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

Rodriguez C.A. Lodi S. Horsburgh C.R. Mitnick C.D. Bastard M. Huerga H. Khan U. Rich M. Seung K.J. Atwood S. Manzur-Ul-Alam M. Melikyan N. Mpinda S. Myint Z. Naidoo Y. Petrosyan O. Salahuddin N. Sarfaraz S. Vilbrun S.C. Yae K. Achar J. Ahmed S. Algozhina E. Beauchamp J. de Guadelupe Perea Moreno S. Gulanbaeva M. Gergedava M. Sari C.Y.I. Hewison C. Khan P. Franke M.F.
April 2023 Public Library of Science

PLOS Global Public Health
2023 #3 Issue 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 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/RRTB 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.

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Department of Epidemiology, Boston University, School of Public Health, Boston, MA, United States
Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, United States
Department of Biostatistics, Boston University, School of Public Health, Boston, MA, United States
Department of Global Health, Boston University, School of Public Health, Boston, MA, United States
Department of Medicine, Boston University, School of Medicine, Boston, MA, United States
Partners In Health, Boston, MA, United States
Division of Global Health Equity, Brigham and Womens Hospital, Boston, MA, United States
Epicentre, Paris, France
Interactive Research and Development Global, Singapore, Singapore
Interactive Research and Development, Dhaka, Bangladesh
Partners In Health, Maseru, Lesotho
National Tuberculosis Program, Ministry of Health, Yangon, Myanmar
Interactive Research and Development, Johannesburg, South Africa
Médecins Sans Frontières, Yerevan, Armenia
Indus Hospital & Health Network (IHHN), Karachi, Pakistan
GHESKIO, Port-au-Prince, Haiti
Partners In Health, Addis Ababa, Ethiopia
Médecins Sans Frontières, United Kingdom
Interactive Research and Development, Karachi, Pakistan
Partners In Health, Almaty, Kazakhstan
Zanmi Lasante, Cange, Haiti
Socios En Salud Sucursal, Lima, Peru
Médecins Sans Frontières, Osh, Kyrgyzstan
Médecins Sans Frontières, Tbilisi, Georgia
Rumah Sakit Islam Jakarta Cempaka Putih, Jakarta, Indonesia
Médecins Sans Frontières, Paris, France

Department of Epidemiology
Department of Global Health and Social Medicine
Department of Biostatistics
Department of Global Health
Department of Medicine
Partners In Health
Division of Global Health Equity
Epicentre
Interactive Research and Development Global
Interactive Research and Development
Partners In Health
National Tuberculosis Program
Interactive Research and Development
Médecins Sans Frontières
Indus Hospital & Health Network (IHHN)
GHESKIO
Partners In Health
Médecins Sans Frontières
Interactive Research and Development
Partners In Health
Zanmi Lasante
Socios En Salud Sucursal
Médecins Sans Frontières
Médecins Sans Frontières
Rumah Sakit Islam Jakarta Cempaka Putih
Médecins Sans Frontières

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