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Comparative effectiveness of adding delamanid to a multidrug-resistant tuberculosis regimen comprised of three drugs likely to be effective.

ABSTRACT: Clarity about the role of delamanid in longer regimens for multidrug-resistant TB is needed after discordant Phase IIb and Phase III randomized controlled trial results. The Phase IIb trial found that the addition of delamanid to a background regimen hastened culture conversion; the results of the Phase III trial were equivocal. We evaluated the effect of adding delamanid for 24 weeks to three-drug MDR/RR-TB regimens on two- and six-month culture conversion in the endTB observational study. We used pooled logistic regression to estimate the observational analogue of the intention-to-treat effect (aITT) adjusting for baseline confounders and to estimate the observational analogue of the per-protocol effect (aPP) using inverse probability of censoring weighting to control for time-varying confounding. At treatment initiation, 362 patients received three likely effective drugs (delamanid-free) or three likely effective drugs plus delamanid (delamanid-containing). Over 80% of patients received two to three Group A drugs (bedaquiline, linezolid, moxifloxacin/levofloxacin) in their regimen. We found no evidence the addition of delamanid to a three-drug regimen increased two-month (aITT relative risk: 0.90 (95% CI: 0.73-1.11), aPP relative risk: 0.89 (95% CI: 0.66-1.21)) or six-month culture conversion (aITT relative risk: 0.94 (95% CI: 0.84, 1.02), aPP relative risk: 0.93 (95% CI: 0.83, 1.04)). In regimens containing combinations of three likely effective, highly active anti-TB drugs the addition of delamanid had no discernible effect on culture conversion at two or six months. As the standard of care for MDR/RR-TB treatment becomes more potent, it may become increasingly difficult to detect the benefit of adding a single agent to standard of care MDR/RR-TB regimens. Novel approaches like those implemented may help account for background regimens and establish effectiveness of new chemical entities.

SUBMITTER: Rodriguez CA

PROVIDER: S-EPMC10146539 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Comparative effectiveness of adding delamanid to a multidrug-resistant tuberculosis regimen comprised of three drugs likely to be effective.

Rodriguez Carly A CA Lodi Sara S Horsburgh C Robert CR Mitnick Carole D CD Bastard Mathieu M Huerga Helena H Khan Uzma U Rich Michael M Seung Kwonjune J KJ Atwood Sidney S Manzur-Ul-Alam Md M Melikyan Nara N Mpinda Stephanie S Myint Zaw Z Naidoo Yugandran Y Petrosyan Ofelya O Salahuddin Naseem N Sarfaraz Samreen S Vilbrun Stalz Charles SC Yae Kalkidan K Achar Jay J Ahmed Saman S Algozhina Elena E Beauchamp Jude J de Guadelupe Perea Moreno Sara S Gulanbaeva Munara M Gergedava Marika M Indah Sari Cut Yulia CY Hewison Catherine C Khan Palwasha P Franke Molly F MF

PLOS global public health 20230428 4

Clarity about the role of delamanid in longer regimens for multidrug-resistant TB is needed after discordant Phase IIb and Phase III randomized controlled trial results. The Phase IIb trial found that the addition of delamanid to a background regimen hastened culture conversion; the results of the Phase III trial were equivocal. We evaluated the effect of adding delamanid for 24 weeks to three-drug MDR/RR-TB regimens on two- and six-month culture conversion in the endTB observational study. We u ...[more]

PMID: 37115740

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Project description:BackgroundTreatment of multidrug-resistant tuberculosis (MDR-TB) is complex, lengthy, and involves a minimum of four drugs termed a background regimen (BR), that have not previously been prescribed or that have proven susceptible to patient sputum culture isolates. In recent years, promising new treatment options have emerged as add-on therapies to a BR. The aim of this study was to evaluate the long-term costs and effectiveness of adding the novel or group 5 interventions bedaquiline, delamanid, and linezolid to a background regimen (BR) of drugs for the treatment of adult patients with pulmonary multidrug-resistant tuberculosis (MDR-TB), within their marketing authorisations, from a German healthcare cost-effectiveness perspective.MethodsA cohort-based Markov model was developed to simulate the incremental cost-effectiveness ratio of bedaquiline plus BR, delamanid plus BR, or linezolid plus BR versus BR alone in the treatment of MDR-TB, over a 10-year time horizon. Effectiveness of treatment was evaluated in Quality-Adjusted Life-Years (QALYs) and Life-Years Gained (LYG), using inputs from clinical trials for bedaquiline and delamanid and from a German observational study for linezolid. Cost data were obtained from German Drug Directory costs (€/2015), published literature, and expert opinion. A 3% yearly discount rate was applied. Probabilistic and deterministic sensitivity analyses were conducted.ResultsThe total discounted costs per-patient were €85,575 for bedaquiline plus BR, €81,079 for delamanid plus BR, and €80,460 for linezolid plus BR, compared with a cost of €60,962 for BR alone. The total discounted QALYs per-patient were 5.95 for bedaquiline plus BR, 5.36 for delamanid plus BR, and 3.91 for linezolid plus BR, compared with 3.68 for BR alone. All interventions were therefore associated with higher QALYs and higher costs than BR alone, with incremental costs per QALY gained of €22,238 for bedaquiline, €38,703 for delamanid, and €87,484 for linezolid, versus BR alone. In a fully incremental analysis, bedaquiline plus BR was the most cost-effective treatment option at thresholds greater than €22,000 per QALY gained. In probabilistic analyses, the probability that bedaquiline plus BR was the most cost-effective treatment strategy at a willingness-to-pay threshold of €30,000 was 54.5%, compared with 22.9% for BR alone, 18.2% for delamanid plus BR, and 4.4% for linezolid.ConclusionsIn Germany, the addition of bedaquiline, delamanid, or linezolid to a BR would result in QALY gains over BR alone. Based on this analysis, bedaquiline is likely to be the most cost-effective intervention for the treatment of MDR-TB, when added to a BR regimen at thresholds greater than €22,000 per QALY.

Dataset Information

Comparative effectiveness of adding delamanid to a multidrug-resistant tuberculosis regimen comprised of three drugs likely to be effective.

Publications

Comparative effectiveness of adding delamanid to a multidrug-resistant tuberculosis regimen comprised of three drugs likely to be effective.

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