Sputum lipoarabinomannan (LAM) as a biomarker to determine sputum mycobacterial load: exploratory and model-based analyses of integrated data from four cohorts

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dc.contributor.authorJones, Aksana
dc.contributor.authorSaini, Jay
dc.contributor.authorKriel, Belinda
dc.contributor.authorVia, Laura E
dc.contributor.authorCai, Yin
dc.contributor.authorAllies, Devon
dc.contributor.authorHanna, Debra
dc.contributor.authorHermann, David
dc.contributor.authorLoxton, Andre G
dc.contributor.authorWalzl, Gerhard
dc.contributor.authorDiacon, Andreas H
dc.contributor.authorRomero, Klaus
dc.contributor.authorHigashiyama, Ryo
dc.contributor.authorLiu, Yongge
dc.contributor.authorBerg, Alexander
dc.date.accessioned2022-04-13T09:44:03Z
dc.date.available2022-04-13T09:44:03Z
dc.date.issued2022-04-02
dc.date.updated2022-04-03T03:11:09Z
dc.description.abstractBackground Despite the high global disease burden of tuberculosis (TB), the disease caused by Mycobacterium tuberculosis (Mtb) infection, novel treatments remain an urgent medical need. Development efforts continue to be hampered by the reliance on culture-based methods, which often take weeks to obtain due to the slow growth rate of Mtb. The availability of a “real-time” measure of treatment efficacy could accelerate TB drug development. Sputum lipoarabinomannan (LAM; an Mtb cell wall glycolipid) has promise as a pharmacodynamic biomarker of mycobacterial sputum load. Methods The present analysis evaluates LAM as a surrogate for Mtb burden in the sputum samples from 4 cohorts of a total of 776 participants. These include those from 2 cohorts of 558 non-TB and TB participants prior to the initiation of treatment (558 sputum samples), 1 cohort of 178 TB patients under a 14-day bactericidal activity trial with various mono- or multi-TB drug therapies, and 1 cohort of 40 TB patients with data from the first 56-day treatment of a standard 4-drug regimen. Results Regression analysis demonstrated that LAM was a predictor of colony-forming unit (CFU)/mL values obtained from the 14-day treatment cohort, with well-estimated model parameters (relative standard error ≤ 22.2%). Moreover, no changes in the relationship between LAM and CFU/mL were observed across the different treatments, suggesting that sputum LAM can be used to reasonably estimate the CFU/mL in the presence of treatment. The integrated analysis showed that sputum LAM also appears to be as good a predictor of time to Mycobacteria Growth Incubator Tube (MGIT) positivity as CFU/mL. As a binary readout, sputum LAM positivity is a strong predictor of solid media or MGIT culture positivity with an area-under-the-curve value of 0.979 and 0.976, respectively, from receiver-operator curve analysis. Conclusions Our results indicate that sputum LAM performs as a pharmacodynamic biomarker for rapid measurement of Mtb burden in sputum, and thereby may enable more efficient early phase clinical trial designs (e.g., adaptive designs) to compare candidate anti-TB regimens and streamline dose selection for use in pivotal trials. Trial registration NexGen EBA study (NCT02371681)en_US
dc.identifier.apacitationJones, A., Saini, J., Kriel, B., Via, L. E., Cai, Y., Allies, D., ... Berg, A. (2022). Sputum lipoarabinomannan (LAM) as a biomarker to determine sputum mycobacterial load: exploratory and model-based analyses of integrated data from four cohorts. <i>BMC Infectious Diseases</i>, 22(1), 327. http://hdl.handle.net/11427/36368en_ZA
dc.identifier.chicagocitationJones, Aksana, Jay Saini, Belinda Kriel, Laura E Via, Yin Cai, Devon Allies, Debra Hanna, et al "Sputum lipoarabinomannan (LAM) as a biomarker to determine sputum mycobacterial load: exploratory and model-based analyses of integrated data from four cohorts." <i>BMC Infectious Diseases</i> 22, 1. (2022): 327. http://hdl.handle.net/11427/36368en_ZA
dc.identifier.citationJones, A., Saini, J., Kriel, B., Via, L.E., Cai, Y., Allies, D., Hanna, D. & Hermann, D. et al. 2022. Sputum lipoarabinomannan (LAM) as a biomarker to determine sputum mycobacterial load: exploratory and model-based analyses of integrated data from four cohorts. <i>BMC Infectious Diseases.</i> 22(1):327. http://hdl.handle.net/11427/36368en_ZA
dc.identifier.ris TY - Journal Article AU - Jones, Aksana AU - Saini, Jay AU - Kriel, Belinda AU - Via, Laura E AU - Cai, Yin AU - Allies, Devon AU - Hanna, Debra AU - Hermann, David AU - Loxton, Andre G AU - Walzl, Gerhard AU - Diacon, Andreas H AU - Romero, Klaus AU - Higashiyama, Ryo AU - Liu, Yongge AU - Berg, Alexander AB - Background Despite the high global disease burden of tuberculosis (TB), the disease caused by Mycobacterium tuberculosis (Mtb) infection, novel treatments remain an urgent medical need. Development efforts continue to be hampered by the reliance on culture-based methods, which often take weeks to obtain due to the slow growth rate of Mtb. The availability of a “real-time” measure of treatment efficacy could accelerate TB drug development. Sputum lipoarabinomannan (LAM; an Mtb cell wall glycolipid) has promise as a pharmacodynamic biomarker of mycobacterial sputum load. Methods The present analysis evaluates LAM as a surrogate for Mtb burden in the sputum samples from 4 cohorts of a total of 776 participants. These include those from 2 cohorts of 558 non-TB and TB participants prior to the initiation of treatment (558 sputum samples), 1 cohort of 178 TB patients under a 14-day bactericidal activity trial with various mono- or multi-TB drug therapies, and 1 cohort of 40 TB patients with data from the first 56-day treatment of a standard 4-drug regimen. Results Regression analysis demonstrated that LAM was a predictor of colony-forming unit (CFU)/mL values obtained from the 14-day treatment cohort, with well-estimated model parameters (relative standard error ≤ 22.2%). Moreover, no changes in the relationship between LAM and CFU/mL were observed across the different treatments, suggesting that sputum LAM can be used to reasonably estimate the CFU/mL in the presence of treatment. The integrated analysis showed that sputum LAM also appears to be as good a predictor of time to Mycobacteria Growth Incubator Tube (MGIT) positivity as CFU/mL. As a binary readout, sputum LAM positivity is a strong predictor of solid media or MGIT culture positivity with an area-under-the-curve value of 0.979 and 0.976, respectively, from receiver-operator curve analysis. Conclusions Our results indicate that sputum LAM performs as a pharmacodynamic biomarker for rapid measurement of Mtb burden in sputum, and thereby may enable more efficient early phase clinical trial designs (e.g., adaptive designs) to compare candidate anti-TB regimens and streamline dose selection for use in pivotal trials. Trial registration NexGen EBA study (NCT02371681) DA - 2022-04-02 DB - OpenUCT DP - University of Cape Town IS - 1 J1 - BMC Infectious Diseases KW - Tuberculosis KW - Lipoarabinomannan KW - LAM KW - Biomarker KW - Mycobacterium LK - https://open.uct.ac.za PY - 2022 T1 - Sputum lipoarabinomannan (LAM) as a biomarker to determine sputum mycobacterial load: exploratory and model-based analyses of integrated data from four cohorts TI - Sputum lipoarabinomannan (LAM) as a biomarker to determine sputum mycobacterial load: exploratory and model-based analyses of integrated data from four cohorts UR - http://hdl.handle.net/11427/36368 ER - en_ZA
dc.identifier.urihttps://doi.org/10.1186/s12879-022-07308-3
dc.identifier.urihttp://hdl.handle.net/11427/36368
dc.identifier.vancouvercitationJones A, Saini J, Kriel B, Via LE, Cai Y, Allies D, et al. Sputum lipoarabinomannan (LAM) as a biomarker to determine sputum mycobacterial load: exploratory and model-based analyses of integrated data from four cohorts. BMC Infectious Diseases. 2022;22(1):327. http://hdl.handle.net/11427/36368.en_ZA
dc.language.isoenen_US
dc.language.rfc3066en
dc.publisher.departmentInstitute of Infectious Disease and Molecular Medicineen_US
dc.publisher.facultyFaculty of Health Sciencesen_US
dc.rights.holderThe Author(s)
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.sourceBMC Infectious Diseasesen_US
dc.source.journalissue1en_US
dc.source.journalvolume22en_US
dc.source.pagination327en_US
dc.source.urihttps://bmcinfectdis.biomedcentral.com/
dc.subjectTuberculosisen_US
dc.subjectLipoarabinomannanen_US
dc.subjectLAMen_US
dc.subjectBiomarkeren_US
dc.subjectMycobacteriumen_US
dc.titleSputum lipoarabinomannan (LAM) as a biomarker to determine sputum mycobacterial load: exploratory and model-based analyses of integrated data from four cohortsen_US
dc.typeJournal Articleen_US
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