
The 24-week, all-oral BPaLM regimen is safe and efficacious for the treatment of pulmonary rifampicin-resistant tuberculosis, and was added to the WHO guidance for treatment of this condition in 2022. These findings will be key to BPaLM becoming the preferred regimen for adolescents and adults with pulmonary rifampicin-resistant tuberculosis.
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Conference Material > Poster

ECG findings in BPaL-based TB treatment regimens: the geographical effect on QT prolongation

Motta I, Cusinato M, Ludman A, Abdrasuliev T, Butabekov I,  et al.
MSF Scientific Day International 2023. 7 June 2023; DOI:10.57740/vz2n-4971
Conference Material > Slide Presentation

Patient-reported experiences and quality of life outcomes in the TB-PRACTECAL clinical trial (PRACTECAL-PRO): a mixed-methods, multi-site study

Stringer B, Lowton K, Cusinato M, Fielding K, Liverko I,  et al.
MSF Scientific Day International 2023. 7 June 2023; DOI:10.57740/by3w-4h53
Conference Material > Video

Patient-reported experiences and quality of life outcomes in the TB-PRACTECAL clinical trial (PRACTECAL-PRO): a mixed-methods, multi-site study

Stringer B
MSF Scientific Day International 2023. 7 June 2023; DOI:10.57740/gpb9-ds36