Results from breakthrough trials, including the first-ever controlled trial designed exclusively to inform treatment of pre-extensively drug-resistant TB (XDR-TB) and a trial into the safe use of bedaquiline in infants, children and adolescents presented at The Union World Conference on Lung Health
- Breakthrough research into bedaquiline, delamanid, clofazimine, and linezolid (BDCL) reveals promising, shorter, tailored alternative to longer, WHO-recommended regimens for people with pre-extensively drug-resistant tuberculosis (pre-XDR-TB)
- New findings indicate a high degree of safety and tolerance of bedaquiline in children
- Multinational study reveals the need for optimised drug susceptibility testing methods and expanding access to new TB compounds
Bali, Indonesia; November 13, 2024: Breakthrough research presented at The Union World Conference on Lung Health has revealed crucial insights and experimental new strategies for preventing extensively drug-resistant TB (XDR TB).
The full results of the NGO-led endTB consortium endTB-Q trial, the first-ever randomised and internally-controlled trial designed exclusively to inform treatment of pre-XDR TB – a very hard-to-treat form of TB - revealed an experimental new strategy which could offer a shorter alternative to the current WHO-recommended regimens.
Results from endTB-Q showed high rates of favourable outcomes overall in the shorter treatment strategy, although slightly lower to those in the control arm; with 87% of participants undergoing the shorter, experimental strategy, compared to 89% in the control.
BCDL started at six months – and extended to nine months in case of delayed treatment response – achieved excellent results in people with non-severe TB disease at the start of treatment (93% cure).
However, in people with severe TB disease, BCDL for nine months was not sufficient to prevent relapse compared to the long regimen.
Lorenzo Guglielmetti, MD, PhD, Médecins Sans Frontières Director for the endTB project and Co-Principal Investigator of the trial said: “Our trial innovated in several important ways. Since we know that treatment for TB is not ‘one size fits all’, we tested a strategy that tailored treatment duration to disease severity and treatment response based on simple criteria.
“Emerging evidence highlights that the BCDL regimen may be well suited for people with non-severe TB disease but riskier for those with severe disease.”
New data from a pivotal trial undertaken by the NIH-funded IMPAACT network including experts from Stellenbosch University on the pharmacokinetics and safety of the antibiotic bedaquiline in infants, children and adolescents with drug-resistant TB was also presented, indicating that the treatment is both safe and well-tolerated.
The investigators concluded that the findings, which informed WHO guidelines and access to bedaquiline, are crucial in further optimising drug-resistant TB in children– providing new, key data and access in children, an under-served population.
Researcher Prof Simon Schaaf said: “The P1108 trial has paved the way for access, finally, to effective, shorter and safer treatment for children with drug-resistant TB. For too long children with TB have been left behind.”
A TBNet-led study has attempted to describe treatments for people with XDR-TB under the WHO’s definition of the condition, updated in 2021, which considers XDR-TB to include resistance to any fluoroquinolone and at least one Group A drug (bedaquiline or linezolid).
Study participants were prescribed, on average, six anti-TB drugs. Results indicate that each additional effective drug significantly reduces the odds of unsuccessful outcomes.
The researchers behind the study explained that this highlights the need for optimised drug susceptibility testing methods and expanding access to new TB compounds for people with life-threatening TB.
Speaking from Bali, Dr. Cassandra Kelly-Cirino, Executive Director of The International Union Against Tuberculosis and Lung Disease (The Union) said: “Antimicrobial resistance is among the greatest global health threats we face today. For people at-risk of TB, this threat is multiplied”.
“The new research presented at the Union Conference this week represents an invaluable step in managing this challenge and in offering hope to patients of all ages living with extensively drug-resistant TB”.
Speaking from her experience of surviving multidrug-resistant TB, Akshata Acharya advocates for patient rights and encourages other TB survivors to speak out about the challenges of DR-TB.
She said: “TB is more than just a physical disease - it also has a massive emotional toll. We need to keep advocating for better access to treatment for drug-resistant TB – particularly for those who might face barriers to access, such as women, the elderly, and LGBTQIA++ populations.”
Note: Full abstracts below
ENDS
Notes to editors:
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ANNEX – Abstract Summaries
endTB-Q: interim results of a randomised controlled trial testing a shorter treatment strategy for pre-XDR TB
Background: Pre-extensively drug-resistant (pre-XDR, resistant to rifampin and fluoroquinolones) tuberculosis has unsatisfactory outcomes. New and re-purposed drugs have improved treatment options. However, no randomized, internally controlled trials have been conducted which are powered to draw inference on pre-XDR TB.
Design/Methods: endTB-Q is a randomized, internally-controlled Phase 3 trial evaluating efficacy and safety of bedaquiline, delamanid, clofazimine, and linezolid (BDCL) compared to WHO-recommended longer regimens. People with pulmonary pre-XDR TB, without known resistance to BDCL, were randomized (2:1) to the experimental, stratified-medicine strategy (BDCL: 6 months for limited and 9 months for extensive TB disease) and the control. This preliminary analysis uses interim data extracted for a data safety and monitoring board meeting. We report frequency of favorable and unfavorable outcomes at 39 weeks post-randomization and of serious adverse events (SAEs) occurring during treatment or follow-up and reported prior to data extraction. Full results, available in September 2024, will be presented including risk differences and non-inferiority evaluation at 73 weeks post-randomization of the efficacy of experimental strategy versus the control using the -12% non-inferiority margin.
Results: 323 participants were randomized across 6 WHO regions, 218 (67.5%) to the experimental strategy and 105 (32.5%) to the control. All control arm participants received bedaquiline, linezolid, and clofazimine. Favorable outcomes at 39 weeks occurred in 187 (85.8%) experimental strategy participants and 92 (87.6%) in the control arm. 42 (19.3%) and 25 (23.8%) participants experienced at least one SAE in the experimental strategy and control regimen, respectively. Deaths occurred in 9 participants, 7 (3.2%) and 2 (1.9%) in the experimental strategy and control regimen, respectively.
Conclusions: Interim results from endTB-Q, the first-ever controlled trial designed exclusively to inform treatment of pre-XDR TB, provisionally reveal that an experimental strategy containing BDCL offers a promising, shorter, tailored alternative to longer regimens.
Pharmacokinetics and safety of bedaquiline in infants, children, and adolescents with rifampicin-resistant tuberculosis
Background: Bedaquiline forms the backbone of current RR/MDR-TB treatment regimens, yet data on optimal and safe dosing has lagged dramatically in children, precluding access to shorter, safer effective regimens.
Design/Methods: P1108 (FDA IND 31,832) is a dose-finding study evaluating the pharmacokinetics, safety and tolerability of bedaquiline over 24-weeks in children 0 <18 years with RR-TB, over 96-120 weeks’ follow-up. Younger children (Cohort 2: ≥2 to <6 years, Cohort 3: ≥0 to <2 years) were enrolled in parallel after pharmacokinetic and safety targets were met in 12 participants in Cohort 1 (6-<18 years), using model-predicted weight-banded doses, with interim analysis after 6 new participants per cohort completed week-2 intensive pharmacokinetic sampling. The observed median weekly bedaquiline area-under-the-curve at steady state (wAUCss) within each cohort was estimated and compared with the pre-defined adult target range (50-400 µg*h/mL). Nonlinear mixed-effects modelling was used to estimate wAUCss based on week-24 clearance and weekly dose. Safety review was in real-time. Data through May 24, 2024, were analyzed.
Results: Of 55 participants enrolled, data were included on 54, ranging from 1 month-17.2 years at enrolment; 24 (44%) were male, 40 (74%) African and 14 (26%) mixed-race. Eight children (5 in Cohort 1) were living with HIV, 5 received lopinavir/ritonavir. Ten children (Cohort 1) were on 400mg daily bedaquiline for 14 days, then 200mg 3x/week for 22-weeks (400/200 mg), 39 (8 in Cohort 1, 18 in Cohort 2, 13 in Cohort 3) on 200/100mg, and 5 (Cohort 3) on 100/50 mg. Retention was 100% at 24-weeks. Pharmacokinetic and safety data are shown in Table 1
Conclusions: Bedaquiline was safe and well-tolerated in children across all ages at doses evaluated, with exposures (predicted wAUCss) within adult target range. The population pharmacokinetic model developed will be useful to further optimize paediatric bedaquiline dosing strategies and regimens.
Extensively drug-resistant tuberculosis: back to the pre-antibiotic era? A Tbnet/ESGMYC multi-country study
Background: In 2021, the World Health Organization (WHO) redefined extensively drug-resistant tuberculosis (XDR-TB) to include resistance to any fluoroquinolone and at least one Group A drug (bedaquiline or linezolid). Given the lack of multinational data on managing these patients, we aimed to describe XDR-TB treatment outcomes in Europe under the new definition.
Design/Methods: This observational, retrospective cohort study included patients with XDR-TB, diagnosed by phenotypic and/or genotypic drug susceptibility testing from January 2017 to December 2023 in the WHO European Region. Participating centers collected patient-level data for XDR-TB and aggregate data for consecutive rifampicin-/multidrug-resistant TB (RR-/MDR-TB) and pre-extensively drug-resistant tuberculosis (pre-XDR-TB) patients (defined as MDR-TB with additional fluoroquinolone resistance), using a standardized electronic case report form. We applied 2021 WHO treatment outcome definitions and evaluated risk factors for unsuccessful outcomes using logistic regression.
Results:
Overall, we included 179 XDR-TB patients from 15 countries. Of these, 50% were resistant to bedaquiline (n=90/179), 31% to linezolid (n=56/179), and 18% to both drugs (n=33/179). On average, patients were prescribed six anti TB-drugs, with three being effective. Outcomes were not evaluated for 18% (n=32/179). Among the 147 evaluated patients, 35% achieved successful outcomes (95% confidence interval [95% CI] 27%-43%) (n=51/147). Compared to RR-/MDR-TB and pre-XDR-TB, treatment outcomes were significantly worse for XDR-TB patients (figure 1). Adjusted for disease severity, each additional effective drug reduced the odds of unsuccessful outcomes by 30% (adjusted odds ratio [aOR]: 0.70, 95% CI: 0.50-0.96, p = 0.033), whereas treatment in middle-income countries compared with high-income countries increased the odds 15-fold (aOR: 15.9, 95% CI: 4.4-68.5, p < 0.001).
Conclusions: Only 35% of XDR-TB patients achieved successful outcomes, significantly lower than for RR-/MDR-TB and pre-XDR-TB. Each additional effective drug significantly reduces the odds of unsuccessful outcomes, highlighting the need for optimized drug susceptibility testing methods and new TB compounds in compassionate use programs.